Gene Therapy Proves Effective in Treating Severe Heart Failure; Holds Potential to Drastically Reduce Healthcare Costs for Heart Failure Patients

/PRNewswire/ -- The 14th Annual Scientific Meeting of the Heart Failure Society of America (HFSA) will feature a discussion titled "Latest Developments in Stem Cell and Gene Therapy in Heart Failure" which includes a presentation by Dr. Roger Hajjar, Director of the Cardiovascular Research Institute, one of the 12 translational science institutes at The Mount Sinai Medical Center in New York. Dr. Hajjar's discussion will focus on the injection of a gene into patients with advanced heart failure to reverse the debilitating and life-threatening condition.

Over ten years, Dr. Hajjar and his team have validated the cardiac sarcoplasmic reticulum calcium ATPase pump, SERCA2a, as a target in heart failure and developed methodologies for cardiac-directed gene transfer. This work has led to the initiation and recent completion of phase 1 and phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure.

Patients treated with high dose therapy have shown 90 percent risk reduction for heart failure-related cardiovascular events such as significantly worsening health, the need for a transplant or cardiovascular device support, intravenous treatment or death.

"The patients receiving this gene therapy have shown marked improvements," said Dr. Hajjar. "Through our tests we've observed heart failure patients' quality of life improves greatly for significantly less cost than traditional therapies."

Patients treated with the gene therapy treatment may result in a large decrease in personal health care costs across their trial period. In nine months, individuals treated with the trial's placebo spent an average of $27,118 on health care, paying for expenses such as hospital stays, emergency medicine, and home care. Comparatively, in the same period of time, individuals treated with gene therapy spent an average of $329 on health care.

"Gene Therapy is a breakthrough in the treatment of heart failure patients that holds the potential to reverse the disease while also making treatment and recovery more affordable than ever," said Dr. Douglas Mann, HFSA President. "It is critical for the medical community to continue to integrate science and clinical medicine so biomedical research can improve patient care."

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Epilepsy Organizations Award Grants for New Gene Therapy to Treat Epilepsy and Novel Surgical Intracranial EEG to Detect Seizures in Uncontrolled Patients

/PRNewswire/ -- The Epilepsy Therapy Project (ETP) and the Epilepsy Foundation (EF) today announced the latest grant recipients of its New Therapy Grants Program, a unique joint venture of the non-profit epilepsy organizations, to advance promising epilepsy research in clinical development. The grant awards, totaling approximately $200,000 in funding, will support an experimental gene therapy that directly targets epileptogenic brain tissue, as well as an electrode system that has the potential to improve the efficacy of surgical therapies for certain epilepsy syndromes.

"Patients need new options to treat and manage epilepsy, and through this grant program we are excited to see such remarkable innovation in the field. The fields of gene therapy and surgical treatment of epilepsy remain cutting-edge with much to be explored in terms of advancing epilepsy treatment outcomes," said Orrin Devinsky, MD, ETP Co-Founder and Vice President for Translational Programs, Professor of Neurology, Neurosurgery, and Psychiatry, and Director, NYU Comprehensive Epilepsy Center, New York University. "By choosing to support these two promising programs, we hope to see important strides made while encouraging researchers and companies to pursue new ideas and approaches in epilepsy and seizure conditions."

The New Therapy Grants program grants are designated to facilitate the advancement of new treatments through critical early-stage clinical development or to bridge the gap from preclinical to clinical development to ensure patients will have the opportunity to benefit from groundbreaking progress in the field of epilepsy. The award committee, which is comprised of clinical, scientific and industry representatives, evaluates applications to support new therapeutic approaches submitted by highly qualified clinical experts and scientists with the greatest potential for near-term patient benefit.

"The need and market opportunity for new therapies in epilepsy is unmistakable," said Warren Lammert, Chairman of the Epilepsy Therapy Project. "One third of the people with epilepsy live with uncontrolled seizures despite all available therapies and perhaps another one third achieve seizure control but at the price of unacceptable side-effects including fatigue and impact to cognition. Yet moving promising ideas out of research labs and on through the process of clinical and commercial development is an enormously expensive process with miniscule odds of success for each individual project. Further, epilepsy therapy development has been neglected by government and private funding sources, and current economic uncertainties have further diminished the availability of risk capital. In this environment, the importance of our New Therapy Grants in moving the most promising new research ideas across the starting line on to a path of clinical development cannot be overstated. My hope is that we can mobilize increased support and expand this vital program so necessary to improving the lives of people living with epilepsy."

"These research projects represent the essence of translational research and the focus of our New Therapy Grants Program," said Joyce Bender, chair of the Epilepsy Foundation board of directors. "We proudly applaud our grant recipients because their studies may provide new treatment options, which could lead to an improved quality of life for the nearly 3 million people in the United States and 50 million people worldwide living with epilepsy."

The Grant Recipients

Galanin Gene Delivery to the Hippocampus for Mesial Temporal Lobe Epilepsy

-- Prospect of one-time gene therapy that produces anti-convulsant and
neuroprotective benefits
-- Experimental therapy may offer less invasive therapeutic option and a
prospective paradigm shift in patient care for certain forms of
epilepsy


Scott McPhee, Ph.D., Vice President of Clinical Development, Asklepios BioPharmaceutical Inc., and Nicholas Boulis, M.D., Assistant Professor, Neurosurgery, Emory University, will be conducting preclinical studies of a Galanin gene delivery for selected patients with uncontrolled Mesial Temporal Lobe Epilepsy (MTLE). Direct delivery of a gene therapy to the temporal lobe offers the significant potential of a less invasive, more effective alternative approach that precludes the trauma and resulting complications of surgical tissue removal, and avoids the side effects of standard pharmacological treatments. The protein galanin has been shown to suppress seizures. Gene delivery of galanin DNA has been shown to have anticonvulsant and neuroprotective effects in models of MTLE. Unlike traditional anti-epileptic medications, galanin gene delivery may be administered in a one-time intervention that provides long-term supplemental galanin in the epileptogenic tissue. The proposed therapeutic approach represents a paradigm shift in the treatment of epilepsy because gene delivery offers to locally regulate activity rather than destroying tissue. In addition, it has the unique and significant potential to one day provide a strategy for the treatment of critical brain tissue in which tissue removal is not currently a therapeutic option. These experiments may not only provide a unique opportunity for the development of novel epilepsy therapies but may also advance the cause of neurological gene therapy in general.

The preclinical research outlined by the grant recipients is expected to support the filing of an

Investigational New Drug (IND) Application for a Phase I clinical trial. Funding of the preclinical protocol is subject to appropriate institutional review and approvals, as well as securing the additional financial support needed to complete the research.

Intracranial EEG Acquisition System with Online Fast Ripple Detection

-- New technology to refine how surgeons will identify and define
epileptogenic regions of the brain
-- Potential to improve surgical outcomes and broaden viability of
treatment for certain epilepsy syndromes


A Columbia University Medical Center research team headed by Catherine Schevon, M.D., Assistant Professor, Neurology, received funding to support the refinement of an intracranial EEG recording system, an online detection system to better define the epileptogenic region of the brain, the area of the brain related to seizure activity, before therapy or surgery.

Surgical excision of the epileptogenic brain region is an important treatment modality for medically refractory partial epilepsy, with greater than 60 percent or more of patients achieving seizure freedom. The success rate is notably worse, however, when a structural lesion cannot be identified, and may be as low as 35 percent in patients with extratemporal non-lesional syndromes. In these cases, the resection choice depends almost entirely on accurate interpretation of the intracranial EEG (iEEG), obtained by recording from electrodes implanted directly onto the brain surface or into the parenchyma. Recognizing these limitations surgical therapy for extratemporal epilepsy syndromes is not currently recommended for widespread clinical use.

High frequency oscillations (HFO) in the brain can identify areas for epilepsy surgery treatments, but are technically difficult to detect, largely limiting their clinical utility. Grant funding will be applied to the development of this new system to bring automatic online HFO detection into clinical practice, making current surgical treatments more effective, and potentially simplifying surgeries for many epilepsy syndromes. By increasing the specificity of the identification of the epileptogenic region, seizure outcomes can be improved while the area of brain that must be removed is minimized.

Upcoming Grant Applicants: Note Deadline for Letter of Intent is September 3, 2010

The New Therapy Grants Program is requesting proposals from scientific and clinical investigators pursuing innovative projects that demonstrate a clear path to commercialization. The program accepts the submission of proposals ranging from $50,000 to $500,000. The deadline to submit a Letter of Intent (LOI) is September 3, 2010. Applicants who have an accepted LOI have until October 15, 2010, to submit their full proposals. To view additional requirements, please visit http://www.epilepsy.com/etp/support_translational.

The New Therapy Grants Program is a unique partnership between two leading epilepsy non-profit organizations, the Epilepsy Therapy Project and the Epilepsy Foundation. The mission of the New Therapy Grants Program is to drive the development of new therapies for epilepsy, accelerating the advancement of research from the laboratory to the patient. Funding is provided for grants supporting the research and development of new therapies in both academic and commercial settings worldwide.

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Type 2 Diabetes Gene Predisposes Children to Obesity

/PRNewswire/ -- Pediatric researchers have found that a gene already implicated in the development of type 2 diabetes in adults also raises the risk of being overweight during childhood. The finding sheds light on the genetic origins of diabetes and may present an avenue for developing drugs to counteract the disease, which has been on the upswing in childhood and adolescence.

Researchers from The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine published the study Nov. 23 in the online version of the journal Diabetes.

"It has been a bit of a mystery to scientists how or even if these adult diabetes genes function during childhood," said study leader Struan F.A. Grant, Ph.D., a researcher and associate director of the Center for Applied Genomics of The Children's Hospital of Philadelphia. "This finding suggests that there may be genetic activity during childhood that lays the foundation for the later development of type 2 diabetes."

Type 2 diabetes occurs either when the pancreas produces too little insulin, or when the body cannot efficiently use the insulin that is produced because the cells have become resistant. Formerly called adult-onset diabetes and still most common in adults, type 2 diabetes has been increasing sharply among children and teenagers.

Grant and study co-leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at Children's Hospital, investigated 20 gene variants, known as single nucleotide polymorphisms (SNPs), previously reported to be associated with type 2 diabetes. The researchers drew on a cohort of nearly 7,200 Caucasian children, aged 2 to 18 years, in an ongoing genome-wide association study of childhood obesity at Children's Hospital. Dividing the cohort randomly in half allowed the team to follow their discovery study with a replication study.

Researchers continue to unravel the complicated role of different diabetes-related genes in influencing body weight toward both lower and higher ends of the scale. The risk of developing type 2 diabetes in adulthood is often influenced by factors in the first year of life, including lower birth weight, as well as by higher body mass index (BMI) during childhood. Obesity is a well-known risk factor for type 2 diabetes.

A previous study earlier this year by the same study team found that another type 2 diabetes gene, CDKAL1, affects fetal growth and increases the likelihood that a baby will be underweight at birth.

The current study found that the gene HHEX-IDE does not affect birth weight, but makes it more likely that a child will become obese during childhood. The gene does not appear to predispose to obesity in adults, although by contributing to childhood obesity, it may set the stage for type 2 diabetes in adulthood.

Grant cautioned that HHEX-IDE accounts for only a small proportion of the genetic contribution to the risk of type 2 diabetes, so many other gene variants remain to be discovered. However, he adds, HHEX-IDE may represent an important underpinning of the disease. "Previously we thought that this gene affects insulin production during adulthood, but we now see that it may play an early role in influencing insulin resistance through its impact on body size during childhood," said Grant. "One implication is that if we can develop medicines to target specific biological pathways in childhood, we may be able to prevent diabetes from developing later in life."

The National Institutes of Health, the Cotswold Foundation and The Children's Hospital of Philadelphia supported this study.

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Mutant Genes in High-Risk Childhood Leukemias Identified

/PRNewswire / -- A research team has pinpointed a new class of gene mutations, which identify cases of childhood acute lymphoblastic leukemia (ALL) that have a high risk of relapse and death. The finding suggests specific drugs that could treat this high-risk leukemia subtype in children, particularly because such drugs are already in clinical trials for similar blood diseases in adults.

While the cure rate in pediatric ALL has reached about 85 percent, the remaining high-risk cases have proven especially intractable because they arise from different, unidentified genetic mutations.

Discovery of the mutations was led by scientists from St. Jude Children's Research Hospital, the Children's Oncology Group (COG), the University of New Mexico Cancer Research and Treatment Center, Albuquerque, N.M., and the National Cancer Institute (NCI), part of the National Institutes of Health (NIH). This research was done as part of the NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which seeks to utilize the study of genomics to identify therapeutic targets in order to develop more effective treatments for childhood cancers. The article appears online May 18 in the early edition of the Proceedings of the National Academy of Sciences.

"We have made such great progress in curing children with ALL that the main challenge is now the remaining high-risk patients," said St. Jude Scientific Director, James Downing, M.D., a co-senior author of the study. "We still do not know how to accurately identify these patients and effectively treat them to provide the highest chance for a cure. The problem is that this high-risk group is likely a heterogeneous mixture of biologic subtypes."

The new study builds on the researchers' previous genetic analysis of the leukemic cells from pediatric ALL patients.

"The findings from our previous studies have hinted that some high-risk ALL cases might arise from mutations in genes that produce enzymes called kinases, which function as biological on-off switches in cells," said Charles Mullighan, M.D., Ph.D., assistant member in the St. Jude Department of Pathology and a co-first author of the study. "Such mutations would cause those kinases to be stuck in the on position, triggering the uncontrolled proliferation of white blood cells that is seen in leukemia."

Thus, the researchers began to analyze the genetic sequences of many kinases known to be components of the proliferation machinery of white blood cells. The team analyzed the leukemic cells from 187 patients with high-risk ALL. That analysis revealed mutations in about 10 percent of the cases in a family of protein kinases called JAK, whose members were also known to be mutated in other types of leukemias and related diseases.

"Further studies of these mutant JAK proteins revealed that the changes in their molecular structures could switch them on to drive the blood cell proliferation that is characteristic of ALL," said Stephen Hunger, M.D., chairman of the COG ALL committee and a co-senior author of the study. "What's more, in test tube studies, we found that drugs blocking the activation of the mutant JAK kinases prevented uncontrolled growth suggesting that drugs that target JAK proteins might be effective in this subtype of ALL."

The researchers discovered, in some high-risk ALL patients, that mutations in JAK appeared to work in concert with another mutation -- in the gene IKZF1 -- which they had earlier found to underlie such cases.

"Our studies of these leukemia subtypes indicate that leukemia is not necessarily a single-cause disease," said Cheryl Willman, M.D., director and CEO of the University of New Mexico Cancer Research and Treatment Center and a co-senior author of the study. "A patient may have multiple different genetic lesions that target different cellular pathways to induce leukemia. Thus, it is very important to develop new therapies that target these specific mutations, and our discovery of JAK as target now allows us to begin to develop clinical trials with JAK inhibitors for children and adults with this form of disease."

In further studies, the researchers plan to identify mutations in kinase genes and other enzymes that underlie high-risk ALL, as well as explore how these abnormalities might work together to drive the cancers.

The discovery that mutations in JAK underlie some cases of high-risk ALL is enough to warrant clinical trials of inhibitory drugs to treat such cancers.

"JAK-inhibiting drugs are now moving into clinical trials for treatment of such adult myeloproliferative diseases as polycthemia vera, essential thrombocytosis and primary myelofibrosis," Downing said. "We expect that there will soon be initial clinical studies to assess the safety and effectiveness of these drugs in children with relapsed ALL in which JAK mutations have been identified within their leukemic cells."

Such studies would be coordinated by the COG, an international clinical trial cooperative group supported by the NCI.

Other authors of the paper are Racquel Collins-Underwood, Letha A. Phillips, Xiaoping Su, Wei Liu and Brenda Schulman (St. Jude); Sarah Tasian and Mignon Loh (University of California San Francisco); Meenakshi Devidas (Children's Oncology Group); Susan Atlas, I-Ming Chen and Richard C. Harvey (University of New Mexico Cancer Research and Treatment Center, Albuquerque); Robert J. Clifford, Daniela Gerhard, Malcolm Smith and Jinghui Zhang (National Cancer Institute); William Carroll (New York University Cancer Institute); and Gregory H. Reaman (The George Washington University).

This research was supported in part by a supplement to the Children's Oncology Group Chair's award; a National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures Program award; the National Institutes of Health/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database; National Institutes of Health Cancer Center Core Grants; the Children's Oncology Group and Statistical Center; the Leukemia and Lymphoma Society Specialized Center of Research grant supporting University of New Mexico Cancer Center; CureSearch; St. Baldrick's Foundation; a National Health and Medical Research Council (Australia) CJ Martin Traveling Fellowship; and ALSAC.

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