Patients on drug had significant weight gain, reduced sweat chloride and were less likely to experience a pulmonary exacerbation

Bethesda, MD /PRNewswire-USNewswire/ – The Cystic Fibrosis Foundation and Vertex Pharmaceuticals announced today that VX-770, an oral medicine in development that targets the defective protein that causes cystic fibrosis, showed promising results in a Phase 3 clinical trial.

The trial was designed to evaluate patients age 12 and up who carry at least one copy of a CF mutation called G551D. The study included 161 patients who received at least one dose of VX-770 or placebo.

Patients who took the drug, compared to those on placebo, showed a marked improvement in lung function at 24 weeks, which was sustained for the duration of the 48-week trial.

Patients also showed improvement across all key secondary endpoints in the study, including reduced likelihood of experiencing a pulmonary exacerbation, decreased respiratory symptoms and improved weight gain. each of these areas is critically important to the health of people with CF.

In addition, average sweat chloride levels of patients on VX-770 dropped toward normal levels, while those on placebo did not change—indicating the drug is impacting the underlying defect in CF. Excessive sweat chloride (salt) is a key clinical indicator of CF.

VX-770 is being developed by Vertex, and was discovered in collaboration with the CF Foundation, which provided substantial support to Vertex throughout the development process, including an approximately $75 million investment.

About four percent of people with CF carry the G551D mutation. more studies are needed to determine whether other CF mutations may benefit from VX-770.

“These results are highly encouraging. They provide scientific evidence that support our long-standing belief that targeting the underlying defect of CF may have a profound effect on the disease,” said Robert J. Beall, Ph.D., president and CEO of the Cystic Fibrosis Foundation. “We have much more to do to end the suffering caused by this disease, but these data are extremely exciting, especially for people with the G551D mutation and their families. The results also offer significant hope that a similar approach to treatment may help the majority of patients living with CF.”

The Phase 3 data support Vertex’s plan to submit a new Drug Application for VX-770 to the U.S. Food and Drug Administration (FDA) in the second half of 2011. Generally, the FDA takes between 6 and 12 months to review and rule on a drug application.

“The Cystic Fibrosis Foundation has played an instrumental role in our more than 10-year effort to discover and develop potential new CF medicines such as VX-770,” said Matthew W. Emmens, chairman, president and CEO of Vertex. “The data announced today reflect a significant investment of time, dollars and scientific expertise from both Vertex and the CF Foundation, and we look forward to working closely with the Foundation as we seek to bring VX-770 to people with CF.”

Said Preston W. Campbell III, M.D., executive vice president for medical affairs of the Cystic Fibrosis Foundation: “As a physician who has treated CF patients for many years, the VX-770 results are more than just numbers — they represent hope.” he added, “It’s not surprising that patients felt better on the drug because of the magnitude of lung function improvement and weight gain. these are important clinical outcomes, and the fact they were maintained through 48 weeks is very encouraging.”

Developing a therapy for individuals with the most common CF mutation, Delta F508, remains a top priority of the CF Foundation. A Phase 2 trial for those with Delta F508 is underway to test VX-770 in combination with a drug known as VX-809. Like VX-770, VX-809 resulted from discovery efforts between Vertex and the CF Foundation. Laboratory studies suggest a combination of the two drugs may be more beneficial than either one alone. Results of this clinical trial are expected later this year.

In addition, the CF Foundation is expanding its medical research program by $100 million over the next five years to focus on developing therapies, known as CFTR modulators, which address the underlying defect.

Vertex’s VX-770 Phase 3 program involves three different clinical trials, including the trial for people age 12 and up with the G551D mutation described above. In addition, a VX-770 trial of children ages 6 to 11 with the G551D mutation is ongoing and results are expected in mid-2011. The company also announced results for a trial evaluating VX-770 in patients with two copies of the Delta F508 mutation. Safety was the study’s primary focus, and adverse events were similar between the VX-770 and placebo groups in the study. Patients did not show a clinically meaningful improvement in lung function, although sweat chloride improved by a small amount.

Results from all three studies will be part of the drug application Vertex will submit to the FDA.

About the Cystic Fibrosis Foundation The Cystic Fibrosis Foundation is the world’s leader in the search for a cure for cystic fibrosis. The Foundation funds more CF research than any other organization, and nearly every CF drug available today was made possible because of Foundation support. Based in Bethesda, Md., the Foundation also supports and accredits a national care center network that has been recognized by the National Institutes of Health as a model of care for a chronic disease. The CF Foundation is a donor-supported nonprofit organization. For more information, go to cff.org.

SOURCE Cystic Fibrosis Foundation

Copyright [2011] PR Newswire. All Rights Reserved.

Press Release Source: Crohn’s & Colitis Foundation On Tuesday January 11, 2011, 3:44 pm EST

NEW YORK, Jan. 11, 2011 /PRNewswire/ — In 2010, over 2,000 people ran, walked, or cycled with the Crohn’s & Colitis Foundation’s endurance training and fundraising program, Team Challenge. These participants at all fitness levels raised $8 million for research, education, and support services for patients suffering from Crohn’s disease and ulcerative colitis, chronic and often debilitating digestive diseases affecting over 1.4 million Americans.

To view the multimedia assets associated with this release, please click prnewswire.com/news-releases/team-challenge-endurance-training-program-generates-8-million-for-crohns–colitis-foundation-in-2010-113291069.html

“It was amazing to see the number of people running in the race for this cause,” says Mike McCready, lead guitarist for Pearl Jam, who supported and celebrated with participants during race weekend at the Zappos.com Rock ‘n’ Roll Las Vegas half Marathon, alongside other celebrities including Ali Fedotowsky and fiance Fernando Martinez from the Bachelorette; and meteorologist Bob Van Dillen from HLN’s “Morning Express with Robin Meade.” “As a Crohn’s patient I am grateful that Team Challenge is helping to raise much-needed awareness about this disease and ulcerative colitis. it is so important that people understand what patients go through and that patients understand that they are not alone in their fight.”

In 2010, Team Challenge participants completed the Centurion Cycling’s Blue Mountain race; the 13.1 Boston Marathon; the Napa-to-Sonoma Wine Country half Marathon; and the Zappos.com Rock ‘n’ Roll Las Vegas half Marathon.

And this month, the Foundation invites runners and walkers of all levels around the country learn more about how they can challenge themselves, change lives, and help find cures while training for world-class destination races taking place during summer 2011.

Those interested in learning more about training for an upcoming race can attend an information meeting, which are taking place across the country in January, February, and March. Training takes place over 16-weeks in group sessions led by professional coaches while participants raise much-needed awareness of and funds for Crohn’s and colitis research, education, and support initiatives. Find a local information meeting at ccteamchallenge.org

Team Challenge participants who sign up will train for either the June 4 Virginia half Marathon; the June 26 Kona half Marathon; or the July 17 Napa-to-Sonoma Wine Country half Marathon. during the Virginia Wine Country half Marathon, runners and walkers will experience a fast and peaceful course through the winding country roads of Northern Virginia through hillside vineyards, expansive horse farms, and historic estates. the Kona half Marathon takes place on the beautiful Kona Coast, and offers views of the ocean, mountains, and lava fields of Hawaii. during the Napa-to-Sonoma Wine Country half Marathon, participants will take in rolling vineyards of the Carneros wine region. For all races, event weekend kicks off with a pasta party and concludes with a finish line bash.

This spring, Team Challenge will launch its Triathlon program that will train participants to swim, bike, and run the TriRock Triathlon Series San Diego race on September 11, 2011.

About Crohn’s Disease & Ulcerative Colitis

Crohn’s disease and ulcerative colitis are painful, medically incurable illnesses that attack the digestive system. Crohn’s disease may attack anywhere from the mouth to the anus, while ulcerative colitis inflames only the large intestine (colon). Symptoms may include abdominal pain, persistent diarrhea, rectal bleeding, fever and weight loss. many patients require hospitalization and surgery.  These illnesses can cause severe complications, including colon cancer in patients with long-term disease. Some 1.4 million American adults and children suffer from Crohn’s disease or ulcerative colitis, with as many as 150,000 under the age of 18.  Most people develop the diseases between the ages of 15 and 35.

About the Crohn’s & Colitis Foundation

The Crohn’s & Colitis Foundation of America’s mission is to cure Crohn’s disease and ulcerative colitis, and to improve the quality of life of children and adults affected by these diseases. the Foundation ranks third among leading health non-profits in the percentage of expense devoted to research toward a cure, with more than 81 cents of every dollar the Foundation spends goes to mission-critical programs. the Foundation consistently meets the standards of organizations that monitor charities, including the better Business Bureau’s Wise Giving Alliance (give.org) and the American Institute of Philanthropy (charitywatch.org). For more information, contact the Foundation at 800-932-2423 or visit ccfa.org. Join CCFA on Facebook at apps.facebook.com/supportccfa/and follow CCFA on Twitter at twitter.com/ccfa.  

Related Links

Team Challenge Endurance Training Program

Crohn’s & Colitis Foundation of America

Posted on: Monday, 13 December 2010, 16:52 CST

THOUSAND OAKS, Calif., Dec. 13, 3010 /PRNewswire-FirstCall/ — Amgen (Nasdaq: AMGN) today announced top-line results from a Phase 3 trial evaluating XGEVA(TM) (denosumab) versus placebo in 1,432 men with castrate-resistant prostate cancer. the trial, known as the ’147 study, demonstrated that XGEVA significantly improved median bone metastasis-free survival by 4.2 months (HR=0.85, 95 percent CI 0.73-0.98, p=0.03) compared to placebo (primary endpoint), and significantly improved time to first occurrence of bone metastases (secondary endpoint). overall survival was similar between the XGEVA and placebo groups (secondary endpoint).

Overall rates of adverse events and serious adverse events were generally similar between XGEVA and placebo, with hypocalcemia and osteonecrosis of the jaw (ONJ) observed at increased frequencies in the XGEVA arm. the yearly rate of ONJ in the XGEVA-treated group was similar to what has been observed in prior XGEVA trials.

“Our data demonstrate that XGEVA, which antagonizes the RANK Ligand axis, limits the ability of tumors to colonize bone, an important finding for men at risk for bone metastases and their healthcare providers,” said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. “We look forward to presenting these landmark data at an upcoming medical conference.”

The RANK Ligand pathway, first discovered by Amgen scientists in the mid-1990s, is believed to play a central role in cancer-induced bone destruction, regardless of cancer type. Data suggest that in bone metastasis, the invasion of cancer is facilitated by bone destruction. hence, increased bone resorption due to increased RANK Ligand expression appears to augment bone metastasis.

XGEVA is a fully human monoclonal antibody that binds to RANK Ligand, a protein essential for the formation, function and survival of osteoclasts (the cells that break down bone). XGEVA prevents RANK Ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and halting release of growth factors, making the environment less conducive to tumor growth.

About Study ’147

Study ’147 was a randomized, placebo-controlled, multi-center Phase 3 study comparing the treatment effect of XGEVA with placebo on prolonging bone metastasis-free survival in men with hormone-refractory (castrate-resistant) prostate cancer with rapidly-rising PSA levels who had no bone metastases at baseline. the primary endpoint of the trial was time to first occurrence of bone metastasis or death from any cause, with secondary endpoints including time to first occurrence of bone metastasis (excluding death) and overall survival.

XGEVA Skeletal-Related Events Regulatory Status

XGEVA was approved by the U.S. Food and Drug Administration (FDA) for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors on Nov. 18, 2010. XGEVA is not indicated to prevent SREs in patients with multiple myeloma.

Administered as a single 120 mg subcutaneous injection every four weeks, XGEVA provides a new option for urologists and oncologists to prevent serious bone complications in men with prostate cancer.

Amgen has also submitted marketing applications for XGEVA in the European Union, Australia, Canada and Switzerland. in Japan, Amgen is working with its licensing partner, Daiichi-Sankyo Company, Limited and a marketing application was submitted.

XGEVA Important Safety Information

XGEVA can cause severe hypocalcemia. correct pre-existing hypocalcemia prior to XGEVA treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA. Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. in these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

The most common adverse reactions in patients receiving XGEVA were fatigue/asthenia, hypophosphatemia, and nausea. the most common serious adverse reaction in patients receiving XGEVA was dyspnea. the most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis and hypocalcemia. Please visit amgen.com for full prescribing information.

Denosumab is also marketed as Prolia(TM) in other indications.

Bone Metastases: Prevalence and Impact

Bone metastases occur in more than 1.5 million patients with cancer worldwide and are most commonly associated with cancers of the prostate, lung, and breast, with incidence rates as high as 75 percent of patients with metastatic disease. (i)

The total economic burden of patients with bone metastases in the U.S. alone estimated to be $12.6 billion annually.

Denosumab and Amgen’s Research in Bone Biology

The denosumab development program demonstrates Amgen’s commitment to researching and delivering pioneering medicines to patients with unmet medical needs. Amgen is studying denosumab in numerous tumor types across the spectrum of cancer-related bone diseases. Over 11,000 patients have been enrolled in the denosumab oncology clinical trials. in addition to study 147, XGEVA is also being investigated for its potential to delay bone metastases in breast cancer.

About Amgen

Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science’s promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people’s lives. to learn more about our pioneering science and our vital medicines, visit amgen.com/.

Forward-Looking Statements

This news release contains forward-looking statements that are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission (SEC) reports filed by Amgen, including Amgen’s most recent annual report on Form 10-K and most recent periodic reports on Form 10-Q and Form 8-K. Please refer to Amgen’s most recent Forms 10-K, 10-Q and 8-K for additional information on the uncertainties and risk factors related to our business. unless otherwise noted, Amgen is providing this information as of Dec. 13, 2010 and expressly disclaims any duty to update information contained in this news release.

No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. further, preclinical results do not guarantee safe and effective performance of product candidates in humans. the complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. the length of time that it takes for us to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. we develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products after they are on the market. Our business may be impacted by government investigations, litigation and products liability claims. we depend on third parties for a significant portion of our manufacturing capacity for the supply of certain of our current and future products and limits on supply may constrain sales of certain of our current products and product candidate development.

In addition, sales of our products are affected by the reimbursement policies imposed by third-party payors, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment as well as U.S. legislation affecting pharmaceutical pricing and reimbursement. Government and others’ regulations and reimbursement policies may affect the development, usage and pricing of our products. in addition, we compete with other companies with respect to some of our marketed products as well as for the discovery and development of new products. we believe that some of our newer products, product candidates or new indications for existing products, may face competition when and as they are approved and marketed. Our products may compete against products that have lower prices, established reimbursement, superior performance, are easier to administer, or that are otherwise competitive with our products. in addition, while we routinely obtain patents for our products and technology, the protection offered by our patents and patent applications may be challenged, invalidated or circumvented by our competitors and there can be no guarantee of our ability to obtain or maintain patent protection for our products or product candidates. we cannot guarantee that we will be able to produce commercially successful products or maintain the commercial success of our existing products. Our stock price may be affected by actual or perceived market opportunity, competitive position, and success or failure of our products or product candidates. further, the discovery of significant problems with a product similar to one of our products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on our business and results of operations.

Scientific information discussed in this news release relating to new indications for our products is preliminary and investigative and is not part of the labeling approved by the U.S. Food and Drug Administration (FDA) for the products. the products are not approved for the investigational use(s) discussed in this news release, and no conclusions can or should be drawn regarding the safety or effectiveness of the products for these uses. only the FDA can determine whether the products are safe and effective for these uses. Healthcare professionals should refer to and rely upon the FDA-approved labeling for the products, and not the information discussed in this news release.

(i) Coleman RE. Skeletal complications of malignancy. Cancer. 1997; 80(suppl): 1588-1594.

CONTACT: Amgen, Thousand Oaks Christine Regan: +1 (805) 447-5476 (media) Arvind Sood: +1 (805) 447-1060 (investors)

(Logo: photos.prnewswire.com/prnh/20081015/AMGENLOGO)

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Posted on: Wednesday, 17 November 2010, 08:02 CST

Local charity underwrites important kidney research

JUPITER, Fla., Nov. 17, 2010 /PRNewswire-USNewswire/ — The Halpin Foundation and the American Society of Nephrology (ASN) are proud to highlight the research advances in membranous nephropathy made possible by the Halpin Foundation-ASN Research Grant, created to help young faculty develop independent research careers. this award provides recipients transition funding toward successful application for an NIH RO1 grant.

The Halpin Foundation has dedicated itself to the study of membranous nephropathy since 1989, after the Halpins’ 14-year-old son was diagnosed with this rare disorder. to advance research of the disorder and its symptoms, including loss of protein in the urine and a progressive decline in renal function, the Halpin Foundation partnered with the American Society of Nephrology (ASN) to promote research relevant to membranous nephropathy in 2004.

Elena Torban, PhD (McGill University Faculty of Medicine), the 2008-2009 recipient of The Halpin Foundation-ASN Research Grant, recently explained, “The generous financial two-year support provided by the Halpin Foundation has enabled us to conduct a successful experimental program demonstrating for the first time that podocyte architecture is indeed regulated by the PCP pathway. We also showed that the podocyte-specific protein, nephrin, is linked to proteins of the PCP network. this finding establishes a mechanism whereby the PCP pathway regulates nephrin-dependent organization of foot processes.”

The 2009-2010 recipient, Laurence H. Beck, Jr., MD, PhD, wrote of the grant, “The funding provided by the Halpin Foundation has been instrumental in allowing my research to take root and grow. The research award has permitted me to spend the majority of these two years in the laboratory, performing experiments and helping to train young scientists and fellows to conduct similar lines of inquiry. The fruits of this research should soon allow me to successfully apply for individual federal funding. Their ongoing interactions with leaders in this field on a national and international level have been enormously helpful for me in terms of forming productive collaborations to move this research forward. I will always be grateful for this support at such a critical time in the career of a young physician-scientist.”

Dr. Beck and several colleagues will also participate in a Clinical Nephrology Conference (CNC) during Renal Week entitled, “Membranous Nephropathy” on Friday, November 19 from 10:30 am – 12:30 pm in Korbel 2A/3A of the Colorado Convention Center in Denver, CO. The session, “The Human Membranous Antibody: Mechanism and Monitoring” is a way to highlight research advances and stimulate investigations regarding membranous nephropathy.

“We are grateful to the Halpin Foundation for helping us fund new investigators interested in studying this disease to answer the many unanswered questions surrounding membranous nephropathy and nephrotic syndrome,” said ASN’s President, Sharon Anderson, MD, FASN.

About the ASN

Founded in 1966, the American Society of Nephrology (ASN) is the world’s largest professional society devoted to the study of kidney disease. Comprised of 11,000 physicians and scientists, ASN continues to promote expert patient care, to advance medical research, and to educate the renal community. ASN also informs policymakers about issues of importance to kidney doctors and their patients. ASN funds research, and through its world-renowned meetings and first-class publications, disseminates information and educational tools that empower physicians. asn-online.org

About Renal Week

ASN Renal Week 2010, the largest nephrology meeting of its kind, will provide a forum for 13,000 professionals to discuss the latest findings in renal research and engage in educational sessions related to advances in the care of patients with kidney and related disorders. Renal Week 2010 will take place November 16 – November 21 at the Colorado Convention Center in Denver, CO. asn-online.org/education_and_meetings/renal_week

About the Halpin Foundation

The Halpin Foundation is a non-profit medical research organization that seeks to aid the medical community in understanding and overcoming genetic medical conditions. The foundation’s grants are prioritized into two targeted goal areas: kidney disease research and autoimmune disease research. this year the Halpin Foundation partnered with the American Society of Nephrology (ASN) and awarded Dr. Laurence Beck. Jr., the lead researcher in this study, from the Boston University School of Medicine (BUSM), a grant for the continuation of his work on the PLA2R antigen. For more information about the Halpin Foundation, please visit halpin.org.

Other grants this year from the Halpin Foundation included:

In Membranous Nephropathy to:

Ariela Benigni, Paolo Cravedi, and Giuseppe Remuzzi summed up an important study they’ve undertaken with support from the Halpin Foundation, saying, “Understanding how in patients with this syndrome elevated levels of IgG4 may cause the disease represents a unique opportunity to assess the mechanisms – and develop treatments targeted – in most common cases of membranous nephropathy not related to high levels of IgG4. on this basis, we designed a study to analyze the characteristics of immunoglobulins – especially IgG4 – in one of the very rare patients with membranous nephropathy associated with hyper-IgG4 syndrome (so far, less than ten patients have been reported worldwide). as often happens with rare diseases, we expect that the study of a very special case may provide useful information on the causes of membranous nephropathy even in the more frequent cases of patients with normal levels of IgG4.”

In Translational Medical Research to:

Sujit Basu, MD, PhD, an associate professor of Pathology and a member of the Experimental Therapeutics Program at the OSUCCC-James, and Chandrani Sarkar, PhD, research assistant professor of Pathology, have also received a two-year grant from the Halpin Foundation to study the role of neurotransmitter dopamine in multiple myeloma. Basu is principal investigator, and Sarkar is joint-principal investigator. “The Foundation president, mrs. Joan Halpin, and other members of the Foundation became interested in our work after reading about it in high-impact journals. They think our work may answer some puzzles in cancer biology.”

For more information about the Halpin Foundation, please visit halpin.org.

SOURCE The Halpin Foundation

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Posted on: Thursday, 19 August 2010, 15:12 CDT

LEIDEN, The Netherlands, Aug. 19 /PRNewswire-USNewswire/ — nearly two decades after they identified the specific genetic flaw that causes a common type of muscular dystrophy, scientists believe they have figured out how that flaw brings about the disease. The finding by an international team of researchers settles a longstanding question about the roots of facioscapulohumeral muscular dystrophy or FSHD. The work is published in the August 20 issue of Science.

Unraveling how the genetic defect causes FSHD has been especially challenging for scientists. Unlike with many genetic diseases, their identification of the mutation that is the basis of FSHD did not quickly lead to a deeper understanding of how the disease actually comes about. The lack of clarity has posed a significant barrier to researchers hoping to turn the knowledge of the genetic flaw into significant progress for patients.

The latest findings clarify the picture significantly. Scientists have discovered that several deleted versions of a gene trigger the remaining copies of that gene to be much more active than usual. That’s because the DNA that codes for the gene is not as tightly coiled or elusive to the body’s molecular machinery as usual when some copies are missing, and so the gene – known as DUX4, which makes a protein harmful to muscle cells – is more active than it should be.

The work offers up a new therapeutic target to scientists aiming to develop a treatment or cure for the disease.

The research was led by genetics researchers at the University of Leiden in the Netherlands, working together with scientists at the University of Rochester Medical Center, the Fred Hutchinson Cancer Research Center in Seattle, and other investigators. The research was funded by several organizations, including the Fields Center for FSHD and Neuromuscular Research, based at Rochester and at Leiden (urmc.rochester.edu/fields-center/).

“It is amazing to realize that a long and frustrating journey of almost two decades now culminates in the identification of a single small DNA variant that differs between patients and people without the disease. we finally have a target that we can go after,” said Silvere van der Maarel, Ph.D., professor of medical epigenetics at Leiden and the corresponding author of the paper. Working closely with van der Maarel was the first author of the paper, Richard Lemmers of Leiden.

FSHD is an inherited disorder that usually makes its presence felt in the teen years. First symptoms usually are weakness in the upper body; a person might have trouble lifting the arms, for example. Weakness of the facial muscles is also common, for instance, difficulty smiling or whistling, closing the eyelids completely, or even sipping through a straw. Later on, the condition affects the lower body – the muscles of the feet, legs, and hips. Patients usually live a normal life span, but around 20 percent of patients end up using a wheelchair.

Doctors estimate that about 1 in 20,000 people worldwide, including about 15,000 Americans, have FSHD, which is the third most common type of muscular dystrophy.

It was 18 years ago, in 1992, that a team from the same laboratory in Leiden identified the genetic defect at the root of the disease. The scientists found that in healthy people there are 11 or more copies of a certain DNA sequence dubbed D4Z4 near the tip on chromosome 4. nearly all FSHD patients have too-few copies – 10 or fewer of the D4Z4 repeat.

Since then the team has worked to understand how that defect translates into the disease. Meanwhile, the University of Rochester built on its history as a powerhouse of leading muscular dystrophy research and treatment worldwide; Rochester’s studies of FSHD were wide ranging and included both clinical and translational research. The University created the National Registry of Myotonic and FSHD Patients and Family Members, which includes information on hundreds of patients who volunteer for research. The FSHD team at Rochester has also established the world’s largest repository of biological samples, such as blood, skin and muscle specimens, from individuals with FSHD, a resource that has proven to be crucial in advancing knowledge of the disease.

The groups began collaborating, and their interactions accelerated three years ago, thanks to a gift from new York developer and philanthropist Richard T. Fields.

Now, the team has worked out a crucial step in how the defect leads to disease. The finding draws on the genetics expertise at Leiden, the clinical research experience with FSHD patients at Rochester, and epigenetics knowledge in Seattle.

“In most patients with FSHD, a piece of DNA is missing,” said Rabi Tawil, M.D., an author of the Science paper and the neurologist who leads Rochester’s FSHD team and the Fields Center. “For a long time it was thought that this was simply junk DNA that was missing, and that the missing material must affect the function of a nearby gene on chromosome 4.”

It turns out that each of the D4Z4 repeats contains a copy of a gene known as DUX4, but scientists have not known until recently that DUX4 is a functional gene. When a critical number of copies are missing, the structure of the tip of chromosome 4 becomes more open, making the DUX4 gene more accessible for transcription.

When crucial pieces of DNA that introduce and conclude the repetitive string are composed of certain sequences, the ingredients for molecular mischief are in place, making the remaining copies of DUX4 much more stable than they normally are.

“This provides a new and unifying model for FSHD because it will focus future research on determining whether the DUX4 protein causes FSHD, as indicated by our consortium’s genetic analysis,” said Stephen Tapscott, M.D., Ph.D., a member of the Human Biology Division at the Fred Hutchinson Cancer Research Center and one of the authors of the Science paper. The team is currently studying how active DUX4 is in patients in FSHD compared to people who do not have the disease.

In previous research, other investigators had identified a nearby gene known as FRG1 as central to the development of FSHD. The teams in Leiden, Rochester and Seattle teams were unable to reproduce those results and instead point to DUX4.

Currently there is no treatment for FSHD that slows the disease or addresses the underlying problem. Typically patients are treated with medications to alleviate their pain, and are given supportive treatment, such as braces and other aids for their arms and legs to help them deal with weakness. there have been a few studies investigating possible treatments – drugs on the market for other conditions – but those haven’t turned up anything that works in FSHD patients.

“Interventions tried thus far haven’t been based on the science underlying the disease,” said Tawil, a professor in the Department of Neurology. “That’s why this is such an exciting step. instead of guesswork, we now have one unified hypothesis, and one target. This marks the first time we can work solidly from basic science to seek a treatment for FSHD.”

The team plans to screen existing compounds in a search for one that inhibits DUX4. The group also plans to develop rigorous techniques for measuring the effects of test medications on FSHD patients, and to continue to try to understand how DUX4 damages muscles. Early research indicates that DUX4 hinders the body’s ability to regenerate muscle and makes muscles more susceptible to oxidative stress.

In addition to van der Maarel, Lemmers, Tapscott and Tawil, the authors of the Science paper include:

• From Leiden University Medical Center: Patrick van der Vliet, Rinse Klooster, Johannes Dauwerse, Kirsten Straasheijm, Gert Jan van Ommen, and Rune Frants.
• From the Fred Hutchinson Cancer Research Center in Seattle: Lauren Snider.
• From Nice University in France: Sabrina Sacconi.
• From the BioDonostia Health Research Institute in San Sebastian, Spain, as well as the Centro Investigacion Biomedica en Red para Enfermedades Neurodegenerativas: Pilar Camano.
• From Radboud University Nijmegen Medical Center the Netherlands: George Padberg.
• From the University of Washington: Daniel Miller.

Funding to conduct the work came from several organization, including the Fields Center, the Netherlands Organization for Scientific Research, the Netherlands Genomic Initiative NOW, the U.S. National Institutes of Health, the Muscular Dystrophy Assn., the Shaw Family Foundation, a Marjorie Bronfman Fellowship grant from the FSH Society, the Pacific Northwest Friends of FSH Research, the Centro Investigacion Biomedica en Red para Enfermedades Neurodegenerativas, the Basque Government, and the Instituto Carlos III.

One of the nation’s top academic medical centers, the University of Rochester Medical Center (urmc.rochester.edu) forms the centerpiece of the University’s health research, teaching, patient care, and community outreach missions. The Medical Center receives more than $240 million in external research funding per year and the University of Rochester School of Medicine and Dentistry ranks in the top one-quarter of U.S. medical centers in federal research funding. The University’s health care delivery network is anchored by Strong Memorial Hospital – a 754-bed, University-owned teaching hospital. As upstate new York’s premier health care delivery network, patients benefit from the Medical Center’s robust teaching and biomedical research programs.

SOURCE University of Rochester Medical Center

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