Early treatment is key for children with Angelman syndrome

Fixing the gene that’s faulty in Angelman syndrome ameliorates anxiety and motor deficits in a mouse model of the disorder, but only if done when the mice are young.

The findings, published 1 May in the Journal of Clinical Investigation, suggest that experimental treatments for the syndrome must be delivered early in life1.

“If I had to design such a trial for our own Angelman syndrome clinic, I would do the first trial in young children,” says lead researcher Ype Elgersma, professor of neuroscience at Erasmus University in Rotterdam, the Netherlands.

Angelman syndrome occurs in about 1 in 15,000 children and is marked by problems with speech and gait, developmental delay and epilepsy. It stems from mutations in the maternal copy of the UBE3A gene. The paternal copy of that gene is normally silent, raising the possibility of restoring its activity to treat the syndrome.

Researchers have been able to rouse the paternal copy of UBE3A in mouse models of Angelman syndrome. But these mice still show repetitive behaviors and anxiety. The new study suggests this is because the treatment arrives too late in these cases.

In the study, researchers engineered mice in which they silenced the maternal UBE3A gene but can then activate it with a drug. When the researchers switched the gene on at the start of embryonic development, the rodents did not show the repetitive behaviors, clumsiness, anxiety and seizures that ordinarily characterize Angelman mice.

Reviving the gene in 3-week-old mice — the equivalent of toddlerhood in people — improved only their ability to balance on a rotating rod. By 6 weeks of age — rodent adolescence — the window for correcting the motor skill deficit closes.

The researchers also turned on UBE3A in Angelman mice on their first day of life by injecting their lactating mothers with the gene-activating compound, which made its way into the mothers’ milk. This early treatment alleviated anxiety — allowing the mice to explore open spaces — and made them less clumsy. Absorbing the drug only raised UBE3A levels to 63 percent of normal at most, suggesting that if a therapy could boost UBE3A levels higher, it might correct even more symptoms at that age.

The researchers then looked at the treatment’s effect on the brain. They found that restoring UBE3A expression at any age — even into adulthood — normalizes neuronal activity in the hippocampus, a region involved in memory. After the treatment, neurons there could change their connections in response to experience, a process called synaptic plasticity.

This effect on plasticity, which is thought to reflect learning, suggests that researchers could examine the ability to learn and remember in clinical trials for Angelman syndrome drugs, Elgersma says. He also recommends focusing on motor problems — the one symptom he and his team were able to ease in 3-week-old mice.

The remaining symptoms may respond to other treatments. Although activating UBE3A does not alleviate seizures in the mice at any age, standard epilepsy drugs do. “An important point — and quite counterintuitive — is that restoring the gene is not necessarily the best achievable cure,” says Elgersma. Drugs that treat the symptoms might actually be more effective in certain cases.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.


1. Silva-Santos S. et al. J. Clin. Invest. 125, 2069-2076 (2015) PubMed

Author: Jessica Wright
Source: Simons Foundation Autism Research Initiative

The countdown is on for NORD’s 2015 Portraits of Courage

In less than one week, the rare disease community will gather for one of its biggest nights – NORD’s annual Portraits of Courage Gala. If you have not yet registered, there is still time.

This year’s honorees include Francis S. Collins, M.D., Ph.D., Director, National Institutes of Health; Margaret Hamburg, M.D., Former Commissioner, Food and Drug Administration; NORD’s first-ever Rare Disease Public Awareness Award, given to Cindy Abbott, a rare disease patient and only woman in the world to have climbed both Mount Everest and completed the Alaskan Iditarod; six Industry Innovators behind the novel new drugs approved last year; 10 of the most courageous and inspiring patients and caregivers of the year, nominated by the community; and more (below).

The evening will include a cocktail reception, silent auction and seated dinner followed by a champagne and dessert celebration, plus a musical performance by singer-songwriter Sonia Lee. The 2015 Portraits of Courage art gallery, NORD’s annual traveling art exhibit featuring portraits of patients, parents and caregivers, will debut at the event.

The 2015 Portraits of Courage Honorees are:

Abbey S. Meyers Leadership Award

The International Pemphigus & Pemphigoid Foundation
Industry Innovation Award

BioMarin Pharmaceutical Inc. – Vimizim (Mucopolysaccharidosis Type IVA, also known as Morquio A Syndrome)
BOEHRINGER-INGELHEIM Corporation USA – Ofev (Idiopathic Pulmonary Fibrosis)
Genzyme Corporation – Cerdelga (Gaucher Disease Type I)
Lundbeck – Northera (Neurogenic Orthostatic Hypotension)
Novartis Pharmaceuticals – Zykadia (Anaplastic Lymphoma Kinase-Positive Metastatic Non-Small Cell Lung Cancer)
Vanda Pharmaceuticals Inc. – Hetlioz (Non-24-Hour Sleep-Wake Disorder)
Lifetime Achievement Award

Francis S. Collins, M.D., Ph.D. – Director, National Institutes of Health
National Health Leadership Award

The Honorable Lamar Alexander (TN), U.S. Senate
The Honorable Robert Casey, Jr. (PA), U.S. Senate
Portraits of Courage Award

Devin Alvarez (Sprengel Deformity)
Emily Argersinger (Sturge-Weber Syndrome)
Laura Crandall (Sudden Unexplained Death in Childhood)
Anthony Ferrandino (Batten Disease)
Bailey Gribben (Neurofibromatosis)
Sophia Hanson (Lymphedema Praecox)
Savannah Hollis (Cavernous Angioma)
Glenn and Cara O’Neill (Sanfilippo Syndrome)
Yusuf Patel (Methylmelonic Acidemia)
Lori Sames (Giant Axonal Neuropathy)
Rare Disease Public Awareness Award

Cindy Abbott (Wegener’s Granulomatosis)
Special Recognition

Margaret A. Hamburg, M.D. – Former Commissioner, Food and Drug Administration

The Portraits of Courage Gala is NORD’s biggest fundraising event of the year. All proceeds raised support NORD’s mission as a nonprofit to provide education, advocacy, research and patient support on behalf of the 30 million Americans with rare diseases.

More Information & Ticket Registration

To learn more, register for tickets, or for sponsorship opportunities, please visit http://www.rarediseases.org/news-events/gala-2015.

High prices for drugs to treat rare diseases take a toll

Let me start with a confession: I had never heard of little Synageva BioPharma Corp. before another company agreed to buy it for $8.4 billion last week.

The sale of the Lexington biotech company was remarkable on many counts — none more striking than the fact that it has no products for sale.

Synageva hopes to win US approval later this year for a drug to treat a disease estimated to afflict just 3,000 people in the entire developed world. It also has some other potential drugs in its development pipeline.

The fact a company with prospects like that can be worth more than $8 billion to anyone tells you something troubling about the booming business of drugs targeting very small groups of patients.

That business relies on a particular economic premise — medicines that individually are sold at very expensive prices but collectively are palatable to the health care system because so few people take them. They may induce sticker shock, but they won’t bust the budget.

View Story
Lexington biotech fetches $8b
Alexion Pharmaceuticals’s purchase of Synageva BioPharma is the second-largest takeover of a Mass. biotechnology company.

The problem: Those treatments, which can cost $300,000, even $500,000 per patient each year, won’t be a few drops in the bucket much longer. More of them are coming onto the market every year — truly good news for patients who suffered with little hope in the past, but a developing financial headache for us all.

Consider the medicines — both new therapies and existing drugs repurposed for small groups of patients — that are awarded orphan drug status by federal regulators each year. Those drugs earn extended patent protection, tax breaks, and research subsidies because they treat rare disorders.

The Food and Drug Administration granted orphan drug status to 43 medicines just in 2014. A decade earlier, only 13 therapies were recognized as orphan treatments.

Worldwide sales of orphan drugs amounted to less than $20 billion in 2000, but by 2020 are forecast to cost $176 billion, according to EvaluatePharma, a market research firm. By that year, the money spent on orphan drugs will account for about 19 percent of the world’s total drug expense.

Orphan drugs treat diseases that affect fewer than 200,000 people in the United States and cost an average of $137,000 a year. And treatments for so-called ultra-rare diseases, like the disorder that Synageva targets, generally cost much more.

Two important developments have encouraged many more companies and scientists to pursue expensive treatments for very rare diseases during the past decade.

One is simply a matter of technology. Drug developers now have much better tools and resources, especially for work attacking genetic diseases.

The other was the experience of Genzyme, a pioneer in the rare-disease drug business. Former Genzyme chief Henri Termeer showed how a company could thrive and prosper by targeting those diseases. The French drug giant Sanofi was so impressed that it eventually bought the Cambridge company for $20 billion in 2011.

Genzyme became a master at marketing both lifesaving drugs and high prices around the world, as described years ago by a former Globe colleague, Stephen Heuser.

Even better, those drugs often command premium prices for years because the odds of real competition are slim.

Genzyme introduced its therapy to treat Gaucher disease, an enzyme deficiency that affects about 10,000 people worldwide, in the 1990s. As of last fall, the company was charging more than $300,000 per year for its drug. Over many years, Genzyme has probably raked in nearly $15 billion in sales from its Gaucher treatment.

Now there is a new generation of Genzymes. It should come as no surprise that Sanj Patel, chief executive of Synageva, is a Genzyme veteran.

The company that bought Synageva, Alexion Pharmaceuticals Inc., operates from the same kind of biotech playbook. Its drug to treat a rare blood disorder lists for more than $500,000 a year. Alexion will pay half the cost of the Synageva acquisition with its own shares. That stock has appreciated more than 500 percent over the last five years.

Developing drugs to treat rare diseases is still a risky proposition, and companies that succeed certainly deserve rewards. We’re likely to see more of those drugs with even greater frequency in the future.

But something has to change. Health care systems once bent over backward to persuade companies to pursue those treatments — and agreed to pay through the nose for the ones that worked. Now, companies with prospects for treating a tiny population of patients are worth billions. That math won’t work for long.

Steven Syre is a Globe columnist. He can be reached at syre@globe.com.

OPEN ACT HR 971 for Rare Diseases needs your help

Congress is in the process of making pivotal decisions on biomedical innovation that may affect the rare disease community for decades to come. EveryLIfe is proud to have our main legislative initiative, the OPEN ACT HR 971, included as part of the draft 21st Century Cures legislation, but EveryLife need your help to make this bill a reality.everylife-logo

The OPEN ACT creates an incentive for companies to repurpose existing therapies for rare disease indications. We believe this bill has the potential to DOUBLE the number of treatments available to rare disease patients. The OPEN ACT is part of our broader Cure the Process 2 campaign, an EveryLife initiative to improve the drug development process and spur innovation for rare disease patients.

There are four ways you may take action:

1) Contact your Representatives in Congress and ask them to co-sponsor the OPEN ACT HR 971
It takes less than 3 minutes to send an email to your Member of Congress – click the link above, complete the form, and hit send. It’s that easy.

2) Join NORD, Global Genes, and the nearly 150 organizations who have signed-on to support the OPEN ACT
Email mbronstein@everylifefoundation.org to sign-on.

3) Endorse our full Cure the Process 2 campaign
Click to read more about our campaign and help spur the development of lifesaving treatments.

4) Already supporting? Please share this action alert in your organization’s newsletter, website, and social media pages.

New method increases accuracy of ovarian cancer prognosis and diagnosis

Nearly anyone touched by ovarian cancer will tell you: it’s devastating. It’s bad enough that cancer in almost 80 percent of patients reaches advanced stages before diagnosis, and that most patients are expected to die within five years. But just as painfully, roughly one quarter of women diagnosed have no warning that they are resistant to platinum-based chemotherapy, the main line of defense, nor that they will likely have 18 months to live.

Frustratingly, the diagnosis, prognosis, and even treatment of ovarian cancer have remained largely unchanged for 30 years. Until now, the best indicator for how a woman will fare, and how her cancer should be treated, has been the tumor’s stage at diagnosis.

Now, University of Utah scientists have uncovered patterns of DNA anomalies that predict a woman’s outcome significantly better than tumor stage. In addition, these patterns are the first known indicator of how well a woman will respond to platinum therapy. Published in the journal PLOS ONE, the patterns were discovered by using a new mathematical technique in the analysis of DNA profiles from the Cancer Genome Atlas, a national database containing data from hundreds of ovarian cancer patients.

“We believe this is a first step toward bringing ovarian cancer into the age of precision medicine,” says team leader Orly Alter, Ph.D., associate professor of bioengineering, adjunct associate professor of human genetics, and faculty member of the Scientific Computing and Imaging Institute. Pending experimental revalidation in the clinic, the patterns could be the basis of a personalized prognostic and diagnostic laboratory test. This test would predict both the patient’s survival and the tumor’s sensitivity to platinum-based chemotherapy, and doctors could tailor treatment accordingly.

For example, among patients that were diagnosed at late stages, the DNA patterns distinguished short-term survivors, with a median survival time of three years, from long-term survivors, with a median survival time almost twice as long. Among patients treated with platinum-based chemotherapy drugs, the DNA patterns distinguished those with platinum-resistant tumors, with a median survival time of three years, from those with platinum-sensitive tumors, with a median survival time of more than seven years. Alter’s team computationally validated the results by using data from independent sets of patients.

“If we have a tool that can more accurately predict survival, and distinguish who is who, we can revamp our entire approach to how we treat patients,” says Margit-Maria Janát-Amsbury, M.D., Ph.D., research assistant professor in obstetrics and gynecology, director of gynecologic oncology research at the University of Utah School of Medicine, and faculty member of the Huntsman Cancer Institute. She is collaborating with Alter to bring her team’s results to the clinic. “For those with a poor prognosis, we can suggest other therapies, or we can focus on taking measures to improve quality of life.”

“What made our discovery possible is our new technique for mathematical modeling,” said Alter. “It may very well be that the data needed to better treat cancer are already published. The ovarian cancer data, for example, were published back in 2011. The bottleneck to discovery is in the analysis of the data.”

In Alter’s Genomic Signal Processing Lab, Ph.D. graduate students and study co-authors Katherine Aiello and Theodore Schomay of the department of bioengineering develop algorithms to uncover patterns in datasets arranged in multidimensional tables, known as tensors. Rather than simplifying the big data, as is commonly done, the algorithms make use of the complexity of the data in order to tease out the patterns within them. Here, for example, by modeling DNA profiles of tumor and normal cells from the same set of patients, they were able to separate the patterns of DNA anomalies – which occur only in tumor genomes – from those that occur in the genomes of normal cells in the body, and from variations caused by experimental inconsistencies.

The algorithms extend a mathematical technique called the singular value decomposition, or SVD. The SVD helps us understand data arranged in two-dimensional tables, known as matrices, by breaking the data down into individual components. In physics, for example, the SVD describes the activity of a prism, which splits white light into its component colors. “It seemed natural that generalizations of the SVD could separate the multidimensional data that arise in personalized medicine into mathematical patterns that have biological meaning,” explains Alter, who has a Ph.D. in applied physics.

Alter says her algorithms could just as readily be applied to any type of data. She previously used a similar mathematical technique to uncover new prognostic and diagnostic DNA indicators for patients with glioblastoma, the most common brain cancer in adults. The best predictor of glioblastoma survival prior to Alter’s discovery was the patient’s age at diagnosis.

Some of the specific genes that Alter’s team found to be perturbed in glioblastoma, and in ovarian cancer, may be actively involved in promoting or inhibiting cancer development and progression. Future work will explore whether existing drugs that target these genes are effective in treating these diseases.

To read the April 15, 2015 PLOS ONE article go to: http://dx.plos.org/10.1371/journal.pone.0121396

This work was supported by the Utah Science, Technology, and Research (USTAR) Initiative, National Human Genome Research Institute (NHGRI) R01 Grant HG-004302, and National Science Foundation (NSF) CAREER Award DMS-0847173.

Tensor GSVD of patient- and platform-matched tumor and normal DNA copy-number profiles uncovers chromosome arm-wide patterns of tumor-exclusive platform-consistent alterations encoding for cell transformation and predicting ovarian cancer survival. Sankaranarayanan P, Schomay TE, Aiello KA, Alter O. PLOS ONE 10 (4), article e0121396 (April 15, 2015); doi: 10.1371/journal.pone.0121396


Julie Kiefer

Rare Impact

By Carol Dutch

“Not every doctor would go to such lengths to help a patient; thankfully, my doctor did.” Words like these captured the attention of dozens of healthcare providers and medical residents assembled at Children’s Hospital of Orange County (CHOC) and Rady Children’s Hospital-San Diego. Throughout 2015, many more physicians will experience RAREMed Forums, a series of medical educational sessions prompted by Global Genes and hosted by academic centers and hospitals across the country.

I’m deeply grateful for the physician experts, patient advocates and industry colleagues who are bringing this idea to life. As co-chair of the healthcare provider outreach committee at Global Genes, I’m also tremendously inspired and encouraged by the dialogue at these sessions. Patients are sharing stories of courage and perseverance, and physicians are learning the nuances of diagnosing and managing rare disorders.

During the sessions, speakers present on a wide variety of topics, such as outlining steps designed to speed accurate diagnosis and ensure timely care of people with rare disorders. Physicians are encouraged to “think, refer, integrate and challenge themselves” when diagnosing rare diseases. The program also stresses the importance of physicians giving these conditions the consideration they demand and referring promptly to specialists and centers of excellence.

The RAREMed Forums are only one example of patient advocates, medical communities and industry working together to support education and awareness of the porphyrias, a group of rare and debilitating diseases. The American Porphyria Foundation is training the next generation of physicians in the diagnosis and management of these conditions. Called “Protect Our Future,” this program allows younger physicians to learn from the small number of world-renowned experts in the field. I am proud that my company, Recordati Rare Diseases, supports this program as part of our commitment to the rare disease community.

These programs – and many more – show the power of banding together to overcome challenges that seemed impossible just a decade ago. As with any family, our global rare disease community is strongest when united in a common goal. When patients, families, physicians, academic centers, policy makers and industry work together, we can improve our understanding of rare diseases, advance research, and improve diagnosis.

It’s my hope that programs like these will knock down some of the barriers to rare disease diagnoses for patients, reducing their suffering and helping them live fuller and healthier lives.

With 20 years of experience working with rare disease communities, Carol Dutch manages patient advocacy programs at Recordati Rare Diseases, a biopharmaceutical company that specializes in providing high-impact therapies for high-impact rare diseases. The company is passionate about partnering with rare disease communities to help restore the lives of people affected by these disorders.

For more information on RAREMed Forums, contact Katie Mastro at katiem@globalgenes.org.


[Photo 1: For prominent placement near top of blog post] Global Genes was the catalyst for a RARE Rounds medical education session held at Children’s Hospital of Orange County (CHOC). Left to right: Carol Dutch, manager of advocacy at Recordati Rare Diseases and co-chair of the healthcare provider outreach committee at Global Genes; Raymond Y. Wang, M.D., director of multidisciplinary lysosomal storage disorder program at CHOC; and Andrea Epstein, executive director of Global Genes.

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[Photo 2: for secondary placement] Dozens of health care providers and medical residents attending the RARE Rounds session at Rady Children’s Hospital-San Diego.