Hundreds of clinical trials are underway studying the technologys potential use in a wide range of genetic disorders, cancer and HIV/AIDS. There is some debate over whether or not the US already has approved its first gene therapy treatment.

In August 2017, the Food and Drug Administration (FDA) approved a cancer therapya CAR-T treatment marketed as Kymriahthat uses a patients own T cells and is a variation of the gene therapy that is being developed to treat single-gene diseases. The T cells are extracted and genetically altered so that they have a new gene that codes for a protein, known as a chimeric antigen receptor (CAR), that is a hybrid of two immune system proteins. One part guides the cells to the cancer cell targets and the other alerts the immune system. The cells, programmed to target and kill leukemia cells, are then injected back into the patient. Another CAR-T treatment, marketed as Yescarta, was approved for adults with aggressive forms of non-Hodgkins lymphoma in October 2017.

Some in the scientific community have pushed back against the idea of calling Kymriah or Yescarta true gene therapies, since they dont actually repair or replace a deficient gene. Instead, they say the most likely candidate to gain the first US approval is Luxturna, a one-time treatment that targets a rare, inherited form of blindness. A key committee of independent experts voted unanimously in October 2017 to recommend approval by the FDA for the treatment developed by Spark Therapeutics. The FDA is not bound by the panels decision, though the agency traditionally acts on its recommendations.

Hundreds of research studies (clinical trials) are underway to test gene therapies as treatments for genetic conditions, cancer and HIV/AIDS. ClinicalTrials.gov, a service of the National Institutes of Health, provides easy access to information about clinical trials. There is also a list of gene therapy clinical trials that are accepting (or will accept) participants. Among the studies and research:

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Gene Therapy Archives | Genetic Literacy Project

The time is right for gene therapy.

Over the last decade, adeno-associated virus (AAV) has emerged as a highly promising and attractive approach to gene therapy. AAV is a common, naturally occurring virus that has been shown to be a well-toleratedand effective gene therapy delivery vehicle in clinical trials. Advances in AAV vector design and related dosing techniques that enable widespread gene delivery in the brain and spinal cord have made AAV particularly well-suited for the treatment of neurological diseases. Since the targeted cells in the central nervous system (CNS) are long-lived, non-dividing neurons, treatments delivered in a single dose could generate long-lasting, or even lifelong, benefits. More than eight years of durable expression has been seen in the human brain following treatment with an AAV vector.

Importantly, improvements in related technology and approaches have made AAV production more easily scalable and efficient to meet clinical and commercial requirements. Voyager diligently selects and optimizes AAV vectors that are best suited for each program. We continue to invest to advance the science and technology around the three key elements of AAV vectors: capsid, promoter and transgene. We also systematically develop and optimize delivery techniques that are best suited for a particular disease.

Members of our team have co-discovered many of the known naturally occurring AAV capsids, which are the outer viral protein shells that enclose the target gene or micro RNA cassette, and have also created promising genetically engineered AAV capsids. We have efforts underway to genetically engineer capsids to yield vectors with desirable properties, such as enhanced tissue specificity and improved delivery of genes to the brain and spinal cord.Efforts are also underway at Voyager to optimize novel AAV capsids that demonstrate enhanced blood-brain barrier penetration for the potential treatment of CNS diseases following systemic administration of the AAV gene therapy vector.

We then design the vector genome, or payload, that we intend to deliver as a therapeutic, as in the case of our Friedreichs ataxia program, or silence or knockdown, as in the case of our ALS and Huntingtons disease programs.

Identifying the optimal route of administration and delivery parameters, such as infusion volume, flow rate, vector concentration and dose and formulation for a specific disease are critical to achieving safe and effective levels of gene expression in the targeted region of the CNS. For Voyagers current pipeline programs, we are pursuing a surgical approach for direct injection into a targeted region of the brain, coupled with real-time MRI in the case of our advanced Parkinsons disease and Huntingtons disease programs, or injection into the cerebrospinal fluid for broader delivery to the cells within and surrounding the spinal cord for our ALS and Friedreichs ataxia programs.

Led by pioneers in AAV gene therapy and neuroscience, we are deeply committed to developing gene therapies for severe neurological diseases that have the potential to positively impact the lives of people living with these diseases. For more information about how we engage with patients and the advocacy community, please visit our patients and caregivers page.

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Gene Therapy | Voyager Therapeutics

All types of cancer cells appear to have at least one essential thing in common: They have faulty genes. At the center of every cell in our bodies, there is a nucleus containing thousands of genes made of DNA. Genes are coded instructions for making proteins, the molecules that control how cells work.

A cell with healthy DNA will perform its function in the body, create new cells as needed and destroy itself when it is damaged beyond repair. However, when a carcinogen such as asbestos damages the DNA in a cell, it may cause the cell to grow and divide out of control, leading to cancer.

Many researchers believe that just as faulty genes are the key to cancer formation, modified genes may be the key to cancer treatment. Mesothelioma researchers are hopeful that gene therapy will bring us closer to a cure for mesothelioma.

Gene therapy is a broad category that refers to several emerging treatment approaches involving the novel science of genetic modification. It wasnt until recently in 2017 that the U.S. Food and Drug Administration (FDA) approved a gene-therapy-based cancer treatment for the first time.

So far, most gene therapies tested for mesothelioma have shown either limited effectiveness or severe side effects and risks of complications. For this reason, all types of gene therapy for mesothelioma are experimental and only available through clinical trials.

The most obvious gene therapy approach is to fix the genetic fault that causes cells to become cancerous in the first place. To perform this medical feat, however, scientists have to overcome two major challenges.

First, researchers have not been able to pinpoint a specific gene that can stop the progression of mesothelioma in most patients. The likeliest candidates are natural tumor-suppressing genes that prevent genetic mutations or ensure mutant cells self-destruct before they grow into tumors. The p53 gene, the BAP1 gene and microRNA gene 16 have all been studied as genes that may be able to stop the progression of mesothelioma.

Second, inserting these tumor-suppressing genes requires a microscopic delivery vehicle, or vector, that can penetrate deep into a tumor. Genetically modified viruses and specially designed nanoparticles are both in development as gene therapy vectors.

Get help connecting with the nation's top mesothelioma doctors and cancer centers.

The same vectors that could carry tumor-suppressing genes could also insert artificial suicide genes into cancer cells.

If researchers can develop a vector that infects all the cells in a tumor while leaving the rest of the bodys cells alone, it would enable a special form of targeted chemotherapy called suicide gene therapy. The artificial suicide gene causes cancer cells to produce an enzyme that converts an otherwise harmless drug into a lethal toxin, so the drug kills cancer cells while leaving healthy cells unharmed.

Rather than trying to alter cellular DNA, some researchers instead focus on modifying deadly viruses to only kill cancer cells. This approach, known as virotherapy, was discovered by accident when doctors noticed many cancer patients who contract measles experience tumor regressions. Since then, scientists have been developing modified versions of the measles virus as an experimental treatment for several types of cancer, including mesothelioma.

In a 2016 trial of virotherapy for pleural mesothelioma patients, researchers were able to safely inject a special strain of the measles vaccine directly into the cancer site, potentially fighting the cancer through viral infection as well as provoking a natural immune system response against the cancer.

The most exciting recent development lies at the intersection of gene therapy and immunotherapy, another cutting-edge cancer treatment science. The first gene therapy for cancer approved by the FDA is known by the brand name Kymriah and generically referred to as CAR T-cell therapy. Kymriahs makers call it a living drug, because it is produced by extracting the patients own immune cells and reprogramming them to target cancer.

CAR T-cell therapy represents one of the first truly individualized and targeted cancer treatments, but it also has significant limitations: Kymriah is FDA-approved only for leukemia, it is extremely expensive, and it comes with the risk of severe side effects. Nevertheless, this technology has the potential to improve outcomes for mesothelioma patients in the future.

Last Modified September 25, 2018

Registered Nurse and Patient Advocate

Karen Selby joined Asbestos.com in 2009. She is a registered nurse with a background in oncology and thoracic surgery and was the director of a tissue bank before becoming a Patient Advocate at The Mesothelioma Center. Karen has assisted surgeons with thoracic surgeries such as lung resections, lung transplants, pneumonectomies, pleurectomies and wedge resections. She is also a member of the Academy of Oncology Nurse & Patient Navigators.

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Gene-Therapy - Experimental Mesothelioma Treatment

Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by several methods, summarized below. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods).

All viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. This genetic material contains basic 'instructions' of how to produce more copies of these viruses, hacking the body's normal production machinery to serve the needs of the virus. The host cell will carry out these instructions and produce additional copies of the virus, leading to more and more cells becoming infected. Some types of viruses insert their genome into the host's cytoplasm, but do not actually enter the cell. Others penetrate the cell membrane disguised as protein molecules and enter the cell.

There are two main types of virus infection: lytic and lysogenic. Shortly after inserting its DNA, viruses of the lytic cycle quickly produce more viruses, burst from the cell and infect more cells. Lysogenic viruses integrate their DNA into the DNA of the host cell and may live in the body for many years before responding to a trigger. The virus reproduces as the cell does and does not inflict bodily harm until it is triggered. The trigger releases the DNA from that of the host and employs it to create new viruses.[citation needed]

The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes, namely reverse transcriptase and integrase, into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be integrated into the genetic material of the host cell. The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase.[citation needed]

Now that the genetic material of the virus has been inserted, it can be said that the host cell has been modified to contain new genes. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately.[citation needed]

One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus into any arbitrary position in the genome of the host; it randomly inserts the genetic material into a chromosome. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases[1] or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites.

Gene therapy trials using retroviral vectors to treat X-linked severe combined immunodeficiency (X-SCID) represent the most successful application of gene therapy to date. More than twenty patients have been treated in France and Britain, with a high rate of immune system reconstitution observed. Similar trials were restricted or halted in the USA when leukemia was reported in patients treated in the French X-SCID gene therapy trial.[citation needed] To date, four children in the French trial and one in the British trial have developed leukemia as a result of insertional mutagenesis by the retroviral vector. All but one of these children responded well to conventional anti-leukemia treatment. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme (one form of SCID)[2] continue with relative success in the USA, Britain, Ireland, Italy and Japan.[citation needed]

Adenoviruses are viruses that carry their genetic material in the form of double-stranded DNA. They cause respiratory, intestinal, and eye infections in humans (especially the common cold). When these viruses infect a host cell, they introduce their DNA molecule into the host. The genetic material of the adenoviruses is not incorporated (transient) into the host cell's genetic material. The DNA molecule is left free in the nucleus of the host cell, and the instructions in this extra DNA molecule are transcribed just like any other gene. The only difference is that these extra genes are not replicated when the cell is about to undergo cell division so the descendants of that cell will not have the extra gene.[citation needed]

As a result, treatment with the adenovirus will require readministration in a growing cell population although the absence of integration into the host cell's genome should prevent the type of cancer seen in the SCID trials. This vector system has been promoted for treating cancer and indeed the first gene therapy product to be licensed to treat cancer, Gendicine, is an adenovirus. Gendicine, an adenoviral p53-based gene therapy was approved by the Chinese food and drug regulators in 2003 for treatment of head and neck cancer. Advexin, a similar gene therapy approach from Introgen, was turned down by the US Food and Drug Administration (FDA) in 2008.[citation needed]

Concerns about the safety of adenovirus vectors were raised after the 1999 death of Jesse Gelsinger while participating in a gene therapy trial. Since then, work using adenovirus vectors has focused on genetically crippled versions of the virus.[citation needed]

The viral vectors described above have natural host cell populations that they infect most efficiently. Retroviruses have limited natural host cell ranges, and although adenovirus and adeno-associated virus are able to infect a relatively broader range of cells efficiently, some cell types are refractory to infection by these viruses as well. Attachment to and entry into a susceptible cell is mediated by the protein envelope on the surface of a virus. Retroviruses and adeno-associated viruses have a single protein coating their membrane, while adenoviruses are coated with both an envelope protein and fibers that extend away from the surface of the virus. The envelope proteins on each of these viruses bind to cell-surface molecules such as heparin sulfate, which localizes them upon the surface of the potential host, as well as with the specific protein receptor that either induces entry-promoting structural changes in the viral protein, or localizes the virus in endosomes wherein acidification of the lumen induces this refolding of the viral coat. In either case, entry into potential host cells requires a favorable interaction between a protein on the surface of the virus and a protein on the surface of the cell.[citation needed]

For the purposes of gene therapy, one might either want to limit or expand the range of cells susceptible to transduction by a gene therapy vector. To this end, many vectors have been developed in which the endogenous viral envelope proteins have been replaced by either envelope proteins from other viruses, or by chimeric proteins. Such chimera would consist of those parts of the viral protein necessary for incorporation into the virion as well as sequences meant to interact with specific host cell proteins. Viruses in which the envelope proteins have been replaced as described are referred to as pseudotyped viruses. For example, the most popular retroviral vector for use in gene therapy trials has been the lentivirus Simian immunodeficiency virus coated with the envelope proteins, G-protein, from Vesicular stomatitis virus. This vector is referred to as VSV G-pseudotyped lentivirus, and infects an almost universal set of cells. This tropism is characteristic of the VSV G-protein with which this vector is coated. Many attempts have been made to limit the tropism of viral vectors to one or a few host cell populations. This advance would allow for the systemic administration of a relatively small amount of vector. The potential for off-target cell modification would be limited, and many concerns from the medical community would be alleviated. Most attempts to limit tropism have used chimeric envelope proteins bearing antibody fragments. These vectors show great promise for the development of "magic bullet" gene therapies.[citation needed]

A replication-competent vector called ONYX-015 is used in replicating tumor cells. It was found that in the absence of the E1B-55Kd viral protein, adenovirus caused very rapid apoptosis of infected, p53(+) cells, and this results in dramatically reduced virus progeny and no subsequent spread. Apoptosis was mainly the result of the ability of EIA to inactivate p300. In p53(-) cells, deletion of E1B 55kd has no consequence in terms of apoptosis, and viral replication is similar to that of wild-type virus, resulting in massive killing of cells.[citation needed]

A replication-defective vector deletes some essential genes. These deleted genes are still necessary in the body so they are replaced with either a helper virus or a DNA molecule.[3]

Replication-defective vectors always contain a transfer construct. The transfer construct carries the gene to be transduced or transgene. The transfer construct also carries the sequences which are necessary for the general functioning of the viral genome: packaging sequence, repeats for replication and, when needed, priming of reverse transcription. These are denominated cis-acting elements, because they need to be on the same piece of DNA as the viral genome and the gene of interest. Trans-acting elements are viral elements, which can be encoded on a different DNA molecule. For example, the viral structural proteins can be expressed from a different genetic element than the viral genome.[3]

The herpes simplex virus is a human neurotropic virus. This is mostly examined for gene transfer in the nervous system. The wild type HSV-1 virus is able to infect neurons and evade the host immune response, but may still become reactivated and produce a lytic cycle of viral replication. Therefore, it is typical to use mutant strains of HSV-1 that are deficient in their ability to replicate. Though the latent virus is not transcriptionally apparent, it does possess neuron specific promoters that can continue to function normally.[further explanation needed] Antibodies to HSV-1 are common in humans, however complications due to herpes infection are somewhat rare.[4] Caution for rare cases of encephalitis must be taken and this provides some rationale to using HSV-2 as a viral vector as it generally has tropism for neuronal cells innervating the urogenital area of the body and could then spare the host of severe pathology in the brain.[citation needed]

Non-viral methods present certain advantages over viral methods, with simple large scale production and low host immunogenicity being just two. Previously, low levels of transfection and expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques with transfection efficiencies similar to those of viruses.[5]

This is the simplest method of non-viral transfection. Clinical trials carried out of intramuscular injection of a naked DNA plasmid have occurred with some success; however, the expression has been very low in comparison to other methods of transfection. In addition to trials with plasmids, there have been trials with naked PCR product, which have had similar or greater success. Cellular uptake of naked DNA is generally inefficient. Research efforts focusing on improving the efficiency of naked DNA uptake have yielded several novel methods, such as electroporation, sonoporation, and the use of a "gene gun", which shoots DNA coated gold particles into the cell using high pressure gas.[6]

Electroporation is a method that uses short pulses of high voltage to carry DNA across the cell membrane. This shock is thought to cause temporary formation of pores in the cell membrane, allowing DNA molecules to pass through. Electroporation is generally efficient and works across a broad range of cell types. However, a high rate of cell death following electroporation has limited its use, including clinical applications.

More recently a newer method of electroporation, termed electron-avalanche transfection, has been used in gene therapy experiments. By using a high-voltage plasma discharge, DNA was efficiently delivered following very short (microsecond) pulses. Compared to electroporation, the technique resulted in greatly increased efficiency and less cellular damage.

The use of particle bombardment, or the gene gun, is another physical method of DNA transfection. In this technique, DNA is coated onto gold particles and loaded into a device which generates a force to achieve penetration of the DNA into the cells, leaving the gold behind on a "stopping" disk.

Sonoporation uses ultrasonic frequencies to deliver DNA into cells. The process of acoustic cavitation is thought to disrupt the cell membrane and allow DNA to move into cells.

In a method termed magnetofection, DNA is complexed to magnetic particles, and a magnet is placed underneath the tissue culture dish to bring DNA complexes into contact with a cell monolayer.

Hydrodynamic delivery involves rapid injection of a high volume of a solution into vasculature (such as into the inferior vena cava, bile duct, or tail vein). The solution contains molecules that are to be inserted into cells, such as DNA plasmids or siRNA, and transfer of these molecules into cells is assisted by the elevated hydrostatic pressure caused by the high volume of injected solution.[7][8][9]

The use of synthetic oligonucleotides in gene therapy is to deactivate the genes involved in the disease process. There are several methods by which this is achieved. One strategy uses antisense specific to the target gene to disrupt the transcription of the faulty gene. Another uses small molecules of RNA called siRNA to signal the cell to cleave specific unique sequences in the mRNA transcript of the faulty gene, disrupting translation of the faulty mRNA, and therefore expression of the gene. A further strategy uses double stranded oligodeoxynucleotides as a decoy for the transcription factors that are required to activate the transcription of the target gene. The transcription factors bind to the decoys instead of the promoter of the faulty gene, which reduces the transcription of the target gene, lowering expression. Additionally, single stranded DNA oligonucleotides have been used to direct a single base change within a mutant gene. The oligonucleotide is designed to anneal with complementarity to the target gene with the exception of a central base, the target base, which serves as the template base for repair. This technique is referred to as oligonucleotide mediated gene repair, targeted gene repair, or targeted nucleotide alteration.

To improve the delivery of the new DNA into the cell, the DNA must be protected from damage and positively charged. Initially, anionic and neutral lipids were used for the construction of lipoplexes for synthetic vectors. However, in spite of the facts that there is little toxicity associated with them, that they are compatible with body fluids and that there was a possibility of adapting them to be tissue specific; they are complicated and time consuming to produce so attention was turned to the cationic versions.

Cationic lipids, due to their positive charge, were first used to condense negatively charged DNA molecules so as to facilitate the encapsulation of DNA into liposomes. Later it was found that the use of cationic lipids significantly enhanced the stability of lipoplexes. Also as a result of their charge, cationic liposomes interact with the cell membrane, endocytosis was widely believed as the major route by which cells uptake lipoplexes. Endosomes are formed as the results of endocytosis, however, if genes can not be released into cytoplasm by breaking the membrane of endosome, they will be sent to lysosomes where all DNA will be destroyed before they could achieve their functions. It was also found that although cationic lipids themselves could condense and encapsulate DNA into liposomes, the transfection efficiency is very low due to the lack of ability in terms of endosomal escaping. However, when helper lipids (usually electroneutral lipids, such as DOPE) were added to form lipoplexes, much higher transfection efficiency was observed. Later on, it was figured out that certain lipids have the ability to destabilize endosomal membranes so as to facilitate the escape of DNA from endosome, therefore those lipids are called fusogenic lipids. Although cationic liposomes have been widely used as an alternative for gene delivery vectors, a dose dependent toxicity of cationic lipids were also observed which could limit their therapeutic usages.

The most common use of lipoplexes has been in gene transfer into cancer cells, where the supplied genes have activated tumor suppressor control genes in the cell and decrease the activity of oncogenes. Recent studies have shown lipoplexes to be useful in transfecting respiratory epithelial cells.

Polymersomes are synthetic versions of liposomes (vesicles with a lipid bilayer), made of amphiphilic block copolymers. They can encapsulate either hydrophilic or hydrophobic contents and can be used to deliver cargo such as DNA, proteins, or drugs to cells. Advantages of polymersomes over liposomes include greater stability, mechanical strength, blood circulation time, and storage capacity.[10][11][12]

Complexes of polymers with DNA are called polyplexes. Most polyplexes consist of cationic polymers and their fabrication is based on self-assembly by ionic interactions. One important difference between the methods of action of polyplexes and lipoplexes is that polyplexes cannot directly release their DNA load into the cytoplasm. As a result, co-transfection with endosome-lytic agents such as inactivated adenovirus was required to facilitate nanoparticle escape from the endocytic vesicle made during particle uptake. However, a better understanding of the mechanisms by which DNA can escape from endolysosomal pathway, i.e. proton sponge effect,[13] has triggered new polymer synthesis strategies such as incorporation of protonable residues in polymer backbone and has revitalized research on polycation-based systems.[14]

Due to their low toxicity, high loading capacity, and ease of fabrication, polycationic nanocarriers demonstrate great promise compared to their rivals such as viral vectors which show high immunogenicity and potential carcinogenicity, and lipid-based vectors which cause dose dependence toxicity. Polyethyleneimine[15] and chitosan are among the polymeric carriers that have been extensively studies for development of gene delivery therapeutics. Other polycationic carriers such as poly(beta-amino esters)[16] and polyphosphoramidate[17] are being added to the library of potential gene carriers. In addition to the variety of polymers and copolymers, the ease of controlling the size, shape, surface chemistry of these polymeric nano-carriers gives them an edge in targeting capability and taking advantage of enhanced permeability and retention effect.[18]

A dendrimer is a highly branched macromolecule with a spherical shape. The surface of the particle may be functionalized in many ways and many of the properties of the resulting construct are determined by its surface.

In particular it is possible to construct a cationic dendrimer, i.e. one with a positive surface charge. When in the presence of genetic material such as DNA or RNA, charge complimentarity leads to a temporary association of the nucleic acid with the cationic dendrimer. On reaching its destination the dendrimer-nucleic acid complex is then taken into the cell via endocytosis.

In recent years the benchmark for transfection agents has been cationic lipids. Limitations of these competing reagents have been reported to include: the lack of ability to transfect some cell types, the lack of robust active targeting capabilities, incompatibility with animal models, and toxicity. Dendrimers offer robust covalent construction and extreme control over molecule structure, and therefore size. Together these give compelling advantages compared to existing approaches.

Producing dendrimers has historically been a slow and expensive process consisting of numerous slow reactions, an obstacle that severely curtailed their commercial development. The Michigan-based company Dendritic Nanotechnologies discovered a method to produce dendrimers using kinetically driven chemistry, a process that not only reduced cost by a magnitude of three, but also cut reaction time from over a month to several days. These new "Priostar" dendrimers can be specifically constructed to carry a DNA or RNA payload that transfects cells at a high efficiency with little or no toxicity.[citation needed]

Inorganic nanoparticles, such as gold, silica, iron oxide (ex. magnetofection) and calcium phosphates have been shown to be capable of gene delivery.[19] Some of the benefits of inorganic vectors is in their storage stability, low manufacturing cost and often time, low immunogenicity, and resistance to microbial attack. Nanosized materials less than 100nm have been shown to efficiently trap the DNA or RNA and allows its escape from the endosome without degradation. Inorganics have also been shown to exhibit improved in vitro transfection for attached cell lines due to their increased density and preferential location on the base of the culture dish. Quantum dots have also been used successfully and permits the coupling of gene therapy with a stable fluorescence marker. Engineered organic nanoparticles are also under development, which could be used for co-delivery of genes and therapeutic agents.[20]

Cell-penetrating peptides (CPPs), also known as peptide transduction domains (PTDs), are short peptides (< 40 amino acids) that efficiently pass through cell membranes while being covalently or non-covalently bound to various molecules, thus facilitating these molecules entry into cells. Cell entry occurs primarily by endocytosis but other entry mechanisms also exist. Examples of cargo molecules of CPPs include nucleic acids, liposomes, and drugs of low molecular weight.[21][22]

CPP cargo can be directed into specific cell organelles by incorporating localization sequences into CPP sequences. For example, nuclear localization sequences are commonly used to guide CPP cargo into the nucleus.[23] For guidance into mitochondria, a mitochondrial targeting sequence can be used; this method is used in protofection (a technique that allows for foreign mitochondrial DNA to be inserted into cells' mitochondria).[24][25]

Due to every method of gene transfer having shortcomings, there have been some hybrid methods developed that combine two or more techniques. Virosomes are one example; they combine liposomes with an inactivated HIV or influenza virus. This has been shown to have more efficient gene transfer in respiratory epithelial cells than either viral or liposomal methods alone. Other methods involve mixing other viral vectors with cationic lipids or hybridising viruses.[26]

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Vectors in gene therapy - Wikipedia

Scientists have promised that gene therapy will be the next big leap for medicine. It's a term that's tossed about regularly, but what is it exactly? Trace shows us how scientists can change your very genetic code.

Read More:

How does gene therapy work?http://ghr.nlm.nih.gov/handbook/thera..."Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein."

Gene therapy trial 'cures children'http://www.bbc.co.uk/news/health-2326..."A disease which robs children of the ability to walk and talk has been cured by pioneering gene therapy to correct errors in their DNA, say doctors."

Gene therapy cures diabetic dogshttp://www.newscientist.com/article/d..."Five diabetic beagles no longer needed insulin injections after being given two extra genes, with two of them still alive more than four years later."

Gene Therapy for Cancer: Questions and Answershttp://www.cancer.gov/cancertopics/fa..."Gene therapy is an experimental treatment that involves introducing genetic material into a person's cells to fight or prevent disease."

How does gene therapy work?http://www.scientificamerican.com/art..."Gene therapy is the addition of new genes to a patient's cells to replace missing or malfunctioning genes. Researchers typically do this using a virus to carry the genetic cargo into cells, because that's what viruses evolved to do with their own genetic material."

Gene therapy cures leukaemia in eight dayshttp://www.newscientist.com/article/m...eight-days.htmlWITHIN just eight days of starting a novel gene therapy, David Aponte's "incurable" leukaemia had vanished. For four other patients, the same happened within eight weeks, although one later died from a blood clot unrelated to the treatment, and another after relapsing.

Cell Therapy Shows Promise for Acute Type of Leukemiahttp://www.nytimes.com/2013/03/21/hea..."A treatment that genetically alters a patient's own immune cells to fight cancer has, for the first time, produced remissions in adults with an acute leukemia that is usually lethal, researchers are reporting."

Watch More:Tricking the Immune Systemhttp://www.youtube.com/watch?v=Kr_HRl...Babies with 3 Parents?!http://www.youtube.com/watch?v=jQxsW_...Pick Your Poison: Cyanidehttp://www.youtube.com/watch?v=JDBrdE...____________________

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How Does Gene Therapy Work? - YouTube

Definition

Gene therapy is a rapidly growing field of medicine in which genes are introduced into the body to treat diseases. Genomics is the DNA which is found in an organism's total set of genes and is passed on to the offspring as information necessary for survival. Genetics is the study of the patterns of inheritance of specific traits. Genes control heredity and provide the basic biological code for determining a cell's specific functions. Gene therapy seeks to provide genes that correct or supplant the disease-controlling functions of cells that are not performing in a normal manner.

Somatic gene therapy introduces therapeutic genes at the tissue or cellular level to treat a specific individual. Germ-line gene therapy inserts genes into reproductive cells or possibly into embryos to correct genetic abnormalities that could be passed on to future generations. Initially conceived as an approach for treating inherited diseases such as cystic fibrosis and Huntington's disease, the scope of potential gene therapies has grown to include treatments for cancer, arthritis, and infectious diseases.

In the early 1970s, scientists proposed "gene surgery" for treating inherited diseases caused by abnormally functioning genes. The idea was to take out the disease-causing gene and surgically implant a gene that functioned correctly. Although sound in theory, and after some advances in science, this technique has not yet been successful.

However, in 1983, a group of scientists from Baylor College of Medicine in Houston, Texas, proposed that gene therapy could one day be a viable approach for treating Lesch-Nyhan disease, a rare neurological disorder. The scientists conducted experiments in which an enzyme-producing gene (a specific type of protein) for correcting the disease was injected into a group of cells for replication. The scientists theorized the cells could then be injected into people with Lesch-Nyhan disease, thus correcting the genetic abnormality that caused the disease.

As the science of genetics advanced throughout the 1980s, gene therapy grew in the estimation of medical scientists as a promising approach to treatments for specific diseases. One of the major reasons for the growth of gene therapy was the increasing body of knowledge available to assist in identifying the specific genetic malfunctions that caused inherited diseases. Interest grew as further studies of DNA and chromosomes (where genes reside) showed that specific genetic abnormalities in one or more genes occurred in successive generations of certain family members who experienced diseases like intestinal cancer, manic-depression (bipolar disorder), Alzheimer's disease, heart disease, diabetes, and many more. Although genes may not be the only cause of the disease in all cases, they may make certain individuals more susceptible to developing a particular condition due to environmental influences such as smoking, pollution, and stress. In fact, some scientists theorize that all diseases may have a genetic component.

Gene therapy has grown out of the science of genetics or how heredity functions. Scientists know that life begins in a cell, the basic building block of all multicellular organisms. Humans, for instance, are made up of trillions of cells, each performing a specific function. Within each cell's nucleus (the center part of a cell that regulates its chemical functions) are pairs of chromosomes. These threadlike structures are made up of deoxyribonucleic acid (DNA), which carries the blueprint of life in the form of codes, or genes, that determine dominant or recessive inherited characteristics.

A DNA molecule looks like two ladders with one of the sides taken off both and then twisted around each othera formation known as the double helix. The rungs of these ladders meet (resulting in a spiral staircase-like structure) and are called base pairs. Base pairs are made up of nitrogen-containing molecules and arranged in specific sequences. Millions of these base pairs, or sequences, constitute a single gene, specifically defined as a segment of the chromosome and DNA that contains certain hereditary information. The gene, or combination of genes formed by these base pairs, ultimately directs an organism's growth and characteristics through the production of certain chemicalsprimarily proteins that carry out most of the body's chemical functions and biological reactions.

Scientists have long known that alterations in the genes present within cells may cause inherited diseases such as cystic fibrosis, sickle cell disease, and hemophilia. Similarly, errors in entire chromosomes may cause conditions such as Down syndrome or Turner syndrome. As the study of genetics advanced, however, scientists learned that altered genetic sequences may also make people more susceptible to diseases such as atherosclerosis, cancer, and schizophrenia. These diseases have a genetic component, but are also influenced by environmental factors such as diet and lifestyle. The objective of gene therapy is to treat diseases by introducing functional genes into the body to alter the cells involved in the disease process, either by replacing missing genes or by providing copies of functioning genes to replace nonfunctioning ones. The inserted genes may be naturally occurring genes that produce the desired effect or may be engineered (or altered) genes.

Scientists have known how to manipulate a gene's structure in the laboratory since the early 1970s through a process called gene splicing. The process involves removing a fragment of DNA containing a specific desired genetic sequence and then inserting it into the DNA of another gene. The resultant product is called recombinant DNA, and the process is called genetic engineering. This technique is used in preparing some new therapies (monoclonal antibodies, blood component replacements for hemophilia, anti-inflammatory therapy for collagen diseases).

There are two types of gene therapy. Germ-line gene therapy introduces genes into reproductive cells (sperm and eggs) to participate in germination. Some scientists hope that it may eventually be possible to insert genes into embryos in hopes of correcting genetic abnormalities that can then be passed on to future generations. Most of the current work in applied gene therapy, however, has been in the realm of somatic therapy. In this type of gene therapy, therapeutic genes are inserted into tissue or cells to produce a naturally occurring protein or substance that is lacking or not functioning correctly in an individual.

In both types of therapy, scientists need a mechanism to transport either an entire gene or a recombinant DNA to a cell's nucleus, where the chromosomes and DNA reside. In essence, vectors are molecular delivery trucks. One of the first and most widely used vectors to be developed were viruses, because they invade cells as part of their natural infection process. Viruses have the potential to be excellent vectors because they have a specific relationship with a host in that they colonize certain cell types and tissues in specific organs. As a result, vectors are chosen according to their attraction to certain cells and areas of the body.

One of the first classes of vectors used were retroviruses. Because these viruses are easily cloned (artificially reproduced) in the laboratory, scientists have studied them extensively and learned a great deal about their biologic action. They have also learned how to remove the genetic information that governs viral replication, thus reducing the chances of infection from the host vector.

Retroviruses work best in actively dividing cells, but most cells in a human body are relatively stable and do not often divide. As a result, these cells are used primarily for ex vivo (outside the body) manipulation. First, the cells are removed from a person's body, and the vector, or virus carrying the gene, is inserted into them. Next, the cells are placed into a nutrient culture where they grow and replicate. Once enough cells are gathered, they are returned to the body, usually by injection into the blood stream. Theoretically, as long as these cells survive, they will provide the desired therapy.

Another class of viruses, called adenoviruses, may also prove to be good gene vectors. These viruses effectively infect non-dividing cells in the body, where the desired gene product is then expressed naturally. In addition to being a more efficient approach to the problem of gene transportation, these viruses, which are known to cause respiratory infections, are more easily purified and stabilized than are retroviruses. The result is less liklihood of unintended viral infection. However, these viruses live for several days in the body, and there is some concern about the possibility of infecting other people with the viruses through sneezing or coughing. Other viral vectors include influenza viruses, Sindbis virus, and a herpes virus that infects nerve cells.

Scientists have also studied nonviral vectors. These vectors rely on the natural biologic process in which cells take up (or gather) macromolecules. One approach is to use liposomes, globules of fat produced by the body and taken up by cells. Scientists are also investigating the introduction of raw recombinant DNA by injecting it into the bloodstream or placing it on microscopic beads of gold injected into the skin using air pressure. Another possible vector under development is based on dendrimer molecules. A class of polymers (naturally occurring or artificial substances that have a high molecular weight and are formed by smaller molecules of the same or similar substances) is constructed in a laboratory by combining these smaller molecules. They have been used in manufacturing styrofoam, polyethylene cartons, and Plexiglas. In the laboratory, dendrimers have shown the ability to transport genetic material into human cells. They can also be designed to form an affinity for particular cell membranes by attaching to certain sugars and protein groups. Much additional research must be conducted before dendrimers can be used on a routine basis.

On September 14, 1990, a four-year old girl who had a genetic disorder that prevented her body from producing a crucial enzyme became the first person to undergo gene therapy in the United States. Because her body could not produce adenosine deaminase (ADA), she had a weakened immune system, making her extremely susceptible to severe, life-threatening infections. W. French Anderson and colleagues at the National Institutes of Health's Clinical Center in Bethesda, Maryland, took white blood cells (which are crucial to proper immune system functioning) from the girl, inserted ADA-producing genes into them, and then transfused the cells back into the girl. Although the young girl continued to show an increased ability to produce ADA, debate arose as to whether the improvement resulted from the gene therapy or from an additional drug treatment she received.

Although gene therapy testing in humans has advanced rapidly, many questions surround its use. For example, some scientists are concerned that the therapeutic genes themselves may cause disease. Others fear that germ-line gene therapy may be used to control human development in ways not connected with disease, such as intelligence or physical appearance.

Nevertheless, a new era of gene therapy began as more and more scientists sought to conduct clinical trial (testing in humans) research in this area. In that same year, gene therapy was tested on persons with melanoma (skin cancer). The goal was to help them produce antibodies (disease fighting substances in the immune system) to battle the cancer.

The relative success of these experiments prompted a growing number of attempts at gene therapies designed to perform a variety of functions in the body. For example, a gene therapy for cystic fibrosis aims to supply a gene that alters cells, enabling people with cystic fibrosis to produce a specific protein to battle the disease. Another approach was used for people with brain cancer, in which the inserted gene was designed to make the cancer cells more likely to respond to drug treatment. A third gene therapeutic approach for people experiencing artery blockage, which can lead to strokes, induces the growth of new blood vessels (collateral circulation) near clogged arteries, thus ensuring relatively normal blood circulation.

In the United States, both nucleic acid-based (in vivo) treatments and cell-based (ex vivo) treatments are being investigated. Nucleic acid-based gene therapy uses vectors (such as viruses) to deliver modified genes to target cells. Cell-based gene therapy requires removal of cells from a person, genetically altering the cells and then reintroducing them into the body of the person being treated. Presently, gene therapies for the following diseases are being studied: cystic fibrosis (using adenoviral vector), HIV infection (cell-based), malignant melanoma (cell-based), Duchenne muscular dystrophy (cell-based), hemophilia B (cell-based), kidney cancer (cell-based), Gaucher disease (retroviral vector), breast cancer (retroviral vector), and lung cancer (retroviral vector). When a cell or individual is treated using gene therapy and successful incorporation of engineered genes has occurred, the cell or individual is said to be transgenic.

The medical establishment's contribution to transgenic research has been supported by increased government funding. In 1991, the U.S. government provided $58 million for gene therapy research, with increases in funding of $15-40 million dollars a year over the following four years. With fierce competition over the promise of societal benefits in addition to huge profits, large pharmaceutic corporations have moved to the forefront of transgenic research. In an effort to be first in developing new therapies, and armed with billions of dollars of research funds, such corporations are making impressive progress toward making gene therapy a viable reality in the treatment of once elusive diseases.

Although great strides have been made in gene therapy in a relatively short time, its potential usefulness has been limited by lack of scientific data concerning the multitude of functions that genes control in the human body. For instance, it is now known that much genetic material is contained in non-coding regions. That is, they merely store information that may be used at different times in a cell's life cycle. Some of these large portions of the genome are involved in control and regulation of gene expression. Each individual cell in the body carries thousands of genes that have coding for proteins. Some experts estimate this number to be 150,000 genes. For gene therapy to advance to its full potential, scientists must discover the biologic role for each of these individual genes and identify the location on the DNA helix for each of the base pairs that comprise them.

To address this issue, the National Institutes of Health initiated the Human Genome Project in 1990. Led by Dr. James Watson (one of the co-discoverers of the chemical makeup of DNA) the project's 15-year goal is to map the entire human genome (a combination of the words gene and chromosome). A genome map would clearly identify the location of all genes as well as the more than three billion base pairs that comprise them. With a precise knowledge of gene locations and functions, scientists may one day be able to conquer or control diseases that have plagued humanity for centuries.

Scientists participating in the Human Genome Project have identified an average of one new gene a day, but many expect this rate of discovery to increase. In February of 2001, scientists published a rough draft of the complete human genome; the final complete sequence was published in 2003.

Some of the genes identified through this project include a gene that predisposes people to obesity; one associated with programmed cell death (apoptosis); a gene that guides HIV viral reproduction; and the genes of inherited disorders like Huntington's disease, amyotrophic lateral aclerosis (Lou Gehrig's disease), and some colon and breast cancers.

The potential scope of gene therapy is enormous. More than 4,200 diseases have been identified as resulting directly from non-functioning or abnormal genes, and countless others that may be partially influenced by a person's genetic makeup. Initial research has concentrated on developing gene therapies for diseases whose genetic origins have been established and for other diseases that can be cured or ameliorated by substances genes produce.

The following are examples of potential gene therapies. People with cystic fibrosis lack a gene needed to produce a salt-regulating protein. This protein regulates the flow of chloride into epithelial cells (the cells that line the inner and outer skin layers), that cover the air passages of the nose and lungs. Without this regulation, people with cystic fibrosis have a buildup of thick mucus in their lungs. In turn, this mucus makes these patients prone to lung infections and respiratory problems, and usually leads to death within the first 29 years of life. A gene therapy technique to correct this abnormality might employ an adenovirus to transfer a normal copy of what scientists call the cystic fibrosis transmembrane conductance regulator (CTRF) gene. The gene is introduced into a person by spraying it into the nose or lungs.

Familial hypercholesterolemia (FH) is also an inherited disease, resulting in the inability to process cholesterol properly, which leads to high levels of artery-clogging fat in the bloodstream of even the youngest family members. Persons with FH often suffer heart attacks and strokes because of blocked arteries. A gene therapy approach used to address FH is much more intricate than most gene therapies because it involves partial surgical removal of persons' livers (ex vivo transgene therapy). Corrected copies of a gene that acts to reduce cholesterol buildup are inserted into the liver sections, which are then transplanted back into the people.

Gene therapy has also been tested on persons with acquired immune difficiency syndrome (AIDS ). AIDS is caused by the human immunodeficiency virus (HIV), which weakens the body's immune system to the point that people with the condition are unable to fight off diseases such as pneumonia and cancer. In one approach, genes that produce specific HIV proteins have been altered to stimulate immune system functioning without causing the negative effects that a complete HIV molecule has on the immune system. These genes are then injected in a person's blood stream. Another approach to treating AIDS is to insert, via white blood cells, genes that have been genetically engineered to produce a receptor that would attract HIV and reduce its chances of replicating. These approaches are still primarily experimental.

Several cancers also have the potential to be treated with gene therapy. A therapy tested for melanoma, a progressive, agressive skin cancer, would introduce a gene with an anticancer protein called tumor necrosis factor (TNF) into test tube samples of a person's own cancer cells, which are then reintroduced into the person's body. In brain cancer, the approach is to insert a specific gene that increases the cancer cells' susceptibility to a common drug used in fighting the disease.

Gaucher disease is an inherited disease caused by a mutant gene that inhibits the production of an enzyme called glucocerebrosidase. Persons with Gaucher disease have enlarged livers (hepatomegaly) and spleens (splenomegaly). Clinical gene therapy trials will focus on inserting the gene for producing the missing enzyme.

Gene therapy is also being considered as an approach to solving a problem associated with a surgical procedure known as balloon angioplasty. In this procedure, a stent (a piece of tubular material resembling a straw) is used to open the clogged artery. However, in a "fail-safe" response to the trauma of the stent insertion, the body initiates a natural healing process that produces too many cells in the artery and results in restenosis or reclosing of the artery. The gene therapy approach to preventing this unwanted side effect is to cover the outside surfaces of an inserted stent with a soluble gel containing vectors for genes that may reduce an overactive healing response.

Gene therapy seems elegantly simple in its concept: supply the human body with a gene that can correct a biologic malfunction causing a disease. However, there are many obstacles and some distinct questions concerning the viability of gene therapy. For example, viral vectors must be carefully controlled lest they infect a person with a viral disease. Some vectors, like retroviruses, can also enter normally functioning cells and interfere with natural biologic processes, possibly leading to other diseases. Other viral vectors, such as adenoviruses, are often recognized and destroyed by the immune system so their therapeutic effects are short-lived. Maintaining gene expression so that it performs its role properly after vector delivery is difficult. As a result, some therapies need to be repeated often to provide long-lasting benefits.

One of the most pressing issues, however, is gene regulation. Genes work in concert to regulate their functioning. In other words, several genes may play a part in turning other genes on and off. For example, certain genes work together to stimulate cell division and growth; but if these are not regulated, the inserted genes could cause tumor formation and cancer. Another difficulty is learning how to make the gene go into action only when needed. For the best and safest therapeutic effort, a specific gene should turn on, for example, when certain levels of a protein or enzyme are low and must be replaced. But the gene should also remain dormant when not needed to ensure that it does not oversupply a substance and disturb the body's delicate chemical balance.

One approach to gene regulation is to attach other genes that detect certain biologic activities and then react as a type of automatic off-and-on switch, regulating the activity of other genes according to biologic cues. Although still in the rudimentary stages, researchers are making progress in inhibiting some gene functioning by using a synthetic DNA to block gene transcriptions (the copying of genetic information). This approach may have applications for gene therapy.

While gene therapy holds promise as a revolutionary approach for treating disease, ethical concerns over its use and ramifications have been expressed by scientists and lay people alike. For example, since much needs to be learned about how these genes actually work and their long-term effects, is it ethical to test these therapies on humans, in whom they could have a disastrous result? As with most clinical trials concerning new therapies, including many drugs, the people participating in these studies have usually not responded to more established therapies and are often so ill that the novel therapy is their only hope for long-term survival.

Another questionable outgrowth of gene therapy is that scientists could potentially manipulate genes to control traits in human offspring that are not related to health. For example, perhaps a gene could be inserted to ensure that a child would not be bald, a seemingly harmless goal. However, what if genetic manipulation was used to alter skin color, prevent homosexuality, or ensure good looks? If a gene is found that can enhance intelligence of children who are not yet born, will all members of society have access to the technology, or will it be so expensive that only the elite can afford it?

The Human Genome Project, which plays such an integral role for the future of gene therapy, also has social repercussions. If individual genetic codes can be determined, will such information be used against people? For example, will someone more susceptible to a disease have to pay higher insurance premiums or be denied health insurance altogether? Will employers discriminate between two potential employees, one with a healthy genome and the other with genetic abnormalities?

Cells The smallest living units of the body that carry a full complement of the DNA, and which group together to form tissues and help the body perform specific functions.

Chromosome Threadlike structures in a cell that carry most of the genetic material in the form of DNA and genes.

Clinical trial The testing of a drug or some other type of therapy in a specific human population.

Clone A cell or organism derived through asexual (without sex) reproduction, and which contains the identical genetic information of the parent cell or organism.

DNA (deoxyribonucleic acid) The specific molecules that comprise chromosomes and genes.

Embryo The earliest stage of development of the zygote before the human or animal is considered a fetus (which is usually the point at which the embryo takes on the basic physical form of its species). Embryos are formed in vivo (in utero) or in vitro (in a laboratory) in preparation for implantation.

Enzyme Atypeofmoleculemadebycells that,when released, facilitates chemical reactions in the body.

Eugenics A social movement in which the population of a society, country, or the world is to be improved by selective mating, controlling the passage of hereditary information.

Gene A specific biologic component found in the cell nucleus that carries the instructions for the formation of an organism and its specific traits, such as eye or hair color.

Gene transcription The process by which genetic information is copied from DNA to RNA, resulting in a specific protein formation.

Genetic engineering The manipulation of genetic material to produce specific results in an organism.

Genetics The study of hereditary traits passed on through genes.

Genome The total set of genes carried by an individual or cell.

Genomics The DNA which is found in the organism's total set of genes carried by an individual or cell and is passed on to offspring as information necessary for survival.

Germ-line gene therapy The introduction of genes (natural or engineered) into reproductive cells or embryos to correct inherited genetic abnormalities that can cause disease by replication.

Liposome Fat organelle made up of layers of lipids.

Macromolecule A large molecule composed of thousands of atoms.

Nitrogen An element that is a component of the base pairs in DNA.

Nucleus The central part of a cell that contains most of its genetic material, including chromosomes and DNA.

Protein Macromolecule made up of long sequences of amino acids. Proteins comprise the dry weight of most cells and are involved in structures, hormones, and enzymes in muscle contraction, immunological response, and many other functions essential to life.

Somatic gene therapy The introduction of genes into tissue or cells to treat a genetic disease in an individual.

Vector Something used to transport genetic information to a cell.

Some of these concerns can be traced back to the eugenics movement that was popular in the first half of the twentieth century. This genetic philosophy was a societal movement that encouraged people with so-called positive traits to reproduce while those with less desirable traits were sanctioned from having children. Eugenics was used to pass strict immigration laws in the United States, barring less suitable people from entering the country lest they reduce the quality of the country's collective gene pool. Probably the most notorious example of eugenics in action was the rise of Nazism in Germany, which fostered the Eugenic Sterilization Law of 1933. The law required sterilization for those with certain disabilities and even for some persons who were simply deemed to be unattractive. To ensure that this novel science is not abused, many governments have established organizations specifically for overseeing the development of gene therapy. In the United States, the Food and Drug Administration and the National Institutes of Health require scientists to take a precise series of steps and meet stringent requirements before approving clinical trials.

In fact, gene therapy has been immersed in more controversy and is surrounded by more scrutiny from both the health care and ethics communities than most other technologies (except, perhaps, for cloning) that have the potential to substantially change society. Despite the health and ethical questions surrounding gene therapy, the field will continue to grow and is likely to change medicine more quickly than any previous medical advancement.

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Gomez-Navarro, Jesus, Guadalupe Bilbao, and David T. Curiel. "Gene therapy." In Cecil Textbook of Medicine, 21st ed., edited by Goldman, Lee and Bennett, J. Claude. Philadelphia: W.B. Saunders, 2000, 140-143.

Hengge, Ulrich R., and Beatrix Volc-Platzer. The Skin and Gene Therapy. New York: Springer Verlag, 2000.

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American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672, (913) 906-6000, http://www.aafp.org.

American Society of Gene Therapy. 611 East Wells Street, Milwaukee, WI 53202, (414) 278-1341, (414) 276-3349. http://www.asgt.org.

World Health Organization. 20 Avenue Appia, 1211 Geneva 27, Switzerland, +41 (22) 791 4140, +41 (22) 791 4268. http://www.who.int/gtb.

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gene therapy | Encyclopedia.com

Gene therapy is an experimental method of fighting disease that involves correcting or replacing a persons mutated or malfunctioning genes. This promising research is now being used in clinical trials and may lead to improved health outcomes for patients with inherited bleeding and immune disorders as well as some forms of blood cancer and other diseases.

What Is Gene Therapy?

Genes carry the DNA information needed to make proteins that are the building blocks of the human body. Some of these genes can become damaged through mutation, which can lead to disease conditions. Gene therapy is a scientific technique that uses genes to prevent or treat disease in a number of different ways:

Finding the Keys to Alter Body Chemistry

Currently, gene therapy can be used for conditions in which a change in the genetic coding of somatic cells can alter the course of a disease. For example, to correct a disease in which a specific enzyme is missing, the addition of a necessary gene component for production of the enzyme would fix the underlying problem of the disease. In many cases, harmless viruses are employed to serve as packets to carry the new gene to where it is needed. When used this way, the viruses are called vectors, and their own genes may be removed and replaced with the working human gene. Once the gene is correctly placed, it can be switched on to provide the working instructions for correct function.

Conditions Being Treated with Gene Therapy

Although much of this may still sound like the realm of mad scientists tinkering with the human body, gene therapy is an accepted experimental technique that is currently being used to help patients with certain types of cancer to target specific antibodies that can be used to fight the disease. Gene therapy is also being used to correct deficiencies in the production of dopamine, such as in Parkinsons disease, correct some immune system problems, and restore components needed for normal blood cell function in those with certain blood diseases, such hemophilia and beta-Thalassemia. Gene therapy holds promise for treating a wide range of diseases, including cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Potential Risks

Gene therapy does come with some potential risks, all of which, researchers are hoping to overcome. Because the genes have to be delivered using a carrier or vector, the bodys immune system may see the newly introduced viruses as intruders and attack them. Its also possible that the altered viruses may infect additional cells, not just the targeted cells containing mutated genes. There may also be some concern that the viruses may recover their original ability to cause disease, or that the new genes get inserted in the wrong spot in a patients DNA, leading to tumor formation.

Hope for the Future

Gene therapy holds promise as an effective treatment option for a variety of diseases at some point in the near future. An estimated 4,000 medical conditions are a result of gene disorders. If some of these genetic problems can be corrected through gene replacement or manipulation, individuals suffering from these diseases may enjoy longer, healthier lives, free of symptoms and the associated medical expenses.

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Gene Therapy The Future of Medicine? | Science Care

Gene therapy, the use of genetic material to treat a disease or disorder, is making strides in muscular dystrophy. Although the approach is still considered experimental, studies in animal models have shown promising results and clinical trials in humans are underway.

Gene therapy has the potential to help people with inherited disorders, in which a gene mutation causes cells to produce a defective protein or no protein at all, leading to disease symptoms.

To deliver the genetic material to the cells, scientists use a tool called a vector. This is typically a virus that has been modified so that it doesnt cause disease. It is hoped that the vector will carry the therapeutic gene into the cells nucleus, where it will provide the instructions necessary to make the desired protein.

The most common form of muscular dystrophy, Duchenne muscular dystrophy, is caused by a mutation in the DMD gene, which codes for a protein called dystrophin. Dystrophin is part of a protein complex that strengthens and protects muscle fibers. When the cells dont have functional dystrophin due to the gene mutation, muscles progressively weaken. Scientists think that supplying a gene that codes for a functional form of dystrophin might be an effective treatment for Duchenne muscular dystrophy.

Using gene therapy to deliver a correct form of the dystrophin gene has been challenging because of the size of the DMD gene, which is the largest gene in the human genome so it does not fit into commonly used vectors.

Scientists are having more success with a shortened version of the DMD gene that produces a protein called micro-dystrophin. Even though its a smaller version of dystrophin, micro-dystrophin includes key elements of the protein and is functional.

Administering a gene for micro-dystrophin to golden retriever dogs that naturally develop muscular dystrophy showed promising results in a study published in July 2017. Muscular dystrophy symptoms were reduced for more than two years following the treatment and the dogs muscle strength improved. The gene was delivered using a recombinant adeno-associated virus, or rAAV, as the vector.

A similar therapy is now being tested in people in a Phase 1/2 clinical trial (NCT03375164)at Nationwide Childrens Hospital in Columbus, Ohio. A single dose of the gene therapytreatment containing the gene encoding for micro-dystrophinwill be infused into the blood system of 12 patients in two age groups: 3 months to 3 years, and 4 to 7 years. The first patient in the trial, which is recruiting participants, already has received the treatment, according to a January 2018 press release.

The biopharmaceutical company Sarepta Therapeutics is contributing funding and other support to the project.

Sarepta is developing another potential gene therapy for Duchenne muscular dystrophy where rather than targeting the DMD gene that codes for dystrophin, the therapy will be used to try to increase the expression of a gene called GALGT2. The overproduction of this gene is thought to produce changes in muscle cell proteins that strengthen them and protect them from damage, even in the absence of functional dystrophin.

A Phase 1/2a clinical trial (NCT03333590) was launched in November 2017 at Nationwide Childrens Hospital for the therapy, called rAAVrh74.MCK.GALGT2.

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Muscular Dystrophy Newsis strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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Gene Therapy in Muscular Dystrophy

Gene therapy is a field of biomedical research with the goal of influencing the course of various genetic and acquired (so-called multi factorial) diseases at the DNA/RNA level. Cell therapy aims at targeting various diseases at the cellular level, i.e. by restoring a certain cell population or using cells as carriers of therapeutic cargo. For many diseases, gene and cell therapy are applied in combination. In addition, these two fields have helped provide reagents, concepts, and techniques that are illuminating the finer points of gene regulation, stem cell lineage, cell-cell interactions, feedback loops, amplification loops, regenerative capacity, and remodeling.

Gene therapy is defined as a set of strategies that modify the expression of an individuals genes or repair abnormal genes. Each strategy involves the administration of a specific nucleic acid (DNA or RNA). Nucleic acids are normally not taken up by cells, thus special carriers, so-called 'vectors' are required. Vectors can be of either viral or non-viral nature.

Cell therapy is defined as the administration of living whole cells for the patient for the treatment of a disease. The origin of the cells can be from the same individual (autologous source) or from another individual (allogeneic source). Cells can be derived from stem cells, such as bone marrow or induced pluripotent stem cells (iPSCs), reprogrammed from skin fibroblasts or adipocytes. Stem cells are applied in the context of bone marrow transplantation directly. Other strategies involve the application of more or less mature cells, differentiated in vitro (in a dish) from stem cells.

Historically, the discovery of recombinant DNA technology in the 1970s provided the tools to efficiently develop gene therapy. Scientists used these techniques to readily manipulate bacterial and viral genomes, isolate genes, identify mutations involved in human diseases, characterize and regulate gene expression and produce human proteins from genes (e.g. production of insulin in bacteria revolutionized medicine). Later, various viral and non-viral vectors were developed along with the development of regulatory elements (e.g. promoters that regulate gene expression), which are necessary to induce and control gene expression. Gene transfer in animal models of disease have been attempted and led to early success. Various routes of administrations have been explored (injection into the bloodstream, into the ventricles of the brain, into muscle etc).

The development of suitable gene therapy treatments for many genetic diseases and some acquired diseases has encountered many challenges, such as immune response against the vector or the inserted gene. Current vectors are considered very safe and recent gene therapy trials documented excellent safety profile of modern gene therapy products. Further development involves uncovering basic scientific knowledge of the affected tissues, cells, and genes, as well as redesigning vectors, formulations, and regulatory cassettes for the genes. While effective long-term treatments for many genetic and inherited diseases are elusive today, some success is being observed in the treatment of several types of immunodeficiency diseases, cancers, and eye disorders.

Historically, blood transfusions were the first type of cell therapy and are now considered routine. Bone marrow transplantation has also become a well-established medical treatment for many diseases, including cancer, immune deficiency and others. Cell therapy is expanding its repertoire of cell types for administration. Cell therapy treatment strategies include: isolation and transfer of specific stem cell populations, induction of mature cells to become pluripotent cells, administration of effector cells and reprogramming of mature cells into iPSCs. Administration of large numbers of effector cells has benefited cancer patients, transplant patients with unresolved infections, and patients with vision problems.

Several diseases benefit most from treatments that combine the technologies of gene and cell therapy. For example, some patients have a severe combined immunodeficiency disease (SCID) but unfortunately, do not have a suitable donor of bone marrow. Scientists have identified that patients with SCID are deficient in adenosine deaminase gene (ADA-SCID), or the common gamma chain located on the X chromosome (X-linked SCID). Several dozen patients have been treated with a combined gene and cell therapy approach. Each individuals hematopoietic stem cells were treated with a viral vector that expressed a copy of the relevant normal gene. After selection and expansion, these corrected stem cells were returned to the patients. Many patients improved and required less exogenous enzymes. However, some serious adverse events did occur and their incidence is prompting development of theoretically safer vectors and protocols. The combined approach also is pursued in several cancer therapies.

Genome editing (gene editing) has recently gained significant attention, due to the discovery and application of the clustered regularly interspaced short palindromic repeats (CRISPR) system. Actually, genome editing dates back several years and earlier generation genome editing systems are currently tested in clinical trials (such as zinc-finger nucleases). The aim of genome editing is to disrupt a disease-causing mutation or correct faulty genes at the chromosomal DNA. Genome editing can be performed in the patients own cells in vitro and edited cells can be administered to the patient (thus genome editing can be combined with cell therapy). However, it is also possible to perform genome editing in vivo by administering the genome editing agent packaged in viral and non-viral vectors.

Continue reading here:

Gene & Cell Therapy Defined | ASGCT - American Society of ...

Learning Objectives

Many types of genetic engineering have yielded clear benefits with few apparent risks. Few would question, for example, the value of our now abundant supply of human insulin produced by genetically engineered bacteria. However, many emerging applications of genetic engineering are much more controversial, often because their potential benefits are pitted against significant risks, real or perceived. This is certainly the case for gene therapy, a clinical application of genetic engineering that may one day provide a cure for many diseases but is still largely an experimental approach to treatment.

Human diseases that result from genetic mutations are often difficult to treat with drugs or other traditional forms of therapy because the signs and symptoms of disease result from abnormalities in a patients genome. For example, a patient may have a genetic mutation that prevents the expression of a specific protein required for the normal function of a particular cell type. This is the case in patients with Severe Combined Immunodeficiency (SCID), a genetic disease that impairs the function of certain white blood cells essential to the immune system.

Gene therapy attempts to correct genetic abnormalities by introducing a nonmutated, functional gene into the patients genome. The nonmutated gene encodes a functional protein that the patient would otherwise be unable to produce. Viral vectors such as adenovirus are sometimes used to introduce the functional gene; part of the viral genome is removed and replaced with the desired gene (Figure1). More advanced forms of gene therapy attempt to correct the mutation at the original site in the genome, such as is the case with treatment of SCID.

Figure1. Gene therapy using an adenovirus vector can be used to treat or cure certain genetic diseases in which a patient has a defective gene. (credit: modification of work by National Institutes of Health)

So far, gene therapies have proven relatively ineffective, with the possible exceptions of treatments for cystic fibrosis and adenosine deaminase deficiency, a type of SCID. Other trials have shown the clear hazards of attempting genetic manipulation in complex multicellular organisms like humans. In some patients, the use of an adenovirus vector can trigger an unanticipated inflammatory response from the immune system, which may lead to organ failure. Moreover, because viruses can often target multiple cell types, the virus vector may infect cells not targeted for the therapy, damaging these other cells and possibly leading to illnesses such as cancer. Another potential risk is that the modified virus could revert to being infectious and cause disease in the patient. Lastly, there is a risk that the inserted gene could unintentionally inactivate another important gene in the patients genome, disrupting normal cell cycling and possibly leading to tumor formation and cancer. Because gene therapy involves so many risks, candidates for gene therapy need to be fully informed of these risks before providing informed consent to undergo the therapy.

The risks of gene therapy were realized in the 1999 case of Jesse Gelsinger, an 18-year-old patient who received gene therapy as part of a clinical trial at the University of Pennsylvania. Jesse received gene therapy for a condition called ornithine transcarbamylase (OTC) deficiency, which leads to ammonia accumulation in the blood due to deficient ammonia processing. Four days after the treatment, Jesse died after a massive immune response to the adenovirus vector.

Until that point, researchers had not really considered an immune response to the vector to be a legitimate risk, but on investigation, it appears that the researchers had some evidence suggesting that this was a possible outcome. Prior to Jesses treatment, several other human patients had suffered side effects of the treatment, and three monkeys used in a trial had died as a result of inflammation and clotting disorders. Despite this information, it appears that neither Jesse nor his family were made aware of these outcomes when they consented to the therapy. Jesses death was the first patient death due to a gene therapy treatment and resulted in the immediate halting of the clinical trial in which he was involved, the subsequent halting of all other gene therapy trials at the University of Pennsylvania, and the investigation of all other gene therapy trials in the United States. As a result, the regulation and oversight of gene therapy overall was reexamined, resulting in new regulatory protocols that are still in place today.

Presently, there is significant oversight of gene therapy clinical trials. At the federal level, three agencies regulate gene therapy in parallel: the Food and Drug Administration (FDA), the Office of Human Research Protection (OHRP), and the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health (NIH). Along with several local agencies, these federal agencies interact with the institutional review board to ensure that protocols are in place to protect patient safety during clinical trials. Compliance with these protocols is enforced mostly on the local level in cooperation with the federal agencies. Gene therapies are currently under the most extensive federal and local review compared to other types of therapies, which are more typically only under the review of the FDA. Some researchers believe that these extensive regulations actually inhibit progress in gene therapy research. In 2013, the Institute of Medicine (now the National Academy of Medicine) called upon the NIH to relax its review of gene therapy trials in most cases. However, ensuring patient safety continues to be of utmost concern.

Beyond the health risks of gene therapy, the ability to genetically modify humans poses a number of ethical issues related to the limits of such therapy. While current research is focused on gene therapy for genetic diseases, scientists might one day apply these methods to manipulate other genetic traits not perceived as desirable. This raises questions such as:

The ability to alter reproductive cells using gene therapy could also generate new ethical dilemmas. To date, the various types of gene therapies have been targeted to somatic cells, the non-reproductive cells within the body. Because somatic cell traits are not inherited, any genetic changes accomplished by somatic-cell gene therapy would not be passed on to offspring. However, should scientists successfully introduce new genes to germ cells (eggs or sperm), the resulting traits could be passed on to offspring. This approach, called germ-line gene therapy, could potentially be used to combat heritable diseases, but it could also lead to unintended consequences for future generations. Moreover, there is the question of informed consent, because those impacted by germ-line gene therapy are unborn and therefore unable to choose whether they receive the therapy. For these reasons, the U.S. government does not currently fund research projects investigating germ-line gene therapies in humans.

While there are currently no gene therapies on the market in the United States, many are in the pipeline and it is likely that some will eventually be approved. With recent advances in gene therapies targeting p53, a gene whose somatic cell mutations have been implicated in over 50% of human cancers, cancer treatments through gene therapies could become much more widespread once they reach the commercial market.

Bringing any new therapy to market poses ethical questions that pit the expected benefits against the risks. How quickly should new therapies be brought to the market? How can we ensure that new therapies have been sufficiently tested for safety and effectiveness before they are marketed to the public? The process by which new therapies are developed and approved complicates such questions, as those involved in the approval process are often under significant pressure to get a new therapy approved even in the face of significant risks.

To receive FDA approval for a new therapy, researchers must collect significant laboratory data from animal trials and submit an Investigational New Drug (IND) application to the FDAs Center for Drug Evaluation and Research (CDER). Following a 30-day waiting period during which the FDA reviews the IND, clinical trials involving human subjects may begin. If the FDA perceives a problem prior to or during the clinical trial, the FDA can order a clinical hold until any problems are addressed. During clinical trials, researchers collect and analyze data on the therapys effectiveness and safety, including any side effects observed. Once the therapy meets FDA standards for effectiveness and safety, the developers can submit a New Drug Application (NDA) that details how the therapy will be manufactured, packaged, monitored, and administered.

Because new gene therapies are frequently the result of many years (even decades) of laboratory and clinical research, they require a significant financial investment. By the time a therapy has reached the clinical trials stage, the financial stakes are high for pharmaceutical companies and their shareholders. This creates potential conflicts of interest that can sometimes affect the objective judgment of researchers, their funders, and even trial participants. The Jesse Gelsinger case (see Gene Therapy Gone Wrong above) is a classic example. Faced with a life-threatening disease and no reasonable treatments available, it is easy to see why a patient might be eager to participate in a clinical trial no matter the risks. It is also easy to see how a researcher might view the short-term risks for a small group of study participants as a small price to pay for the potential benefits of a game-changing new treatment.

Gelsingers death led to increased scrutiny of gene therapy, and subsequent negative outcomes of gene therapy have resulted in the temporary halting of clinical trials pending further investigation. For example, when children in France treated with gene therapy for SCID began to develop leukemia several years after treatment, the FDA temporarily stopped clinical trials of similar types of gene therapy occurring in the United States. Cases like these highlight the need for researchers and health professionals not only to value human well-being and patients rights over profitability, but also to maintain scientific objectivity when evaluating the risks and benefits of new therapies.

At what point can the FDA halt the development or use of gene therapy?

Answer d. The FDA halt the development or use of gene therapy at any of the points listed above.

_____________ is a common viral vector used in gene therapy for introducing a new gene into a specifically targeted cell type.

Adenovirus is a common viral vector used in gene therapy for introducing a new gene into a specifically targeted cell type.

Excerpt from:

Gene Therapy | Microbiology

What is Gene Therapy?

Gene therapy is a technique used to correct defective genes genes that are responsible for disease development. Specifically, according to the American Society of Gene and Cell Therapy-

Gene therapy is defined as a set of strategies that modify the expressionof an individuals genes or that correct abnormal genes. Each strategyinvolves the administration of a specific DNA (or RNA).

Gene therapy is the manipulation of the expression of specific genes in a persons body, in hopes of treating a disease or disorder. Gene therapy is still considered experimental and only available via clinical trial. Although many successful trials have been documented (see Interesting Links below), gene therapy has a checkered history. In some gene therapy trials, there were cases of leukemia as an unintended side-effect, and even cases of death (see link on Jesse Gelsinger below).

Image courtesy of Wikimedia Commons

How Does Gene Therapy Work?

Although there are several strategies for gene therapy, the most commonly used method involves inserting a therapeutic gene into the genome to replace the abnormal or disease-causing gene. The gene that is inserted is delivered into a target cell via a vector. Usually, this vector is a virus, although non-viral vectors are in development. Viruses are a good choice for introducing genes into a cell because they typically operate by transferring their own genetic material while replicating themselves. Once target cells are infected with the viral vector, the vector releases its therapeutic gene which then incorporates into the cells DNA. The goal is that the cell will start using the new gene to make functional, healthy proteins.

There are three main strategies for using gene therapy to restore the target cells or target tissues to a normal, healthy state.

1. Insert the functional version of a gene in hopes of replacing the abnormal form. This is used to treat single-gene disorders like hemophilia A and B and cystic fibrosis.

2. Insert a gene that encodes for a therapeutic protein that treats a disease. This is used to treat acquired diseases likeinfection or ischemic heart disease.

3. Use gene transfer to down-regulate gene expression in hopes of decreasing the activity of a harmful gene.

Current Areas of Research

Although gene therapy is still experimental, many diseases have been targets for gene therapy in clinical trials. Some of these trials have produced promising results. Diseases that may be treated successfully in the future with gene therapy include (but are not limited to):* Anemias* Cardiovascular diseases* Cystic Fibrosis* Diabetes* Diseases of the bones and joints* Eye disease and Blindness* Gauschers Disease* Hemophilia* Huntingtons Disease* Lysosomal storage diseases* Muscular Dystrophy* Sickle cell disorder

The main challenges facing gene therapy are the identification of disease causing genes, the targeted delivery of the therapeutic gene specifically to the affected tissues, and the prevention of side effects (such as an immune response) in the patient.

Gene Therapy for Enhancement Purposes

If gene therapy becomes routine medical practice, then it is reasonable to believe that some will seek it out for enhancement purposes. For example, a gene therapy designed to help patients with Alzheimers disease may be appealing to a normal individual hoping to boost memory. One potential area of enhancement that has been discussed is gene doping in sports. Gene doping is defined by the World Anti-Doping Agency (WADA) as the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance. The purpose of gene doping is toenhancea given gene rather thancorrecta faulty one. Potential targets of gene doping include:

* Erythropoietin (EPO) for increased production of red blood cells* Insulin-like Growth Factor-1 gene for increased muscle mass* Myostatin for increased muscle mass* Vascular Endothelial Growth Factor (VEGF) for an increase in blood flow

This form of doping would be hard to detect because the doping substances are produced directly in an individuals own cells after these genes with performance-enhancing effects have been expressed. Whether or not to use gene therapy in the future for enhancement purposes, and how to regulate it, will require a complex discussion of ethics in which there will likely be many differing opinions.

Interesting Links*The American Society of Gene and Cell Therapy* National Geographic articleon gene doping* Science Daily article onrecent gene therapy news* New York Times article on the death of Jesse Gelsinger* Scientific American article on treating blindness with gene therapy

CLICK HERE to read our case study involving ethical issues associated with gene therapy

REFERENCES

Gene Therapy and Cell Therapy Defined. American Society of Gene and Cell Therapy, n.d. Web. 04 Nov. 2012. <http://www.asgct.org/general-public/educational-resources/gene-therapyand-cell-therapy-defined>.

Gene Therapy..Human Genome Project Information, n.d. We. 04 Nov. 2012. <http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml>

Pawliuk R et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science. 2001; 294:2368-2371.

Unal M, Unal DO. Gene doping in sports. Sports Medicine. 2004; 34:357-362.

Wells DJ. Gene doping: the hype and the reality. British Journal of Pharmacology. 2008 January; 154: 623-631.

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Gene Therapy - Genetics Generation

Gene Therapy

A few years ago, a clinical trial began in France in the hope of curing children with a type of genetic immune deficiency called SCID-X1. Children with this disease have a defective gene, called gamma-c, which prevents a subset of the cells of the immune system from forming, and predisposes the children to life-threatening infections. In an attempt to cure the childrenwho would otherwise die at a young agephysicians used gene therapy to provide them with normal gamma-c genes.

This particular trial has had striking success as well as tragedy. Eight of the eleven children are currently thriving. However, in two cases the therapy successfully introduced gamma-c genes, but these children have since developed leukemia. In both children, a gamma-c gene inserted next to another gene, called LMO2. The LMO2 gene has previously been linked to leukemia, and scientists speculate that the insertion of the gamma-c gene next to LMO2 may have overstimulated the gene, causing T cells to proliferate in excess. An LMO2 effect, in combination with the proliferation-inducing effects of the gamma-c gene itself, may be the cause of the leukemia in these two patients. Scientists are still investigating other possible causes.

From this single trial, it is clear that gene therapy holds significant promise, yet it is also clear that it poses significant risks. To learn more about the application of gene therapy in SCID, view the accompanying animation.

Read more:

Gene Therapy - Sumanas, Inc.

Overview

Gene therapy involves altering the genes inside your body's cells in an effort to treat or stop disease.

Genes contain your DNA the code that controls much of your body's form and function, from making you grow taller to regulating your body systems. Genes that don't work properly can cause disease.

Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve your body's ability to fight disease. Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Researchers are still studying how and when to use gene therapy. Currently, in the United States, gene therapy is available only as part of a clinical trial.

Gene therapy is used to correct defective genes in order to cure a disease or help your body better fight disease.

Researchers are investigating several ways to do this, including:

Gene therapy has some potential risks. A gene can't easily be inserted directly into your cells. Rather, it usually has to be delivered using a carrier, called a vector.

The most common gene therapy vectors are viruses because they can recognize certain cells and carry genetic material into the cells' genes. Researchers remove the original disease-causing genes from the viruses, replacing them with the genes needed to stop disease.

This technique presents the following risks:

The gene therapy clinical trials underway in the U.S. are closely monitored by the Food and Drug Administration and the National Institutes of Health to ensure that patient safety issues are a top priority during research.

Currently, the only way for you to receive gene therapy is to participate in a clinical trial. Clinical trials are research studies that help doctors determine whether a gene therapy approach is safe for people. They also help doctors understand the effects of gene therapy on the body.

Your specific procedure will depend on the disease you have and the type of gene therapy being used.

For example, in one type of gene therapy:

Viruses aren't the only vectors that can be used to carry altered genes into your body's cells. Other vectors being studied in clinical trials include:

The possibilities of gene therapy hold much promise. Clinical trials of gene therapy in people have shown some success in treating certain diseases, such as:

But several significant barriers stand in the way of gene therapy becoming a reliable form of treatment, including:

Gene therapy continues to be a very important and active area of research aimed at developing new, effective treatments for a variety of diseases.

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

Dec. 29, 2017

Read more here:

Gene therapy - About - Mayo Clinic

Gene therapy is a revolutionary approach to treating genetic diseases. It involves a one-time delivery of a normal copy of the defective gene which ideally causes the body to naturally produce the missing enzyme. It is the most promising cure that these boys desperately need.

Gene therapy has shown promise as a cure for Hunter Syndrome.

A clinical trial is required to get FDA approval.

Funding is the final barrier to beginning the clinical trial.

In 2013, after it had been performed on other forms of MPS with positive results, a group of Hunter Syndrome families initiated a partnership with researchers at Nationwide Childrens Hospital in Columbus, Ohio to begin gene therapy research in Hunter Syndrome / MPS II. Now, the researchers are in the final stages of developing the first gene therapy clinical trial for boys with Hunter Syndrome. The only obstacle is the substantial funding required for such a trial. If the necessary funds are raised, the trial could begin as early as late 2017 or early 2018.

In the world of medicine, this treatment is considered an orphan drug because of the small patient population it seeks to treat. In the US, an orphan drug is a treatment for a disease that affects less than 200,000 people. Drug companies fund much of the research for more common diseases because in developing a potential blockbuster drug for a large patient population, they also are more likely to make a profit. Few companies are willing to invest in research for such a small population only an estimated 500 boys with Hunter Syndrome live in the United States. Without drug companies pursuing a cure for Hunter Syndrome, families tackled that lofty goal and have finally reached the point where a potential cure is ready and waiting with one obstacle: funding it.

Link:

Project Alive | The hope for a cure: Gene therapy

Editor-in-Chief: Terence R. Flotte, MDDeputy Editors, Europe: Nathalie Cartier, MD and Thierry VandenDriessche, PhDDeputy Editors, U.S.: Barry J. Byrne, MD, PhD and Mark A. Kay, MD, PhDHuman Gene Therapy Editor: Guangping Gao, PhDMethods Editor: Hildegard Bning, PhDClinical Development Editor: James M. Wilson, MD, PhD

Latest Impact Factor* is 4.187 *2016 Journal Citation Reports (Clarivate Analytics, 2017)

Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.

The Journal is divided into three parts. Human Gene Therapy, the flagship, is published 12 times per year. HGT Methods, a bimonthly journal, focuses on the applications of gene therapy to product testing and development. HGT Clinical Development, a quarterly journal, serves as a venue for publishing data relevant to the regulatory review and commercial development of cell and gene therapy products.

Human Gene Therapy was voted one of the most influential journals in Biology and Medicine over the last 100 years by the Biomedical & Life Sciences Division of the Special Libraries Association.

Human Gene Therapy, HGT Methods, and HGT Clinical Development are under the editorial leadership of Editor-in-Chief Terence R. Flotte, MD, University of Massachusetts Medical School; Deput Editors Europe Nathalie Cartier, MD, INSERM, andThierry VandenDriessche, PhD, Free University of Brussels (VUB); Deputy Editors U.S. Barry J. Byrne, MD, PhD,Powell Gene Therapy Center, University of Florida, College of Medicine and Mark A. Kay, MD, PhD, Stanford University School of Medicine; Human Gene Therapy Editor Guangping Gao, PhD, University of Massachusetts Medical School; Methods Editor Hildegard Bning, PhD, University of Cologne; Clinical Development Editor James M. Wilson, MD, PhD,University of Pennsylvania School of Medicine, Gene Therapy Program; and other leading investigators. View the entire editorial board.

Audience: Geneticists, medical geneticists, molecular biologists, virologists, experimental researchers, and experimental medicine specialists, among others.

Human Gene Therapy and HGT Methods provide Instant Online publication 72 hours after acceptance

Indexed/Abstracted in:MEDLINE;PubMed;PubMed Central;Current Contents/Life Sciences;Science Citation Index Expanded;Science Citation Index;Biotechnology Citation Index;Biological Abstracts;BIOSIS Previews;Journal Citation Reports/Science Edition;Derwent Drug File;EMBASE/Excerpta Medica;EMBiology;Scopus;Chemical Abstracts;ProQuest databases

The views, opinions, findings, conclusions and recommendations set forth in any Journal article are solely those of the authors of those articles and do not necessarily reflect the views, policy or position of the Journal, its Publisher, its editorial staff or any affiliated Societies and should not be attributed to any of them.

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Human Gene Therapy

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The mission of ACGT is to seek out and support revolutionary scientific research into the causes, treatment and prevention of all types of cancer using cells and genes as medicine.

Cell and gene therapies are destroying tumors every day in the laboratory and in human trials, targeting only the cancer with few side effects to healthy tissue. ACGTs rigorous grant review process, under the guidance of a preeminent Scientific Advisory Council, have resulted in some of the most successful breakthroughs in the history of cancer treatments and led to many patients in complete remission.

100% of our funding supports innovation and translational science that is proving again and again to offer better treatment options than the traditional therapies of chemotherapy, surgery and radiation. Every donation brings us closer to saving lives and changing the way we treat cancer forever.

Video:ACGT fellow, Dr. Samuel Katz,Yale Medical Center, speak about cell and gene therapies for cancer treatment.

See all ACGT videos here

At the ACGT anniversary gala in April, Robert Vonderheide, MD, DPhil, the Hanna Wise Professor in Cancer Research and newly appointed Director of the Abramson Read More

This fourth in our blog series on the progress of cell and gene therapy for cancer focuses on a treatment that has made huge strides Read More

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2017 All rights reserved by ACGT. ACGT is a 501(c)(3) organization and all contributions are tax-deductible under the law of your state.

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Alliance for Cancer Gene Therapy (ACGT) Foundation

Krystal Biotech has filed to raise about $35 million in a Nasdaq IPO. The money will equip Krystals ex-Intrexon executive team to file an IND for its rare skin disease gene therapy in the first quarter of next year.

That gene therapy, KB103, is designed to treat dystrophic epidermolysis bullosa, a rare disease that makes the skin fragile and susceptible to blisters and tears. Krystal thinks it can improve outcomes in these patients, who currently only have palliative options, by using a HSV-1-based vector to fix defects in the COL7A1 gene.

Pittsburgh, Pennsylvania-based Krystal has yet to back up the idea with clinical data. But having run preclinical tests of topical and intradermal formulations of KB103 and met with the FDA late last year, it plans to embark on a whistle-stop development program. The plan is to file an IND in the first quarter, have results by the middle of the year and use that readout to guide the design of a pivotal trial.

Krystal will need more than the forecast IPO haul to execute that strategy, although it does expect to have some money left over from the Nasdaq listing to fund work on its follow-up program, KB104. That gene therapy treatment for Netherton syndrome is due to reach the IND stage by the second half of next year.

The early-stage nature of Krystals pipeline is one of several characteristics that mark it out as a biotech trying to make the leap to public markets early in its development as a company. Notably, given the financial reporting requirements for public companies, Krystal has yet to hire a full-time CFO or in-house principal accounting officer. The biotechs seven-person team is heavily skewed towardR&D.

Krish Krishnan, CEO, and Suma Krishnan, COO, lead this small team. The pair have worked together for most of the past 13 years, starting at New River Pharmaceuticals in the run-up to its takeover by Shire. Both Krishnans popped up next at Pinnacle Pharmaceuticals, where Krish was CEO, before reuniting with their former New River boss Randal Kirk at Intrexon.

Krystal sees the pair strike out on their ownand stand to win big if their gene therapies succeed.A family trust owned by Krish and Suma owns more than two-thirds of Krystals stock. The only other organization to own more than 5% of the company is Sun Pharma, which bought its 16.5% stake in a $7 million series A round earlier this month. That round bolstered Krystals cash position, which stood at $3.5 million at the end of June.

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Krystal files for IPO to move gene therapies into clinic | FierceBiotech - FierceBiotech

The UK Medicines and Healthcare Products Regulatory Agency (MHRA) has granted a Promising Innovative

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MHRA backs gene therapy in battle with 'bubble baby' disease - The Pharma Letter (registration)

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Apic Bio, Inc., a pre-clinical stage gene therapy company leveraging its proprietary platform to advance therapies to treat rare diseases with complex mechanisms, in particular Alpha-1 Antitrypsin Deficiency (Alpha 1), launched today with an initial investment led by the venture philanthropy arm of the Alpha-1 Foundation and a private investor with the disease.

Its lead product, APB-101, targets the liver via an AAV delivered Dual Function Vector (df-AAV) whereby the Z-AAT protein is silenced and M-AAT protein is augmented. APB-101 has achieved a pre-clinical proof of concept with efficacy demonstrated in vitro and in vivo. It is currently undergoing pre-clinical GLP toxicology studies in non-human primates. Patients living with Alpha 1 lack sufficient levels of circulating AAT protein to protect lung tissue against damage from proteases, and experience the accumulation of mutant AAT polymers in the liver. Clinically, the deficiency is manifested by progressive emphysema and the accumulation presents a significant risk of liver cirrhosis.

John Reilly, Co-Founder & President said: We are grateful to TAP and A1AT Investors, LLC who have supported the successful start of Apic Bio by providing the first tranche of our seed financing round allowing us to secure key intellectual property rights and operational support. With such strong support from the advocacy and patient community, we are confident that we will identify the right corporate partners to help us achieve our business development goals and bring this exciting new therapy to patients.

The df-AAV platform allows treatment of other diseases with complex mechanisms where the mutant gene product must be reduced and the normal gene product must be augmented.

Dr. Chris Mueller, Co-founder and Chief Scientific Officer of Apic Bio said: We are encouraged by the feedback that we have received during our pre-IND meeting with the FDA that there is a clear path for us to conduct a first-in-human Phase 1/2 clinical study. Furthermore, we are very much looking forward to demonstrating the benefit of APB-101 to patients that have been living with alpha-1 and have had very little hope for a cure. Our data suggests this is a liver sparing approach for gene augmentation which may exceed the therapeutic and safety margins when compared to a strict gene augmentation without gene silencing that may exacerbate the underlying liver disease.

TAP is very pleased to provide this funding to Apic Bio. Their cutting-edge work on a therapy that addresses both the liver and lung disease brings us closer to finding a cure for Alpha-1 Antitrypsin Deficiency, thus fulfilling our mission, said Jean-Marc Quach, CEO for The Alpha-1 Project.

Todays launch of Apic Bio has been a long time coming for the hundreds of thousands of people who are challenged by Alpha 1, said Ed Krapels, who has been living with Alpha 1 and is the new companys first individual investor. Now that we are moving forward, we hope to work with patients, their advocates and researchers to make a cure readily available. Krapels added.

About Apic Bio: Apic Bio, Inc. is a spin-off from the University of Massachusetts Medical School (UMMS) and is based upon nearly 30 years of gene therapy research by its scientific founders Christian Mueller, PhD, Associate Professor of Pediatrics and a member of the Horae Gene Therapy Center at the University of Massachusetts Medical School, Terence R. Flotte, MD, the Celia and Isaac Haidak Professor in Medical Education, dean of the School of Medicine and provost and executive deputy chancellor of the University of Massachusetts Medical School; and colleagues at the Horae Gene Therapy Center. Their research is funded in part by an $11M grant from the National Heart, Lung, and Blood Institute (NHLBI).

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Apic Bio Launches to Advance First-in-Class Gene Therapy for ... - Business Wire (press release)

A darling British biotech that is working on the development of the worlds leading gene therapy for cancer has posted reduced losses and a leap in sales.

Oxford BioMedica signed a deal worth up to $100m (77m) with Swiss drugs giant Novartis last month to supply cell material for its potential blockbuster treatment, known as CTL019, for a type of leukaemia.

The living drug was recommended for approval by US regulators in June, with a final determination expected this autumn.

It would be the first gene therapy for cancer and if approved is expected to generate a spike in revenues for Oxford BioMedica, with the potential for further tie-ups on other cancer treatments.

Oxford BioMedica is also trialling its lentiviral vectors, which help manipulate genes, in potential treatments for Parkinsons Disease and an eye condition.

In half-year results today, Oxford BioMedica pared back losses to 2.2m, compared to 6.9m in the red the previous year. Revenues jumped 26pc to 15.7m.

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Gene therapy darling Oxford BioMedica pares losses - Telegraph.co.uk