A rose will bloom, it then will fade. Alas, not so for those afflicted with Hutchison-Gilford Progeria Syndrome (HGPS). Their lives skip the blooming stage. Within a few months of birth their growth is stunted and they begin to show the hallmarks of ageing. Their skin loses its elasticity and their hair falls out. As teenagers they resemble tiny, gnomish octogenarians, with prominent eyes, pinched noses, receding jaws and veins protruding through thin transparent skin. The average age of death is 13 usually from a heart attack or stroke.

Cardiologist John Cooke is trying to help those with the disease by at least slowing the ageing and stiffening of their blood vessels. His approach involves rejuvenating this tissue by delivering transient gene therapy using messenger RNA for a gene called telomerase. Since messenger RNA does not hang around, the technique avoids the pitfalls of gene therapy, like inadvertently triggering cancer.

The results of his research, published this week in the Journal of the American College of Cardiology, show the successful rejuvenation of cells in the test tube from youngsters with HGPS.

It brings tears to my eyes to see these kids but despite the fact theyre trapped in the body of an 80-year-old, he says. Theyre not bitter. They are intelligent and hopeful. They want to count the stars.

The efforts of Cooke and colleagues based at the Houston Methodist Research Institute in Texas wont just benefit children with progeria; there are potential pluses for most of us who are also likely to die of heart disease.

The cells of those afflicted with HGPS have a shortened life span. Compared to normal cells, they multiply fewer times before becoming senescent cells that are no longer able to rejuvenate through dividing. The fault lies with the worn-down tips of their chromosomes, known as telomeres. In normal cells, the telomeres are much longer.

This is all a consequence of the LMNA mutation that is the underlying cause of HGPS. It impairs the way DNA is housed in the nucleus, buckling the appearance of the nucleus and also meaning the DNA cannot be properly maintained particularly the vulnerable ends, which fray. Cells with seriously frayed telomeres become senescent. They no longer divide or respond to the environment in a normal way, and ooze inflammatory factors. In the case of the endothelial cells that line the blood vessels, Cooke says, this means they dont line up against the shear stress and they become stickier, attracting plaque.

For several years Cooke has wondered whether it might be possible to restore ageing endothelial cells to a more youthful state by repairing the telomere ends not just in youngsters with HGPS but everybody.

The enzyme telomerase is designed to do this job; but delivering a hard copy of the gene to the cells is probably a bad idea: cancer cells often rely on activating telomerase.

So Cooke opted for giving the cells a soft copy the messenger RNA that carries the same information as the gene but doesnt hang around. It is sort of like a flimsy photocopy of an important manuscript.

The just-published study was a proof of concept. The Houston researchers took skin cells from 17 youngsters with HGPS aged one to 14 and grew out cells called fibroblasts. (Its much harder to extract endothelial cells that line the blood vessels). In 12 of the patients, the fibroblasts showed abnormally short telomeres. Five of the younger patients (aged eight years or less) had normal length telomeres something that surprised the researchers. When the scientists added the messenger RNA of the telomerase gene, the cells with short telomeres kicked back into replicating again. On the other hand, the cells that had normal length telomeres showed no response.

The study suggests that the delivery of the telomerase messenger RNA is able to rejuvenate fibroblast cells. It presumably might do the same for the endothelial cells and blood vessels of youngsters with HGPS. The next step, Cooke says, is to work on techniques to deliver the telomerase messenger RNA into the body, perhaps using nanoparticles.

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Transient gene therapy may help youngsters with a premature ageing syndrome - Cosmos

Pharmaceutical firm uniQure N.V. has developed an optimized large-scale process to manufacture its lead gene, therapydate, to treat hemophilia B. This new platform will allow the Dutch company to boost production of its AMT-060 gene therapy at its Lexington, Massachusetts, facility, in accordance with Good Manufacturing Practices guidelines.

This should enable uniQure to meet the requirements of both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) by early fall, the companys CEO, Matt Kapusta, said in a press release.

We have made significant progress over the past several months to now be in a position where we have developed a commercial-scale process and are evaluating our completed batches to assess comparability, Kapusta said. We look forward to finalizing this work in anticipation of meetings with regulators to further discuss plans to advance our hemophilia B program into a pivotal study next year.

AMT-060 gene therapy is based on a viral vector to deliver a therapeutic form of human factor IX gene, or FIX. This potential therapy is currently being evaluated in a Phase 1/2 trial (NCT02396342) in patients with severe hemophilia B and advanced joint disease.

The trials most recent long-term resultsshow that AMT-060 is safe and well tolerated, while reducing annual spontaneous bleeding rates by 84 percent to an average of 0.5 annual bleeds after gene transfer.

These results were subject of an oral presentation, Updated Results from a Dose-escalation Study in Adults with Severe or Moderate-severe Hemophilia B Treated with AMT-060 (AAV5-hFIX) Gene Therapy: up to 1.5 Years Follow-up, given during the 26th Biennial Congress of the International Society on Thrombosis and Haemostasisin Berlin. A summary appears in the meetingsbook of abstracts.

Based on the trials results, the FDA granted AMT-060 its breakthrough therapy designation in January 2017.The EMA awarded the gene therapy its PRIME designation in April 2017.In addition, uniQure says it will extend its new manufacturing platform to production ofAMT-130 to treat Huntingtons disease.

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Hemophilia B Gene Therapy AMT-060 Moves to Large-scale Production, Says UniQure - Hemophilia News Today

A safe and effective gene therapy treating Duchenne muscular dystrophy (DMD) in dogs has been demonstratedby researchers from France and the UK.

The gene therapy significantly increased the muscle strength of dogs naturally affected by DMD, improving their ability to walk, run and jump.

'This is very encouraging, as current treatments for muscular dystrophy are merely palliative and patients are under constant medical care throughout their life,' saidDr John Counsell, who was not involved in the study but works at the Gene Transfer Technology Group at University College London.

DMD is a rare, progressive disease affecting all muscles of the body, including the heart and diaphragm. It is caused bymutationsin the dystrophingene, which leads to a deficiency of dystrophinprotein. Dystrophin is important in supporting the muscle fibres during contraction; without it, the muscle fibres become damaged and eventually die.

As it is one of the largest human genes, it is technically challenging to insert the entire dystrophin gene into a viral vector, as is usually done for gene therapy. For this reason, the researchers in this study developed a gene therapy that delivers a smaller but functional version of the dystrophin gene (called micro-dystrophin). This was packaged into a non-pathogenic virus called an adeno-associated virus (AAV).

Twelve dogs with DMD received a single dose of the micro-dystrophin gene therapy and were monitored for up to two years. The researchers observed an increased amount of dystrophin protein in the dogs'muscles and a stabilisation of clinical symptoms in most of the dogs. There were no serious immune reactions to the gene therapy.

'The studies in dogs have been spectacular and exceeded our expectations,' said Professor George Dickson, who led the research at Royal Holloway University of London. My team has worked for many years to optimise a gene therapy medicine for DMD, and now the quite outstanding work of colleagues in France, in Genethon, in Nantes and in Paris has taken us close to clinical trials in DMD patients.'

In a separate study, a group of researchers from the US developed a micro-dystrophin gene therapy using a different type of AAV vector. They tested this in a recently established, severe DMD mouse model that is thought to be more like the human condition than the commonly used mdx mouse.

15 weeks after AAV injection, the researchers detected an increased amount of dystrophin protein in the mouse muscles. There were also improvements in muscle function and a reduction in muscle scarring and inflammation.

Whilst evaluating cardiac function, the researchers unexpectedly found pathological changes in the hearts of control mice, which meant that they were similar to the DMD hearts. For this reason, they could not evaluate the effect of the micro-dystrophin gene therapy on cardiac function and concluded that the mouse was not a good model for DMD-associated cardiomyopathy.

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BioNews - Gene therapy reverses muscular dystrophy in dogs in ... - BioNews

US biotech firm Spark Therapeutics has submitted a Marketing Authorization Application (MAA) to the European

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Spark submission brings first gene therapy for genetic disease closer - The Pharma Letter (registration)

HomeHealthGene Therapy Treats Muscular Dystrophy in Dogs, Provides Hope for Humans

July 29, 2017 WSP

There is new hope for human patients with Duchenne muscular dystrophy. Results released in the journal Nature Communications describe a promising gene therapy performed on dogs. Twelve Golden Labrador dogs were subjected to a breakthrough gene therapy technology and, after two years, the dogs are healthy and appears to be illness-free. Researchers are optimistic about the implication of this study on humans.

Duchenne muscular dystrophy (or DMD) is a hereditary condition characterized by muscle weaknesses and muscle degeneration. Among nine types of muscular dystrophy, DMD is the most severe and life-threatening. Dystrophin protein is vital for muscles to function properly and the absence of this protein makes muscles fragile and easily damaged. At early stages, DMD will affect muscles in the shoulder, upper arms, thighs and hips that are vital to movement and balance. Patients experience muscle weaknesses by age 4 and then start losing the ability to walk by age 12. Later on, DMD will weaken the heart and respiratory muscles. For DMD cases, the average life expectancy is 26 years, with only a few patients living beyond 40.

Duchenne muscular dystrophy was named after French neurologist Guillaume Benjamin Amand Duchenne who described the illness in the 1860s. It was only in 1986 that researchers discovered a specific gene in the X chromosome that is responsible for normal dystrophin production. If a human has inherited the mutated or defective gene, that human can be ill with DMD or be a carrier of the defective gene.

Duchenne muscular dystrophy affects 1 in 5,000 boys at birth but is rare among girls. Girls, which have XX composition, are less likely affected than boys with XY composition as the dystrophin gene is located in the X chromosome. When a young girl inherits a defective dystrophin gene from one parent, she will be DMD-free if she gets a normal gene from her other parent or DMD-affected if she gets another defective gene. However, a DMD-free girl with a defective gene is still a carrier and can pass that gene to her children. On the other hand, it only takes one defective gene for boys to be affected with DMD.

There are no cures for Duchenne muscular dystrophy. Drugs, physical therapy and corrective surgery have been the primary tools for dealing with DMD but researchers are now pursuing newer technologies as possible treatment routes. The team of researchers from Genethon, the AFM-Telethon laboratory, INSERN (UMR 1089, Nantes) and the Royal Holloway of University of London collaborated for a promising gene therapy study conducted on twelve Golden Labrador dogs. The dogs were injected one-time with a gene for microdystrophin, a compressed version of dystrophin. Microdystrophin gene is used instead of dystrophin gene as the latter is too large to fit into a carrier virus that will be injected into a dogs body.

Golden Labrador dogs are chosen for this study as these breed is prone to DMD. Injecting the microdystrophin gene is expected to restore a dogs ability to normally produce dystrophin protein. The chosen dogs were not expected to live beyond six months but they are still alive two years since the study commenced. The dogs have shown improved ability to walk, run and jump. Buoyed by these positive results, researchers hope their study will pave the way in starting human clinical trials in the near future.

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Gene Therapy Treats Muscular Dystrophy in Dogs, Provides Hope ... - Wall Street Pit

Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAVmicrodystrophin gene therapy in DMD patients.

Duchenne muscular dystrophy (DMD) is an X-linked inherited disease affecting 1:5,000 male births, leading to a highly debilitating and ultimately life-limiting muscle-wasting condition. DMD is caused by mutations in the gene coding for dystrophin, a cytoskeletal protein that is critical to the stability and function of myofibres in skeletal and cardiac muscle1,2. Dystrophin establishes a mechanical link between cytoskeletal actin and the extracellular matrix in muscle fibres through the dystrophin-associated protein complex, and when dystrophin is absent the mechanical and signalling functions of the costamer are compromised3. DMD-affected boys develop muscle weakness during the first years of life, and although palliative treatments are available (essentially physiotherapy, assisted ventilation and glucocorticoids) they become wheelchair-bound generally before the age of 15 years. Serious, life-threatening muscle wasting and respiratory and cardiac complications arise in late teens, and patients rarely survive into their fourth decade.

This is the first time a gene therapy based on rAAV-MD gene delivery by LR isolated limb perfusion and without immunosuppression has been performed in young adult GRMD dogs, showing clear prevention of degeneration/regeneration, fibrosis, magnetic resonance imaging and NMR changes and loss in muscle strength.

Unlike rodents, dog immunity shares many common features with its human counterpart with a full development before birth, although the maturity of the immune system completes after birth. An important observation of our study, in view of clinical translation, was the lack of systemic adverse effects and anti-cMD1 T-cell immune responses at the highest, efficacious dose of cMD1 vector, associated with long-term persisting transgene expression despite the occasional and transient detection of anti-cMD1 IgGs in most of the dogs. Importantly, the transient humoral immune response was apparently without serious consequences in the transduced muscles or in peripheral organs.

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Gene therapy cures Duchenne muscular dystrophy in dogs - Next Big Future

Researchers have used a new gene therapy technique to reverse the symptoms of Duchenne muscular dystrophy in dogs (Credit: mvaligursky/Depositphotos)

Duchenne muscular dystrophy (DMD) is the most common and, sadly, the most severe form of the debilitating genetic disorder. Now researchers have used a new gene therapy technique to restore muscle strength and stabilize the symptoms of the disorder in dogs, in an important step that could one day lead to the treatment being applied to children.

Affecting one in 5,000 boys (but very rarely occurring in girls), DMD usually begins to show itself around the age of three to five, and progresses quickly from there. It disrupts dystrophin, a protein that's responsible for maintaining muscle integrity and strength. As a result, DMD causes the muscles to weaken and waste away, often rendering a patient unable to walk by age 12 and unlikely to live beyond their mid-20s.

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To combat genetic disorders, researchers often insert a healthy copy of the affected gene into a viral vector essentially, a harmless shell of a virus that carries the material into cells. Unfortunately, that tactic doesn't work with DMD: the gene contains 2.3 million base pairs, making it far too big a load for a viral vector.

To get around this problem, researchers from the Gnthon laboratory at AFM-Tlthon and the Royal Holloway University of London developed microdystrophin, a shortened version of the dystrophin gene that contains only about 4,000 base pairs. When this is combined with a viral vector and injected into a patient, functional proteins are once again produced.

The scientists tested their new gene therapy technique on 12 Golden Retrievers that were naturally affected by DMD. They injected microdystrophin into the animals intravenously, and observed them for more than two years afterwards. After just one dose, the researchers noted that dystrophin production returned to normal, significantly restoring muscle function in the dogs and stabilizing their other symptoms without any side effects.

This is the first time such a treatment has been seen in large animals, and given the similarities in symptoms and size between dogs and children, this success raise hopes for an eventual human treatment.

"This preclinical study demonstrates the safety and efficacy of microdystrophin, and makes it possible to consider developing a clinical trial in patients," says Caroline Le Guiner, main author of the the study. "Indeed, this is the first time that it has been possible to treat the whole body of a large-sized animal with this protein. Moreover, this innovative approach allows treatment of all patients with Duchenne muscular dystrophy, regardless of the genetic mutation responsible."

The research was published in the journal Nature Communications.

Source: AFM-Tlthon

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Gene therapy reverses muscular dystrophy symptoms in dogs - New Atlas

Although medications exist to treat depression, many scientists arent sure why theyre effective and why they dont work for everyone.

Researchers at the University of Maryland School of Medicine believe they may have found a key to the puzzle of major depression that could lead to therapies for those who dont respond to medications already on the market.

A new study by the researchers has identified the central role a gene known as Slc6a15 plays in either protecting from stress or contributing to depression, depending on its level of activity in a part of the brain associated with motivation, pleasure and reward seeking.

Published in the Journal of Neuroscience in July, the study is the first to illuminate in detail how the gene works in a kind of neuron that plays a key role in depression, according to the University of Maryland School of Medicine.

Specifically, the researchers found that mice with depression had reduced levels of the genes activity, while those with high levels of the genes activity handled chronic stress better.

Though senior researcher Mary Kay Lobos primary studies were done with mice, she also examined the brains of people who had committed suicide and found reduced levels of the genes activity, confirming a likely link.

She hopes now that drugs could be developed that would encourage the genes activity.

I thought it was fascinating we had this system in place that allows us to go after things or be motivated or have pleasure and I was interested in how it becomes dysfunctional in certain diseases like depression, Lobo said. I hope that we can identify molecules that could potentially be therapeutically treated or targeted to treat depression.

Lobo and her colleagues have been examining the gene for years. In 2006, they discovered that it was more common among specific neurons in the brain that they later learned were related to depression. Five years later, other researchers learned the gene played a role in depression and Lobo and her research colleagues decided to investigate what that role is in those specific neurons.

About 15 million adults, or 6.7 percent of all U.S. adults, experience major depression in a given year, according to the Anxiety and Depression Association of America. It is the leading cause of disability for Americans aged 15 to 44. It is more prevalent in women and can develop at any age, but the median age of onset is 32.5.

David Dietz, an associate professor in the Department of Pharmacology and Toxicology at the State University of New York at Buffalo, said little was known previously about the biological basis of depression in the brain. Many drugs used to treat depression were discovered serendipitously, he said, and it wasnt clear why they worked.

Were starting to really get an idea of what does the depressed brain look like, Dietz said. When you put the whole puzzle together, you see where the problem is. For too long weve been throwing things at individual pieces. Its so complex and we have so little information that it was almost bound to be that way. For the first time this is one of those bigger pieces you can slide into the jigsaw puzzle.

Lobo said its not clear yet how Slc6a15 works in the brain, but she believes it may be transporting three types of amino acids into a subset of neurons called D2 neurons in a part of the brain called the nucleus accumbens. The nucleus accumbens and D2 neurons are known to play a role in pleasure, activating when one eats a delicious meal, has sex or drinks alcohol.

The amino acids would then be synthesized into neurotransmitters. Depression previously has been linked to imbalances of the neurotransmitters serotonin, norepinephrine and dopamine.

So even though people may have proper levels of amino acids in their bodies, the neurons in their brains that need them may not be getting enough if the transporter is not working as it should.

This gene is critical for putting very specific amino acids in the right place so that neurotransmitters can be synthesized, said A.J. Robison, an assistant professor in the Department of Physiology at Michigan State University. Its the location, location, location idea. Its not the amino acids, its where theyre at and in which cells.

Robison said Lobos next step would be discovering more about how the transporter gene works.

The fact that this transporter seems to be important is what the paper shows and how it does it is not shown, and thats a challenge for her, he said. Figuring out the how of it is the next step and Dr. Lobo is particularly positioned to do it.

Lobos team was able to use gene therapy, a form of therapy in the early stages of being studied in humans, in the mice to boost the genes activity. The mice were exposed to larger, more aggressive mice, which usually causes depressive symptoms. But the gene therapy helped protect the mice against the stress, the team found. When the team reduced the genes activity in the mice, just one day of exposure to the aggressive mice was enough to cause symptoms of depression.

Gene therapy is starting to be used in the treatment of some types of cancers, but Lobo said science had not yet advanced to the point where it can be used for treating neurological issues in human patients. A more likely treatment would be a drug that targets the genes activity directly, she said.

I think this is a major step toward our understanding of the precise maladaptive changes that occur in response to stress, said Vanna Zachariou, an associate professor in the Department of Neuroscience at the Icahn School of Medicine at Mount Sinai. It can be a more efficient way to target depression because its not simply targeting monoamine receptors or dopamine but targeting molecular adaptations that occur. It doesnt act necessarily as the drugs we have available, so it might create an alternative avenue to treat depression.

Lobo said she wouldnt refer to Slc6a15 as a depression gene, saying the disease was complex and could have many factors.

I wouldnt say theres one depression gene she said. A number of things play a role, and also theres no depression neuron, theres multiple depression neurons.

There also may be different types of depression with different symptoms, she said. With the disease, some sufferers sleep a lot, while others sleep a lot less, for example.

With all these complex diseases, its hard to link it to something, she said. Like Huntingtons disease, we know theres a specific gene that causes Huntingtons disease. For depression we dont have that.

cwells@baltsun.com

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University of Maryland scientists research gene linked to depression - Baltimore Sun

Injectinga smaller but functional form of the dystrophin gene, called microdystrophin, intodogs naturally affected by Duchenne muscular dystrophyallowed them to recover muscle strength and stabilized their overall disease symptoms, a new study shows.

This preclinical study demonstrates the safety and efficacy of microdystrophin, and makes it possible to consider developing a clinical trial in patients, Caroline Le Guiner, first author of the study, said in a news release.

Indeed, this is the first time that it has been possible to treat the whole body of a large-sized animal with this protein. Moreover, this innovative approach allows treatment of all patients with Duchenne muscular dystrophy, regardless of the genetic mutation responsible, Le Guiner added.

The study, titled Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy, was featured in the journalNature Communications.Researchers used a delivery system based on a viral vector, a strategy commonly used in gene therapy, to inject the engineered microdystrophin in 12 Golden Retrievers naturally affected by DMD.

DMD is a rare inherited disorder caused by mutations in the gene that encodes the protein dystrophin, which is essential for normal muscle function. It is one of the longest human genes, which makes therapeutic usein its natural form technically impossible. To overcome this limitation, researchers created the new variant called microdystrophinthat is shorter, but retains the function of the protein.

The results demonstrated microdystrophins potential as a gene therapy for people with DMD. The treatment increased levels of dystrophin protein in the dogs and significantly restored muscle function. Clinical symptoms of DMD in the dogs were stabilized for more than two years following treatment. No significant adverse side effects associated with the treatment were observed, demonstrating that it can be a safe treatment strategy.

This is tremendously exciting progress towards a gene therapy for DMD, said George Dickson, senior author of the study and researcher at Royal Holloway, University of London. The studies in [Golden Retrievers naturally affected by DMD) have been spectacular and exceeded our expectations.

The study also provided important data to support the therapeutic potential of this new gene therapy for DMD in children.

This new evidence of the efficacy of gene therapy in Duchenne muscular dystrophy strengthens the therapeutic arsenal developed (exon skipping, CRISPR Cas-9, pharmacogenetics, etc.), and the first results are there. We need to forge ahead to complete the final phase and transform these scientific advances into drugs for children, said Serge Braun, scientific director of AFM-Telethon.

The study resulted from the collaborative work between researchers from Genethon, the AFM-Telethon laboratory, Inserm (Nantes), and the University of London (Royal Holloway), and was supported by donations from the French Telethon.

My team has worked for many years to optimize a gene therapy medicine for DMD, and now the quite outstanding work of colleagues in France, in Genethon, in Nantes, and in Paris has taken us close to clinical trials in DMD patients, Dickson said. I pay thanks also to the amazing and steadfast support of this research by AFM-Telethon and MDUK (Muscular Dystrophy UK) which has been essential to this achievement.

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Microdystrophin Gene Therapy Shows Promise in Dogs with Duchenne Muscular Dystrophy, Study Shows - Muscular Dystrophy News

Nearly five years ago, MesotheliomaHelp reported about a breakthrough treatment called gene therapy. At the time, it was touted as the next frontier in medicine, and cancer patients from around the world watched closely in the hopes that the treatment could bring a cure to even the rarest of cancers, such as mesothelioma. Now, all eyes are on the U.S. Food and Drug Administration as it is poised to approve two types of gene therapy.

The Oncologic Drugs Advisory Committee (ODAC) sent its recommendation to the FDA on July 12 for CTL019 (tisagenlecleucel) for the treatment of a form of leukemia. Then, on July 17, the FDA accepted a Biologics Licensing Application from Spark Therapeutics for gene therapy for a rare inherited eye disease that causes blindness, approved the name Luxturna for the treatment, and assigned priority status to the treatment for accelerated review.

To better understand these two pending landmark approvals and the future of gene therapy, MesotheliomaHelp turned to Ricki Lewis, a New York-based geneticist and author.

Its not right for every disease, said Lewis. But it is an approach that can be considered some day along with drugs, surgery and everything else.

Tisagenlecleucel is an investigational chimeric antigen receptor (CAR) T cell therapy from Novartis, developed by researchers at the University of Pennsylvania. The pharmaceutical company wants to use the therapy to treat a rare form of leukemia, B-cell acute lymphoblastic leukemia affecting children and young adults under the age of 25, according to NPR.

Lewis explains that CAR-T therapy is not conventional gene therapy, which has been in clinical trials to treat single-gene diseases since 1990. However, she notes that CAR T cell technology has had astonishing success in treating a form of leukemia and its being tested for multiple myeloma, brain cancer, breast cancer, and soft tissue cancers.

Although both approaches deliver DNA in viruses, classical gene therapy adds a working copy of a single mutant gene, restoring a specific proteins function, says Lewis. Revving up a not-naturally-occurring immune response isnt the same thing as replacing an enzyme, which is what Luxturna does.

According to the National Cancer Institute, in CAR-T treatment, T cells are removed from the patients blood and genetically altered in a lab to have chimeric antigen receptors on their surface. The T cells are then multiplied, into the billions, in the lab and infused back into the patients blood, where they seek out the cancer cells and launch a precise immune attack against them.

Lewis offers the following explanation of CAR-T:

CAR operates like a drone, targeting and obliterating cancer cells. It introduces a gene manufactured to contain instructions for making two immune system components in one, something that doesnt exist in nature: an antibody and a T cell receptor. When delivered in a virus, the CAR enters the persons T cells, which then manufacture the hybrid (chimeric) protein.

The engineered receptor portion guides the T cells to a specific target such as cancerous B cells where the antibody part binds. The action alerts the immune system to respond and kill the cancer cells.

Ultimately, CAR-T, also described as a process that genetically alters a patients own cells to fight cancer, could be used for many more diseases and cancers, and bring an effective treatment to mesothelioma patients.

In a 2013 article for MesotheliomaHelp, Lewis wrote about CAR-T treatment saying, An ingenious technique that has vanquished leukemia in a handful of patients is also being applied to mesothelioma.

Lewis highlighted the CAR-T process being used in a mesothelioma clinical trial from the University of Pennsylvania that uses the doctored T cells, known as chimeric immune receptor (CIR) instead of CAR, against mesothelin, a protein that is found to be in excess in mesothelioma and other cancers. The idea is that T cells led to the mesothelioma cells will attract an immune response, said Lewis.

Find out more about the mesothelioma clinical trial from the University of Pennsylvania here.

In her book The Forever Fix, Lewis followed the journey of the use of gene therapy to restore the vision of a young boy who was nearly blind from a hereditary disorder. The doctors added a working copy of a single defective gene in the New York boys eyes that prevented his eyes from using vitamin A to send visual signals to his brain. The treatment was a success: the boys vision was restored and no further treatments or surgery were required.

Last weeks FDA advisory committees greenlight for CAR technology overshadowed a milestone for what is likely to be the first approval of classic gene therapy for a form of inherited blindness, Lewis told MesotheliomaHelp. Thats the Leber congenital amaurosis type 2 renamed RPE65-mediated inherited retinal dystrophy that I wrote my book about.

In an interview with Lewis last week, Dr. Katherine High, MD, President, Chief Scientific Officer, and a founder of Spark Therapeutics, said of the future of gene therapy:

I hope we will see continued accumulation of successful clinical results in a range of target tissues and continued progress in bringing gene therapy products to licensing. When gene therapy products are licensed, there will be increased interest in the medical community, and that will help to expand opportunities.

Mesothelioma patients typically show disease symptoms years or even decades after exposure to asbestos, a known carcinogen. The cancer is eventually fatal, but aggressive therapy may prolong the lives of patients who are diagnosed early. Approximately 3,000 Americans are diagnosed with the cancer each year.

Getting at the basis of why one person develops mesothelioma and another person doesnt, that is going to hold a clue to really fighting it, Lewis said, referring to a clinical trial conducted at Wake Forest University in 2013 to determine whether some mesothelioma patients are genetically predisposed to developing mesothelioma. Then we will know what to do the gene therapy on.

The pending FDA approvals could bring groundbreaking treatment to cancer patients and to patients with genetic diseases. Perhaps someday, mesothelioma patients will enjoy long, productive lives through gene therapy.

The FDA is not bound to follow the ODACs recommendations, however, the Agency nearly always follows the recommendation. Approval for CTL019 is expected in November. The FDA will decide on Luxturna in January, 2018.

About Ricki Lewis,PhD Ricki Lewis is a science writer with a PhD in genetics. The author of several textbooks and thousands of articles in scientific, medical, and consumer publications, Rickis first narrative nonfiction book, The Forever Fix: Gene Therapy and the Boy Who Saved It, was published by St. Martins Press in March 2012. In addition to writing, Ricki provides genetic counseling for parents-to-be at CareNet Medical Group in Schenectady, NY and teaches Genethics an online course for masters degree students at the Alden March Bioethics Institute of Albany Medical Center.

Read more about gene therapy on Ricki Lewiss DNA Science blog.

Find out more about Ricki Lewis at her website.

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Two Gene Therapy Approaches Pending Approval from FDA Bring Hope to Mesothelioma Community - MesotheliomaHelp.org (blog)

July 26, 2017

An article published in Experimental Biology and Medicine (Volume 242, Issue 13, July, 2017) reports that gene therapy may be used to as an intermediate therapy for newborns with surfactant protein deficiencies until lung transplantation becomes an option. The study, led by Dr. David Dean in the Division of Neonatology at the University of Rochester in Rochester NY reports that electroporation-mediated delivery of the surfactant B gene to deficient mice improves lung function and survival.

Surfactant is present in the lungs of all humans. This important protein makes it easier for people to breath. Without it, lungs would collapse with each breath. Surfactant protein B (SPB) deficiency is a rare but fatal disease that affects full term babies after an apparently uncomplicated pregnancy and delivery. Babies with SBP deficiency have severe breathing problems from birth, and die in infancy even with aggressive medical treatment. To date the only effective treatment is a lung transplant. Given how quickly these babies become ill, and the limited number of available organs, transplantation is often not even an option.

The most promising therapy for this devastating disease is replacement of the absent SPB gene, a process called gene therapy. Gene therapy approaches using viral-based delivery techniques have not achieved therapeutic levels of SPB protein and induce inflammation, which can exacerbate the disease. The current study used electroporation-based delivery techniques which result in higher levels of transgene expression and are well-tolerated even in animals with existing lung injury. Delivery of SPB DNA into the lung cells of SPB-deficient mice reduced lung inflammation, improved lung function, and extended survival. Since the DNA is eventually silenced, SPB expression does not last forever and this is approach cannot provide a cure.

Dr. Barnett, a neonatology fellow and coauthor said "although this treatment does not provide lifelong correction, our data suggest that this may be a useful approach for improving the survival and stability of infants until lung transplant can occur." Dr. Dean added "we are excited to help optimize an approach that may treat and someday even cure this and other devastating diseases."

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, said, "Dean and colleagues provide evidence that gene therapy may restore surfactant activity in SPB deficiency for sufficient time to allow lung transplants in a greater number of affected neonates. This is represents an important advance in this field of research."

Explore further: Gene delivery to the lung can treat broad range of diseases within and beyond the lung

Data demonstrating sustained protein expression five years after a single intramuscular injection of a gene-based therapy for the treatment of alpha-1 antitrypsin (AAT) deficiency also shows improvements in multiple indicators ...

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Gene therapy to correct surfactant protein B deficiency in newborns - Medical Xpress

LONDON (Reuters) - GlaxoSmithKline is swimming against the tide by getting out of treatments for rare diseases at a time when rivals like Sanofi and Shire see the field as a rich seam for profits.

Successful medicines for rare conditions are potentially very lucrative, since prices frequently run into hundreds of thousands of dollars, but patient numbers can be extremely low.

New GSK Chief Executive Emma Walmsley announced the strategic review and potential divestment of rare diseases on Wednesday as part of a wide-ranging drive to streamline pharmaceutical operations.

It follows a less than impressive experience for GSK in the field, including the fact that its pioneering gene therapy Strimvelis only secured its first commercial patient in March, 10 months after it was approved for sale in Europe in May 2016.

Since then a second patient has also been treated and two more are lined up to receive the therapy commercially, a spokesman said.

Strimvelis, which GSK developed with Italian scientists, is designed for a tiny number of children with ADA Severe Combined Immune Deficiency (ADA-SCID). SCID is sometimes known as "bubble baby" disease, since those born with it have immune systems so weak they must live in germ-free environments.

The new treatment became the first life-saving gene therapy for children when it was approved last year, marking a step forward for the emerging technology to fix faulty genes.

Walmsley said GSK was not giving up on gene and cell therapy entirely. Research will be focused in future in areas with larger potential patient numbers, including oncology.

Reporting by Ben Hirschler; Editing by Adrian Croft

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GSK gives up on rare diseases as gene therapy gets two customers - Reuters

AsianScientist (July 26, 2017) - In a study published in the journal EMBO Molecular Medicine, a group of researchers from the University of Tokyo describe a treatment method that prolonged the lives of mice with symptoms of amyotrophic lateral sclerosis (ALS).

ALS, also known as Lou Gehrigs disease, is a neurodegenerative disorder of motor neurons characterized by the severe deterioration of muscle. The degeneration and loss of neuromuscular junctions (NMJs)the essential chemical synapses that transfer control signals from motor neurons to skeletal muscleslead to the loss of motor function, including the ability to breathe. However, therapies that protect or restore NMJs remain elusive.

The research group led by Professor Yuji Yamanashi and Dr. Sadanori Miyoshi at the Institute of Medical Science at the University of Tokyo, together with collaborators, had previously discovered that the muscle protein known as docking protein 7 (Dok-7) is essential for forming NMJs. Mutations in the related human DOK7 gene cause DOK7 myasthenia, a hereditary disease characterized by a defective NMJ structure.

In the current study, the research group found that by restoring the expression of DOK7 using gene therapy in a mouse model of ALS, the loss of motor nerve terminals was suppressed, resulting in larger NMJs which slowed the progression of muscle atrophy. Importantly, mice treated with this method before the onset of ALS-like symptoms had an average life span of 166.3 days compared with 154.4 days for non-treated mice. After the onset of ALS-like symptoms, the treatment prolonged the duration of survival to an average of 64.2 days compared with 50.3 days in nontreated mice.

The findings suggest that therapeutic approaches aimed at enlarging NMJs might be useful in developing treatments for ALS and other types of motor neuron diseases associated with abnormal development of NMJs. Age-related ailments like sarcopenia, which are likely to become a growing concern in aging societies, could also benefit from such treatments.

This study originates from a finding in basic, biological research, which had no particular disorder as a target; the current outcome was obtained through the participation of numerous collaboratorsboth basic researchers and clinical researchersand the huge support from multiple public grants, said Yamanashi.

By acknowledging the huge contributions of our collaborators and supporters, we would like to do our best to understand the causes of ALS and other intractable disorders, with the aim of developing effective therapies.

The article can be found at: Miyoshi et al. (2017) DOK7 Gene Therapy Enhances Motor Activity and Life Span in ALS Model Mice.

Source: University of Tokyo; Photo: Shutterstock. Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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Gene Therapy Targeting Neuromuscular Junctions Could Alleviate ALS - Asian Scientist Magazine

Gene-altering therapy on the cusp of FDA approval may soon be treating children with advanced leukemia.

The Food and Drug Administration (FDA) is on the verge of approving the first-ever gene therapy treatment for use in the United States.

If it goes through as expected, the therapy will be used to treat children and young adults with advanced acute lymphoblastic leukemia (ALL).

The FDA's Oncologic Drugs Advisory Committee earlier this month recommended that the agency approve Novartis experimental chimeric antigen receptor (CAR-T) therapy, CTL019 (tisagenlecleucel).

Its an individualized therapy in which a persons T cells are removed from their blood and reengineered to fight cancer. Then theyre infused back into the patient.

Thats why its called a living drug.

In a recent clinical trial, 83 percent of patients experienced complete remission or complete remission with incomplete blood count recovery within three months.

The FDA is expected to make a decision in September. The agency usually follows its committees recommendations.

Experts are optimistic about the potential of CAR-T.

Dr. Santosh Kesari is a neuro-oncologist and chair of the Department of Translational Neuro-oncology and Neurotherapeutics at the John Wayne Cancer Institute at Providence Saint John's Health Center in California.

Kesari told Healthline that if approved, the therapy will be a revolutionary breakthrough in cancer treatment.

It will be the first application of this type combining gene therapy and immune therapy to modify a patients own cells to go attack cancer cells, he said.

Kesari explained that this application could work in other cancers where theres a specific target.

He pointed to a City of Hope case study involving a 50-year-old man with recurrent multifocal glioblastoma, a type of brain cancer.

The treatment was part of a phase I clinical trial to test the safety of CAR-T therapy when delivered directly to brain tumors. A successful response was sustained for more than seven months, longer than would usually be expected.

So, there is potential for application in solid tumors if we identify the right marker, making sure we manage side effects, said Kesari.

In an email interview with Healthline, Dr. Swati Sikaria, medical oncologist from Torrance Memorial Medical Center in California, explained that the goal is to choose a target as unique to the cancer as possible while avoiding damage to the noncancerous cells of the body.

This initial success paves the way for creating CAR-T cells with targets for other malignancies, she explained.

Whether the success in ALL can be replicated in other types of cancers, Im cautiously optimistic. Well have to see what ongoing and future clinical trials show. The most notable progress has been in multiple myeloma as well as glioblastoma, the type of tumor Senator [John] McCain was recently diagnosed with, said Sikaria.

In a review article published last year, Sikaria wrote that adult B-acute lymphoblastic leukemia (B-ALL) doesnt share the favorable prognosis seen in pediatric patients with the same disease.

Less than 50 percent of patients experience long-term survival, and for those adults over age 60, long-term survival is only 10 percent. At time of relapse, five-year prognosis is a dismal 7 percent. Novel and less toxic agents are urgently needed, she continued.

Sikaria called CAR-T cells a highly promising new agent, even in patients who are heavily pretreated.

Dr. Samantha Jaglowski is a hematologist at The Ohio State University Comprehensive Cancer Center. She specializes in stem cell transplants for patients with lymphoma and chronic lymphocytic leukemia.

While she hopes this truly is a breakthrough, she told Healthline shes hesitant to declare victory too soon.

It certainly appears promising. I sincerely hope it meets the expectations being put forth, said Jaglowski.

Its an exciting thing to be involved with. There are already many studies in the pipeline for many other kinds of cancers, she said.

There are two main concerns about CAR-T.

The first is the potential for serious side effects.

One of these is a life-threatening reaction called cytokine release syndrome (CRS).

Sikaria said this reaction is common and can occur within hours of the CAR-T cell infusion. But it can be effectively treated.

The drug also commonly causes reversible neurologic symptoms and a drop in blood counts, which can lead to infection. We have to remember that patients receiving CAR-T cells are battling a disease almost certain to be fatal otherwise, so I do think the risks are outweighed by benefits, she explained.

Jaglowski agreed that CRS is usually manageable. She noted that there havent been enough patients yet to evaluate long-term effects.

This will not be a first-line therapy until theres more data behind it. Patients will have had to have a couple of lines of therapy before becoming eligible for this. Im a lymphoma physician. In lymphoma trials, they require failure of previous lines of therapy. Its for people who are further on in the disease course and who have fewer options, said Jaglowski.

The second major concern is the potential cost. Novartis hasnt put a price tag on it, but industry analysts project that it could hit $500,000 per infusion.

Hopefully, well see competition in the market from other companies CAR-T cells, as a number are in development. Some help from Washington is also needed to bring the cost down, said Sikaria.

Kesari compared the therapy with other treatments.

Some drugs we [already] use, especially biologics, cost anywhere from $5,000 to $20,000 a month and involve repeated treatments in a year. Some cost several hundred thousand dollars a year. This is a one-time or few-time treatment. Its not like youre getting treatment for years. It puts all the costs upfront. If you get cured, whos to argue that its not worth it? he said.

Sikaria said that unless theres any new information concerning treatment-related deaths between now and October, the FDA should approve it.

CAR-T cells are exciting and have high response rates, but we need to see how long-lasting these results are as we continue to shoot for a cure. For now, bone marrow transplant is still an important part of the management of a patient with ALL, said Sikaria.

Kesari believes the FDA will approve CAR-T due to an unmet need and lack of options for a disease where patients uniformly end up dying.

This technology of how to modify genes started in the 80s and 90s. Building on that, we learned about the immune system and how to modify it to kill cancers. Its taken so long to prove value out to the point where were getting a drug approval. But its been going on for decades, he continued.

I commend the people that did this and to make it work in humans thats amazing, said Kesari.

Originally posted here:

New Gene Therapy Produces Hope for a New Era in Cancer ... - Healthline

EMERYVILLE, Calif. & COLUMBIA, Md.--(BUSINESS WIRE)--4D Molecular Therapeutics (4DMT), a leader in adeno-associated virus (AAV) gene therapy vector discovery and product development, and the Foundation Fighting Blindness (FFB), the worlds largest non-governmental source of research funding for inherited retinal degenerations (IRD) and dry age-related macular degeneration (AMD), today announced a partnership to develop intravitreal gene therapeutics for patients with these blinding conditions using 4DMT-proprietary AAV vectors. Under the terms of the agreement, 4DMT will provide access to its vector technology, development expertise and manufacturing capabilities while FFB will identify potential academic and business collaborators, provide drug development expertise and fund approved projects to develop transformative gene therapy products. 4DMT retains all patent and commercial rights to its 4DMT proprietary AAV vector variants. FFB and 4DMT will jointly review and approve all programs initiated within this collaboration.

New vector technologies are critical to the successful use of gene therapies for IRDs in order to improve targeting to affected cells within the retina, and to maximize efficacy and safety. Vectors that can be delivered intravitreally would simplify the procedures used for treatment and reduce the costs of administration.

Affecting approximately 200,000 patients in the US, inherited retinal diseases (IRDs) are a major cause of adult and childhood blindness. Mutations in more than 260 genes are known to cause these rare, orphan conditions for which there are currently no approved therapies. Gene therapy holds tremendous promise for the treatment of these conditions by introducing genes to the retina that may be able to replace the lost or dysfunctional genes, correct underlying mutations, or deliver therapeutically-active genes that can prevent cell loss and degeneration.

We are very impressed with 4Ds vector evolution approach, the companys product pipeline and manufacturing expertise. The potential is great for developing a number of gene therapeutics that could treat those affected by retinitis pigmentosa and allied conditions using a simple intravitreal injection approach, said Patricia Zilliox PhD, Chief Drug Development Officer at the FFB.

We are extremely excited by this collaboration with FFB, a globally-recognized leader in the effort to cure blindness due to inherited retinal degenerations. FFB has tremendous expertise identifying the best retinal research as well as an outstanding network of funded investigators and companies with whom we hope to collaborate to develop a portfolio of products that will benefit those affected with retinal degenerative diseases, said David Kirn, MD, co-Founder and CEO of 4DMT.

About Foundation Fighting Blindness (FFB)

Since FFBwas established in 1971 it has raised more than $700 million toward its mission of preventing, treating and curing blindness caused by inherited retinal diseases. In excess of 10 million Americans, and millions more worldwide, experience vision loss due to retinal degenerations. Through its support of focused and innovative science, and by teaming with industry, FFB drives the research that has and will continue to provide treatments and cures for people affected by retinitis pigmentosa, macular degeneration, Usher syndrome and other inherited retinal diseases.

About 4D Molecular Therapeutics (4DMT)

4DMT is focused on the discovery and development of targeted and proprietary AAV gene therapy vectors and therapeutic products for use in patients with severe genetic diseases with high unmet medical need. Our robust discovery platform, termedTherapeutic Vector Evolution, empowers us to create customized gene delivery vehicles to deliver genes to any tissue or organ in the body, by optimal clinical routes of administration with resistance to pre-existing antibodies. These proprietary and targeted products allow us to treat both rare genetic diseases and complex large market diseases. 4DMT is creating a diverse and deep product pipeline through its own internal 4D products, as well as partnered programs. 4DMT partners include: Pfizer (PFE), Roche (SIX: ROG; OTCQX: RHHBY), uniQure (QURE), AGTC, Benitec, Cystic Fibrosis Foundation and Choroideremia Research Foundation.

About 4DMTs Therapeutic Vector Evolution

Current clinical stage gene therapy products are generally based on one of 10 AAV vectors that are wild-type or primitive vectors, meaning they were found in nature as laboratory contaminants or as monkey infections. These first-generation AAV vectors, while generally safe and well-tolerated in patients, do not have optimized delivery properties and often require aggressive and/or invasive dosing to attempt the desired transduction of target cells. 4DMT is advancing the field of AAV vector technology by deploying principles of evolution and natural selection to create vectors that efficiently and selectively target the desired cells within the diseased human organ via clinically optimal routes of administration with resistance to pre-existing antibodies in the population. Our Therapeutic Vector Evolutionplatform deploys approximately 100 million unique AAV variants from proprietary 4DMT AAV libraries with extensive diversity. 4DMT then applies proprietary methods to identify lead vectors that are highly optimized for a specific target cell and organ, route of therapeutic administration, and capacity to evade pre-existing antibodies in patients. The result is a customized, novel, and proprietary pharmaceutical-grade vector uniquely designed for therapeutic gene delivery and efficacy in humans.

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4D Molecular Therapeutics and Foundation Fighting Blindness ... - Business Wire (press release)

Orchard Therapeutics has received rare pediatric disease designation for OTL-101, agene therapy for the treatment of the rare disease ADA-SCID.

Orchard Therapeutics,launched just a year ago in London, is developing what could be a new version of GSKsStrimvelis, the second gene therapy to reach the European market and theonly after uniQures Glybera was withdrawn from the market after being used only by one patient.

Orchards gene therapy, OTL-101, consists of a procedure in which hematopoietic stem cells from the patient are harvested, genetically engineered outside of the body and reinfused. It is intended as a cure foradenosine deaminase severe combined immunodeficiency(ADA-SCID), a rare disease affecting only 350 births per year. Without treatment, children die before their second birthday. In the past, children like David Vetter lived in sterile chambers to protect them, giving it the name of bubble babydisease.

David Vetter, with ADA-SCID, lived until age 12 thanks to sterilized suits and rooms

OTL-101 has been tested in 40 patients so far, all of which have survived since the start of a Phase I/IItrial last December. And despite the low numbers of patients, Orchard seems determined to compete with GSK in the ADA-SCID market. Currently, the only option for children in the US with this disease is enzyme replacement therapy, which still leaves them at high risk of life-threatening infections.

GSK got EU approval for Strimvelis in May 2016, and has since treated only one patient. The price tag, 594,000refundable if the therapy does not work could account for the slow adoption. It remains to see whether the number of patients will rise or if Strimvelis is doomed to a similar fate to that of Glybera.

Strimvelis is currently available to children across the EU but is only performed in the Ospedale San Raffaele in Milan. GSK has mentioned plans to file for FDA approval but it might wait a while given regulations are quite different between Europe and the US for the approval of gene therapies. In fact, no gene therapies are currently approved in the US.Spark Therapeutics might bring the first one this year, against LCA, a form of genetic blindness.

Image via ustas7777777 / Shutterstock; NASA Johnson Space Center / Creative Commons

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Orchard's gene therapy for rare 'bubble baby' disease gets FDA fast ... - Labiotech.eu (blog)

The products closest to approval so far have a limited focus to treat blood cancers like leukemia (for which an F.D.A. advisory panel recommended approval of the first treatment last week) and lymphoma, as opposed to the solid tumors that form in organs like the breasts and lungs and cause many more deaths. About 80,000 people a year have the kinds of blood cancers that the first round of new treatments can fight, out of the 1.7 million cases of cancer diagnosed annually in the United States.

The new treatments are expected to cost hundreds of thousands of dollars, and they come with risks. Patients in the earliest studies nearly died from side effects like raging fever, low blood pressure and lung congestion. Doctors have learned how to control those reactions, but experts also have concerns about possible long-term effects like second cancers that could in theory be caused by the disabled viruses used in genetic engineering. No such cancers have been seen so far, but it is too soon to rule them out.

The new leukemia treatment involves removing millions of white blood cells called T cells often referred to as the soldiers of the immune system from the patients bloodstream, genetically engineering them to recognize and kill cancer, multiplying them and then infusing them back into the patient. The process is expensive because each treatment has to be made separately for each person.

Solid tumors are less amenable to treatment with these altered cells which scientists call CAR-T cells but studies at various centers are trying to find ways to use it against mesothelioma and cancers of the ovary, breast, prostate, pancreas and lung.

These solid tumors are like Fort Knox, Dr. Grupp said. They dont want to let the T cells in. We need combination approaches, CAR-T plus something else, but until the something else is defined were not doing to see the same kind of responses.

The pioneering T-cell therapy for leukemia was created at the University of Pennsylvania, which licensed it to Novartis. The F.D.A. panel recommended approval of it for a narrow subset of severely ill patients, only a few hundred a year in the United States: those ages 3 to 25 who have B-cell acute lymphoblastic leukemia that has relapsed or not responded to the standard treatments. Those patients have poor odds of surviving, but in clinical trials, a single T-cell treatment has produced long remissions in many and possibly even cured some.

Novartis plans to request another approval later this year of the same treatment (which it calls CTL019 or tisagenlecleucel) for adults who have a type of lymphoma diffuse large B-cell lymphoma that has relapsed or resisted treatment. A competitor, Kite Pharma, has also filed for approval of a T-cell treatment for lymphoma. Another competitor, Juno, suffered a setback when it shut down a T-cell study in adults after five patients died from brain swelling. Kite has also reported one such death.

Novartis is studying several other types of T-cells, with different genetic tweaks, to treat chronic lymphocytic leukemia, multiple myeloma as well as glioblastoma.

Some of the more promising work so far involves efforts to make the existing gene treatments even more effective in blood cancers. For lymphoma patients, the T cells are being given along with a drug, ibrutinib, and the combination seems to work better than either treatment alone.

At the Childrens Hospital of Philadelphia, there are not enough study spots for all the patients who hope to receive T-cell treatment, and the waiting time can stretch to months, longer than some can afford to wait. Waiting times should decline after the treatment is approved and becomes more widely available.

Dr. Grupp said that one encouraging avenue of research involved giving the T-cells at an earlier stage of the disease, instead of very late, as rules now require. He said a study was being planned at multiple centers that he hoped would start within the next six months or so. The patients would be children with early signs that the usual chemotherapy which cures many is not working well for them.

We could deploy the treatment considerably earlier and before they get so sick, he said. He added, That is another big step in terms of trying to figure out how to use these cells appropriately.

Earlier treatment, he said, might help some patients avoid bone-marrow transplant, a grueling, last-ditch treatment. Children with less advanced disease also tend to have milder side effects from the T-cell treatment.

Studies in children are also underway to combine T-cell treatment with the immunotherapy drugs called checkpoint inhibitors, which help unleash the cancer-killing power of T cells. There will be many such studies, Dr. Grupp predicted, but, he said, Its early days.

The T cells in the Novartis products, and in the earliest ones its competitors are developing, have been engineered to seek and destroy cells that display on their surfaces a protein called CD19 a characteristic of many leukemias and lymphomas.

Identifying other targets would be a boon, Dr. Grupp said, because sometimes leukemic cells lacking CD19 proliferate, escape the treatment and cause relapse.

Another target is being studied, and Dr. Grupp said the next step, which he called superimportant, would be to attack two cellular targets in the same patient.

In the next year or so, he said, that approach will also be studied in both children and adults who have acute myeloid leukemia, which he described as a tough disease.

Researchers at the University of Texas MD Anderson Cancer Center in Houston are trying a completely different approach to engineering cells, one that they hope might eventually yield an off the shelf treatment that would not have to be tailored to each individual patient and that might be less expensive.

Instead of using T cells, the team uses natural killer cells, another component of the immune system, one that has a powerful ability to fight anything it recognizes as foreign. Instead of extracting the cells from patients, the researchers, Dr. Katy Rezvani and Dr. Elizabeth Shpall, remove the natural killers from samples of umbilical-cord blood donated by women who have just given birth.

They use natural killer cells because T cells from one person cannot be safely given to another, lest they attack the hosts tissue, causing graft-versus-host disease, which can be fatal. Natural killer cells do not cause that deadly reaction, so it is safe to use such cells from a newborns cord blood to treat patients.

The natural killer cells are genetically engineered to attack CD19, and also to produce a substance that activates them and helps them persist in the body. They also have an off switch, a gene that will let the researchers shut down the cells with a certain drug if they cause dangerous side effects that cannot be controlled.

After promising studies in mice, the researchers have opened a study for adults with relapsed or treatment-resistant chronic lymphocytic leukemia, acute lymphocytic leukemia or non-Hodgkin lymphoma. The first patient was to be treated this week, Dr. Rezvani said.

One unit of cord blood yields enough cells to treat five patients, she said, and in two weeks the natural killer cells can be expanded 500-fold, to a billion cells.

We plan to make the product and infuse it fresh to the patient, but we are also working on optimizing the freezing process so we can make the product, freeze it and keep it, so that when patients need it, we can give it.

A version of this article appears in print on July 24, 2017, on Page A1 of the New York edition with the headline: Racing to Alter Patients Cells To Kill Cancer.

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Companies Rush to Develop 'Utterly Transformative' Gene Therapies - New York Times

Philadelphia drug developer Spark Therapeutics said Monday that the Food and Drug Administration has accepted its biologics license application and granted priority review for its lead drug candidate to treat rare inherited blindness.

If approved, the treatment would be the first gene therapy for a genetic disease in the United States.

Sparks treatment, called voretigene neparvovec, streams genes directly into the eyes retina. It has been granted priority review by the FDA because it treats a medical condition where no adequate therapy exists, the company said.

The time frame for possible approval is about six months, around Jan. 12, 2018.

Spark was spun out of Childrens Hospital of Philadelphia, based on decades of research led by Katherine A. High, Sparks co-founder, president, and chief scientific officer.

Its really an exciting moment for medicine, said Spark chief executive officer Jeffrey D. Marrazzo, noting that an FDA panel last week reviewed an experimental T-cell immune therapy being developed by Novartis and the University of Pennsylvania to treat acute lymphocytic leukemia. The original study for the CAR-T cell technology was conductedat Childrens Hospital of Philadelphia, he said.

Spark does not have confirmation, but expects that the FDA may convene an advisory meeting of medical experts in the fall to consider the companys data from three clinical trials, which enrolled 41 participants.

In a late-stage Phase 3 study, 93 percent (27 of 29 participants) had vision improvement and saw restoration of aspects of their functional vision, Marrazzo said.

No serious side effects were reported with the gene therapy itself. Two side effects were reported among 41 participants, due to the surgery, which is an injection in the eye. One participant lost visual acuity, or sharpness of vision. A second participant got a bacterial infection in the eye after the injection.

Patients in an earlier Phase 1 trial have been followed now for four years and continue to maintain their original vision improvement, he added. About 3,500 patients in the U.S. and five large European markets live with the disease. About half, or 1,750, are in the U.S.

Sparks treatment injects particles that are a copy of a normally functioning gene into the back of each eye.

Marrazzo said its too early to set a price. The company hopes the treatment will be a onetime injection, and not a lifetime of treatments, and thus deserves an appropriatepayment.

Were doing a lot of work trying to figure out value of this type of treatment, which could be indicated for restoring sight in kids and adults who otherwise are going to progress to complete blindness, Marrazzo said. Were looking at other rare disease products which are chronically delivered, and whats the value in not having to chronically deliver something for a rare disease.

Spark officials have met with health-care payers, including most large commercial health insurers, to discuss the companys clinical data with the goal of ensuring that patients can have access to the treatment, Marrazzo said. Theres a lot of work still in front of us, but Im very confident and pleased with where we are today in the process.

Spark is also developing treatments for hemophilia A and hemophilia B and for a hereditary retinal degeneration disease, choroideremia, whichusually manifests during childhood in males as night blindness and a reduction of visual field.

Sparks stock closed up $1.29 on Monday, or 2.17 percent, to $60.65.

Published: July 17, 2017 12:22 PM EDT

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Philly biotech's first-ever gene therapy progresses with FDA - Philly.com

(CBS) -- A panel of cancer experts has voted unanimously in favor of a leukemia treatment which could be the first gene therapy available in the U.S.

The Food and Drug Administration advisory panel voted 10-0 on Wednesday to recommend approval of the treatment developed by the University of Pennsylvania and Novartis Corp. The one-time treatment would be for children and young adults with advanced leukemia.

The therapy could be the first of a wave of treatments custom-made to target a patient's cancer. Called CAR-T, it involves removing immune cells from a patients' blood, reprogramming them to create an army of cells to recognize and destroy cancer and injecting them back into the patient.

The FDA is not required to follow the panel's recommendation but often does.

"It's a pretty amazing new treatment," Dr. David Agus, director of the USC Norris Westside Cancer Center and CBS News medical contributor, said on "CBS This Morning." "They take the white [blood] cells out of a child with cancer, they send them to [a lab in] New Jersey, and they put in a gene to reprogram these cells to attack the cancer."

The vote came after lengthy discussion and impassioned pleas from the fathers of two young patients whose lives were saved by the therapy. The one-time leukemia treatment would be for children and young adults with the most common form of childhood cancer, known as ALL.

"Our daughter was going to die and now she leads a normal life," said Tom Whitehead, of Philipsburg, Pennsylvania. His daughter Emily, now 12, was the first child to receive the experimental therapy, five years ago. "We believe when this treatment is approved, it will save thousands of children's lives around the world."

In a key test, results were far better than chemotherapy and even newer types of cancer drugs. Of the 52 patients whose results were analyzed, 83 percent had complete remission, meaning their cancer vanished. Most patients suffered serious side effects. Eleven patients died, four from side effects and seven from their leukemia.

The FDA is expected to decide whether to approve the Novartis treatment in the next few months. The drugmaker is seeking approval to use the treatment for patients aged 3 to 25 with a blood cancer called acute lymphoblastic leukemia whose disease has spread or failed to respond to standard treatment. That happens to more than 600 patients in the U.S. each year. At that point, they have limited options all more toxic than the CAR-T therapy and survival chances are slim. ALL accounts for a quarter of all cancers in children under age 15.

After decades of setbacks and disappointments in efforts to fix, replace, or change genes to cure diseases, several companies are near the finish line in a race to bring CAR-T and other types of gene therapy to patients. Kite Pharma also has a CAR-T therapy under FDA review and Juno Therapeutics and others are in late stages of testing.

In March, CBS News chief medical correspondent Dr. Jon LaPook reported on the results of a clinical trial in which 101 patients with advanced lymphoma who had failed previous therapy received the Kite Pharma CAR-T treatment. About eight months after a single treatment, 39 percent of patients had no evidence of cancer.

"That's actually quite remarkable knowing that at best only one out of 10 of these patients could have complete disappearance of their lymphoma with standard chemotherapy," said Dr. Frederick Locke, who helped lead the trial.

CAR-T therapy starts with filtering key immune cells called T cells from a patient's blood. In a lab, a gene is then inserted into the T cells that prompts them to grow a receptor that targets a special marker found on some blood cancer cells. Millions of copies of the new T cells are grown in the lab and then injected into the patient's bloodstream where they can seek out and destroy cancer cells. Doctors call it a "living drug" permanently altered cells that continue to multiply in the body to fight the disease.

During the patient testing, the whole process took about 16 weeks on average, which can be too long a wait for some desperately ill patients, the FDA advisers noted during Wednesday's meeting in Silver Spring, Maryland. Drug company officials said they can now produce a treatment and get it to a patient in about three weeks.

Novartis said in a statement after the vote that it has long believed CAR-T therapy could "change the cancer treatment paradigm."

"It is encouraging to see the FDA panel's recommendation and continued momentum behind this innovative therapy," said the Penn team's leader, Dr. Carl June.

The cost of CAR-T therapy is likely to be hundreds of thousands of dollars, but it's only given once. Typically, cancer patients take one or more drugs until they stop working, then switch to other drugs, so treatment and side effects can go on for years.

The treatment's short-term side effects, including fever and hallucinations, are often intense as the body's revved-up immune system goes on the attack. The long-term side effects of the treatment are unknown. It's also unclear if patients whose cancer goes into remission will be cured or will have their cancer return eventually. The FDA panel recommended that patients who get the treatment be monitored for 15 years.

Other biotech and pharmaceutical companies are developing types of gene therapy to treat solid cancers and rare gene-linked diseases. A few products have been approved elsewhere one for head and neck cancer in China in 2004 and two in Europe, most recently GlaxoSmithKline's Strimvelis. That was approved last year for a deadly condition called severe combined immunodeficiency and launched with a $670,000 price tag.

UniQure's Glybera was approved for a rare enzyme disorder. It was used only once in five years, likely due to its $1 million-plus price tag, so uniQure is pulling it from the market.

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CAR-T gene therapy for leukemia clears FDA hurdle - Wsaw - WSAW

On July 12, a Food and Drug Administration panel unanimously recommended approval for the first-ever gene therapy treatment for cancer. The treatment, known as CTL019, is a T-cell therapy developed by the pharmaceutical company Novartis. It is tailored for each individual patient and has already been proven effective for treating a type of childhood leukemia. The New York Times reports that in a study of 63 patients, 52 of them went into remission after receiving the treatment.

Researchers have long been working to perfect gene therapy for a variety of cancers, but CTL019 will be the first to reach the market. If the FDA moves to approve CTL019, the decision could open the door for more gene therapy treatments for other diseases.

Mansoor Amiji is University Distinguished Professor inthe Department of Pharmaceutical Sciences at Northeastern. His research focuses on the development of targeted therapies, including gene therapy, for treatment of the most lethal cancers, such as pancreatic, lung, ovarian, and brain tumors, as well as other chronic diseases. For one project, Amijis lab is interested in reprograming immune cells through genetic engineering to become more effective in treating cancer and inflammatory diseases.

Here, Amiji explains more about gene therapy treatment and why the approval of CTL019 would be so significant.

It is still very early to suggest that cancer immunotherapy will lead to the ultimate cure or even long-term control of cancer, says distinguished professor Mansoor Amiji. But the opportunity to use the bodys own defenses to eradicate cancer cells is truly groundbreaking. Photo by Adam Glanzman/Northeastern University

CAR-T cell, or chimeric antigen receptor T-cell therapy, is one of the newer treatment options for cancer. Its based on the patients own immune system. In this approach, the patients T-cells are harvested and then genetically modified outside the body to produce engineered cells. The cells are then re-administered and can destroy the tumor. There have been studies conducted at various medical centers over the past several years, but this is the first time that the FDA committee is allowing a commercial pharmaceutical company to continue with the program, in this case for treatment of pediatric acute lymphoblastic leukemia.

Yes, cancer immunotherapy treatments, including CAR-T cell therapy, have been very successful in cancer treatment. More than 85 percent of patients treated with genetically engineered CAR-T cells are under remission, and that is unprecedented for cancer treatment options. However, it is still very early to suggest that cancer immunotherapy will lead to the ultimate cure or even long-term control of cancer and change it from a death sentence to a treatable chronic disease. But the opportunity to use the bodys own defenses to eradicate cancer cells is truly groundbreaking.

Genetic engineering focuses on using modified cells as drugs. In this approach, the cells are either removed from the body and genetically manipulated outside, such as in CAR-T cell therapy, or genetic constructs are delivered into specific cells in the body. For the latter, the genetic construct has to be packaged in a delivery vehiclenanoparticles, for exampleand be targeted to the right cell in the body. Conventional drugs work by inhibiting a specific molecular target, like a receptor on a cell or an enzyme involved in disease progression. Genetic therapies like CAR-T cell therapy are focused more on the treatment at the DNA or RNA level where the original defects reside. Thats why they can be significantly more effective than conventional therapies, and they also promise to be a lot safer.

The drug development process starts from preclinical discovery and then moves into the clinical phase where patients are treated with experimental methods. Typically, it takes about 10 to 15 years for a drug to go from early discovery up to the approval stage. However, there are exceptions when compelling early-stage clinical results are obtained that encourage the FDA to approve the treatment a lot faster. Also, once a trail-blazing concept like CAR-T cell therapy is approved, there are many other companies that are following behind with their own version of the treatment. Their products will be coming to the marketplace soon as well.

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What makes cancer gene therapy so groundbreaking? - News ... - News@Northeastern