Category Archives: Gene Medicine

PUBLIC RELEASE DATE:

11-Dec-2014

Contact: Michael Petr michael.petr@insilicomedicine.com InSilico Medicine, Inc. @InSilicoMeds

BALTIMORE, December 11, 2014 - Insilico Medicine along with scientists from Vision Genomics and Howard University shed light on AMD disease, introducing the opportunity for eventual diagnostic and treatment options.

The scientific collaboration between Vision Genomics, Inc., Howard University, and Insilico Medicine, Inc., has revealed encouraging insight on the AMD disease using an interactome analysis approach. Resources such as publicly available gene expression data, Insilico Medicine's original algorithm OncoFinderTM, and AMD MedicineTM from Vision Genomics allowed discovery of signaling pathways activated during AMD disease.

"We are thrilled to collaborate with Alex Zhavoronkov and Evgeny Makarev, and their team at InSilico Medicine. Big Data analysis is part of the future of medicine, and with our technique of signaling pathway activation analysis, we will decipher the genetic network alterations that lead to age-related macular degeneration (AMD), and eventually human aging itself", said Antonei Benjamin Csoka, PhD, CEO of Vision Genomics, LLC, and Assistant Professor at Howard University.

The research publication titled "Pathway activation profiling reveals new insights into Age-related Macular Degeneration and provides avenues for therapeutic interventions" was accepted by one of aging research's top-rated journals "Aging", detailing these findings and methodology. This study not only validates the efficacy of interactome analysis within aging, but also allows the investigation of cellular populations within AMD models.

"We are happy to collaborate with Antonei Benjamin Csoka's teams at both Vision Genomics and Howard University on this exciting project. Coupling Big Data with advanced signaling pathway activation analysis may help find new therapeutic approaches for age-related macular degeneration (AMD), a disease that holds many keys to understanding human aging", said Evgeny Makarev, PhD, Director of Aging Research at Insilico Medicine.

On December 9th Insilico Medicine, Inc announced the appointment of 2013 Nobel Laureate in Chemistry, Michael Levitt, to its Scientific Advisory Board. Dr. Levitt's background in computational modeling focused on understanding protein folding processes and molecular interactions, may turn to be extremely valuable for compound discovery related to AMD and other age-related diseases. The concept utilized by Insilico Medicine involves identifying the difference between several signaling states on a tissue-specific level, be it health and disease, or young and old, and evaluating a large number of drugs and drug combinations that can modulate the difference using advanced parametric and machine-learned algorithms. "To create more value from our predictions we will need to identify compounds that are even more effective than top-scoring drugs and that would require multi-scale modeling of macromolecules, the field pioneered by Dr. Michael Levitt ", said Alex Zhavoronkov, PhD, CEO of Insilico Medicine, Inc. Insilico Medicine continues to be represented from top institutions, including Stanford University, Johns Hopkins University, and New York University. With this broad range of expertise, Insilico and its collaborators will pursue AMD disease further and utilize the newly discovered activated pathways as a foundation.

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New discoveries in age-related macular degeneration revealed in industry and academia

Targeted therapies are a growing and groundbreaking field in cancer care in which drugs or other substances are designed to interfere with genes or molecules that control the growth and survival of cancer cells. Now, scientists at Virginia Commonwealth University Massey Cancer Center and VCU Institute of Molecular Medicine (VIMM) have identified a novel interaction between a microRNA and a gene that could lead to new therapies for the most common and deadly form of brain tumor, malignant glioma.

In a study recently published in the journal Neuro-Oncology, a team of scientists led by Luni Emdad, M.B.B.S., Ph.D., and Paul B. Fisher, M.Ph., Ph.D., provided the first evidence of an important link between a specific microRNA, miR-184, and a cancer promoting gene, SND1, in the regulation of malignant glioma. miR-184 is known to suppress tumor development by regulating a variety of genes involved in cancer growth, while SND1 has been shown to play a significant role in the development of breast, colon, prostate and liver cancers. Through a variety of preclinical experiments, the team demonstrated that increasing the expression of miR-184 slows the growth and invasive characteristics of glioma cells through direct regulation of SND1. Additionally, they showed that reduced levels of SND1 led to reduced levels of STAT3, a gene that has been shown to promote the most lethal characteristics of brain cancer.

"Patients suffering from brain tumors are in desperate need of improved therapies," says Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, chairman of the Department of Human and Molecular Genetics at VCU School of Medicine and director of the VIMM. "We're hopeful that this new understanding of the relationship between miR-184 and SND1 ultimately will lead to the development of new drugs that reduce SND1 expression and improve patient outcomes."

Prior studies have shown that levels of miR-184 are unusually low in tissue samples from patients with malignant gliomas. Using advanced computer analysis techniques designed to study and process biological data, the researchers identified SND1 among a handful of other genes that miR-184 helps regulate. Knowing SND1 is implicated in a variety of cancers and having previously defined its role in liver cancer, Emdad, Fisher and their colleagues explored this relationship further. They confirmed low levels of miR-184 expression in human glioma tissue samples and cultured cell lines as well as an increase in the expression of SND1 compared to normal brain tissue. Using data from a large public brain tumor database called REMBRANDT, the researchers confirmed that patients with lower levels of SND1 survived longer than those with elevated SND1 expression.

"We still have a long way to go and many challenges to overcome before we will have therapies that are ready for clinical use, but this is a significant first step in the process," says Emdad, member of the Cancer Molecular Genetics research program at Massey, assistant professor in the VCU Department of Human and Molecular Genetics and member of the VIMM. "Future studies will aim to explore the relationship between SND1 and STAT3, identify additional microRNAs that may be relevant to malignant glioma and explore the effects of drugs that block SND1 expression in more advanced preclinical models."

Story Source:

The above story is based on materials provided by Virginia Commonwealth University. Note: Materials may be edited for content and length.

Excerpt from:
Important gene interaction defined that drives aggressive brain cancer

Andrea Deng

China Daily

Publication Date : 11-12-2014

Targeted therapy was proved effective against a critical mutated gene found in some lung cancer patients. The milestone in lung cancer treatment was achieved by an oncologist at Chinese University of Hong Kong (CUHK).

Molecular targeted treatment, using a medicine called Crizotinib to attack mutated gene EML4-ALK, proved to produce more dramatic effect than standard chemotherapy, said CUHK clinical oncologist Tony Mok Shu-kam on Wednesday (Dec 10).

CUHK oncologists have recommended EML4-ALK test for every lung cancer patient, so that they may choose targeted therapy as a more effective treatment, in the event of testing positive.

Mok worked with Australian expert Benjamin Solomon between 2011 and 2013 to study the effect on 343 stage-four lung cancer patients in 27 countries and regions. Patients were equally divided into two groups, one undergoing standard chemotherapy and the other taking Crizotinib. The study showed that those who received targeted therapy usually lived longer than those subjected to standard chemotherapy.

While a large number of patients of both groups managed to survive for five months, only two out of 171 patients exposed to standard chemotherapy survived 20 months, while only 19 out of the 172 people undergoing targeted therapy did so.

Some of the patients who received Crizotinib are still alive, after more than two years.

Read more from the original source:
Chinese University of Hong Kong oncologist in cancer 'breakthrough'

Ethical questions are crucial, but they shouldnt stall the progress of this promising branch of medicine

In late November, Reuters reported a milestone in medical history: a gene therapy drug could go on sale in Germany next year, after winning the approval of European regulators two years ago. The drug, Glybera, by a Dutch firm called UniQure currently being scrutinised by Germanys federal joint committee would be the first commercial use of gene therapy in the Western world (China has had a gene therapy drug for a specific form of cancer in the market since 2004). This marks a potential turning point in an area of medicine that has been the subject of highs and lows over more than two decades of clinical trials.

Gene therapy which can involve a number of things, including replacing a malfunctioning gene or introducing a new gene with the ability to fight a disease has been in conceptual development for far longer. Its origins could be said to go back as early as the 1920s, well before the discovery of the structure of DNA, when a British scientist, Frederick Griffith, put forward what he described as the transforming principle; he successfully converted a non-virulent strain of bacteria into a virulent one, after injecting mice with both.

From the late 1960s, when the concept of gene therapy began to involve, it took several decades for the first clinical trial to take place in 1990. A young girl in the US with a genetic defect that had left her with a severely weakened immune system was successfully injected with her own white blood cells containing a corrected form of the malfunctioning gene.

However, the boost gene therapy got following that first successful trial was soon tarnished, in the view of the public, by a tragedy in 1999; an 18-year-old American boy, who had a mild version of a liver condition, which meant his body couldnt process ammonia, died during a gene therapy treatment. This was after a massive response by his immune system to the vector or carrier used to introduce the corrected gene.

The episode raised a number of issues including that of informed consent of those participating in clinical trials as well as the fact that identifying and correcting a defective gene was far from the only challenge facing gene therapy. Selecting the appropriate vector was also vital and not without risks.

Despite predictions that gene therapy would be lastingly damaged by the tragedy, research and trials continued with many promising results for a range of conditions ranging from immune system conditions to cancer, cystic fibrosis, Parkinsons disease and hemophilia.

The renewed confidence in gene therapy is highlighted by the fact that the worlds largest pharmaceutical companies have also entered the market (earlier this week, Pfizer announced collaboration with Spark Therapeutics, a Philadelphia based company on the development of a hemophilia B treatment).

Over 1,700 approved gene therapy trials have taken place in the past two decades, estimated an article on the history of gene therapy in Gene magazine last year with many successes and a few hits. Among the latter were trials conducted in France in 2001 on Severe Combined Immunodeficiency, a condition where the immune system is so crippled that in one case it required a boy to live in a germ-free bubble. Several infants involved in the trial subsequently developed leukemia, though other clinical trials for gene therapy since have been successful.

There have been some understandable public concerns about gene therapy and its impact on the one hand it offers that tantalising potential of curing some of the most lethal conditions while on the other, tampering with genetic makeup is something that has long conjured up fears in the public imagination of genetic engineering and exacerbating discrimination against those with disabilities and disease.

See more here:
Gene therapy makes a slow comeback

Published December 10, 2014

A new study on gene expression in brains affected by autism revealed a shared pattern of ramped-up immune responses that researchers say may lead to possible treatment options for some symptoms of the developmental disorder.

Researchers from John Hopkins and the University of Alabama at Birmingham analyzed data collected from 72 autopsied autism and control brains. The findings, published in the journal Nature Communications, focused on samples from two different tissue banks and compared the gene expressions in people with autism to that in controls without the condition.

The study used the largest data set so far in a study of gene expression in autism. Dr. Dan Arking, associated professor in the McKusick-Nathans Institute for Genetic Medicine at Johns Hopkins University School of Medicine said that previous studies of whether and how much genes were being used in brains with autism involved too little data to draw conclusions. Arking said the scarcity of data was because gene expression testing can only be performed on the specific tissue.

Earlier studies pinpointed autism-associated abnormalities in cells that support neurons in the brain and spinal cord, but in this study Arkings said the team was able to target a specific support cell called the microglial cell, which polices the brain for pathogens. In the group with autism, the microglia appeared to be perpetually activate with their genes for inflammation responses remaining turned on, according to the news release.

This type of inflammation is not well understood but it highlights the lack of current understanding about how innate immunity controls neural circuits, Dr. Andrew West, associated professor of neurology at the University of Alabama at Birmingham said in the news release.

Arking notes that inflammation is unlikely to be the root cause of autism.

There are many different ways of getting autism, but we found that they all have the same downstream effect, Arking said in the news release. What we dont know is whether this immune response is making things better in the short term and worse in the long term.

The researchers say the next step would be to find out if treating the inflammation improves symptoms of autism.

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Brain inflammation a shared trait in autism, study finds

The globally recognised medicine company, Pfizer (PFE), announced the agreement with privately held U.S. company, Spark Therapeutics to find a drug to treat haemophilia by adopting the gene therapy platform. Pfizer has been focusing on introducing drugs for treatment of rare diseases for more than a decade now and it has a global portfolio of 22 medicines approved worldwide that treats rare diseases in the areas of hematology, neuroscience, inherited metabolic disorders, pulmonology and oncology. This candid move will mark Pfizers expansion into the field of gene therapy in the latest sign that the technology for fixing faulty genes may finally be ready for prime time, following earlier setbacks. Lets dive in and find out what benefits Pfizer would get from the association and what it wants to achieve in this new domain of interest.

The collaboration with Spark

On December 8, the U.S. drug maker made public that it is establishing a gene therapy platform to study potential treatments, led by a top UK expert, and has struck a deal with privately owned U.S. biotech firm Spark Therapeutics to develop a treatment for haemophilia. The Spark program is expected to enter early stage clinical trials for haemophilia B in the first half of the coming year. The biotech firm would be responsible for the Phase I/II tests, with Pfizer taking over the late-stage studies, any regulatory approvals and potential commercialisation. Spark would be entitled to receive double-digit royalties based on global product sales.

Spark would be given $20 million upfront and would be eligible for additional payments based on product success worth up to $260 million. Through this global collaboration development of SPK-FIX would be tried out, which could lead to potential treatment of haemophilia B. CEO of Spark, Jeffrey D. Marrazzo, shared, We are excited to announce our collaboration with Pfizer, as we believe it marks an important step towards bringing a potentially life-altering therapeutic to patients with hemophilia B. The collaboration also marks another milestone for Spark, following our recent clinical and regulatory progress and key leadership hires."

Why the drug is vital for treatment

Haemophilia B is a rare genetic blood disorder that affects approximately 4,000 males in the U.S. and about 26,000 males worldwide. Current treatment is painful requiring recurrent intravenous infusions of either plasma-derived or recombinant Factor IX to control bleeding episodes. Sparks proprietary, bio-engineered vectors are designed to deliver a high-activity Factor IX gene to patients, allowing endogenous production of Factor IX, with the potential to remain effective for a number of years.

This program leverages a long track record of haemophilia B gene therapy research and clinical development conducted by Sparks scientific team over the past two decades. Sparks scientists are of this opinion when they commented on the association with Pfizer: Pfizer's longtime experience in hemophilia, including strong relationships with physicians, patients and payors, as well as clinical, regulatory and commercial capabilities, will complement our team's deep knowledge of AAV-mediated gene transfer for the disease. We look forward to working with Pfizer with the goal of making gene therapy for hemophilia B a reality for patients.

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Pfizer Spreading Its Wings Into A New Domain Of Life Sciences

SAN FRANCISCO (TheStreet) -- Bluebird Bio (BLUE) has now treated seven beta-thalassemia patients with its experimental, one-time gene therapy. Four of the patients -- all followed for longer than three months -- are producing enough oxygen-carrying hemoglobin on their own to eliminate the need for chronic blood transfusions.

Two of these super-responding beta-thalassemia patients -- followed for a year and nine months, respectively -- have hemoglobin levels of healthy adults. At this point, a single infusion of Bluebird's gene therapy has essentially cured them of this serious, inherited blood disease.

The remaining three beta-thalassemia patients were infused with Bluebird's gene therapy around one month ago so it's too early to assess their response. A single patient with sickle cell disease was also just treated within the past month.

It's still unreasonable to expect an equivalent strong response in every patient, but Bluebird is learning that as its therapy replaces the defective gene causing beta-thalassemia (or sickle cell disease) with a gene that is fully functional, the patient's ability to produce normal-functioning hemoglobin improves over time, said CEO Nick Leschly.

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Bluebird Gene Therapy Inducing Durable Cures in Blood Disorder Patients

PUBLIC RELEASE DATE:

7-Dec-2014

Contact: Glenna Picton picton@bcm.edu 713-798-7973 Baylor College of Medicine @bcmhouston

HOUSTON - (Dec. 7, 2014) - An international consortium of researchers led by Baylor College of Medicine has identified for the first time a gene associated with familial glioma (brain tumors that appear in two or more members of the same family) providing new support that certain people may be genetically predisposed to the disease.

"It is widely thought amongst the clinical community that there is no association between family history and development of glioma. Because we know very little about the contributing genetic factors, when cases occur in two or more family members, it is viewed as coincidental," said Dr. Melissa Bondy, associate director of cancer prevention and population sciences at the NCI-designated Dan L. Duncan Cancer Center at Baylor College of Medicine and lead author of the report that appears in the Journal of the National Cancer Institute today. "By understanding more about the genetic link, we hope that one day we can improve treatments and preventive strategies for those with a family history of glioma."

Bondy estimates that approximately five percent of brain tumors run in families.

The study was conducted through the Gliogene Consortium, a collaborative group of familial brain tumor researchers from around the world, which is primarily supported with funding from the National Cancer Institute.

"I have been researching familial glioma for nearly 30 years, and this study is really the first time we have had a hit when it comes to identifying a gene that is potentially associated with predisposition to the disease," said Bondy, principal investigator of the Gliogene Consortium.

The Gliogene Consortium recruited 435 families in which glioma occurred from 14 centers in the United States, Sweden, Denmark, The United Kingdom and Israel. The recruitment occurred between 2007 and 2011 while Bondy was on faculty at The University of Texas MD Anderson Cancer Center. She joined the Baylor faculty in September 2011.

Once at Baylor, Bondy collaborated with experts in the College's Human Genome Sequencing Center to advance research of the genetics of the disease.

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New study identifies first gene associated with familial glioma

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Newswise Scientists at Penn State College of Medicine, working alongside an international team of researchers, have produced the most complete encyclopedia of functional elements in the mouse genome to date and compared it to the human genome. The findings, published recently in Nature, uphold the mouse model of human disease, but pinpoint important differences in gene expression that will guide future health research.

Mice are the premier model organism for research into human health and disease because they share most of their protein-coding DNA with us. However, only a small fractionless than 2 percentof human and mouse DNA is used to code the building blocks of life. The regulatory elements in our DNA that control the expression of these genes are equally important, if not more so, to disease development and progression, and our understanding of it.

Using high-throughput DNA sequencing techniques, the research team looked at these functional elements in more than 1,000 data sets produced from over 100 mouse cell types and tissues. They were able to assign potential regulatory functions to 12.6 percent of the mouse genome. They then compared these elements and their functions to those of humans.

"This is the most comprehensive effort to do a genomic comparison between humans and mice at this level, including the regulatory elements and gene expression," said Feng Yue, an assistant professor in the department of biochemistry and molecular biology at Penn State College of Medicine. "We looked at regulations of genes, rather than genes themselves, and whether the gene is expressed in certain tissues or how much the gene is expressed there. We wanted to learn which gene expression patterns were conserved between humans and mice during mammalian evolution, and which gene expression patterns diverged."

Major similarities, but also important differences, emerged.

Although much similarity exists, mouse and human gene expression differs significantly in specific biological pathways.

"What we found is that the majority of the gene expression patterns are very similar in human and mouse," Yue said. "That shows that, indeed, the mouse is a good system to use in the study of human disease.

"But there are some genes whose patterns are not quite conserved between human and mouse," he continued. This divergence was most profound for areas of the mouse genome involved in the immune system and metabolic processes. "These genes may function in a different way between human and mouse."

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Mouse Model of Human Disease Still Good, but Significant Differences Exist

BETHESDA, Md., Dec. 4 (UPI) -- Two is often better than one, but not when it comes to the DNA and RNA that make up the human chromosome. Researchers now believe gene duplication in a specific region, key in the regulation of childhood growth, is responsible for the rare disorder known as gigantism.

"Finding the gene responsible for childhood overgrowth would be very helpful, but the much wider question is what regulates growth," Constantine Stratakis, lead author of the new study, said in a press release.

Gigantism is a rare medical condition whereby children grow rapidly. Those affected typically grow to be abnormally tall; gigantism patients may also have delayed puberty, outsized hands and feet, and double vision.

To locate the offending genes, researchers at the National Institutes of Health used whole-genome analysis to study the DNA of 43 people with gigantism. The chromosomes of those afflicted with the rare disorder were then compared to family members who were born without the defect.

The analysis showed that gene duplication varied among the study participants, but researchers were able to narrow down the offending portion of the X chromosome to a stretch containing four duplicated genes. Scientists determined the gene most likely responsible for gigantism was GPR101.

"We believe GPR101 is a major regulator of growth," Stratakis said.

The gene duplication that causes gigantism results in a malfunctioning pituitary, the pea-sized gland that produces growth hormones. Researchers found activity of GPR101 was up to 1,000 times stronger than normal in children with enlarged and overactive pituitary glands.

The research was published this week in the New England Journal of Medicine.

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Duplication of gene on X chromosome causes gigantism