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by Monica Coenraads

In January of this year a gentleman who has a granddaughter with Rett Syndrome introduced me to his neighbor, David Scheer, a 31-year veteran of the life sciences industry. I was eager to meet David, whose entrepreneurial focus lies at the intersection of finance and science. Our planned hour of conversation turned into a three-hour discussion as we delved into David’s network, experiences, and the potential synergies we might explore. Over the past 9 months I’ve come to rely on David’s insights, perspective and advice. I’m delighted that he has agreed to serve on RSRT’s Professional Advisory Council and look forward to working closely with him on our drug development strategies.

MC: David, please start us off by telling us a bit about your background.

DS: I began with an undergraduate degree in biochemical sciences from Harvard and went on to study cell and molecular biology and pharmacology at Yale. While in graduate school during the early 80’s, I started doing consulting work in the emergent fields of molecular biology and biotechnology. This became a life sciences consulting practice that brought together venture capital, transactional advisory services, and corporate strategy. Scheer & Company is best known for having launched a series of companies spanning the fields of infectious disease, cardiology, oncology, and neurology, to name a few. We’ve had some pretty significant successes among the entrepreneurial enterprises we have launched and built. One of our companies launched a product that was ultimately acquired by Johnson & Johnson; another, a company called Esperion Therapeutics, developed a product in HDL (good cholesterol) therapeutics which was sold to Pfizer in 2004 for $1.3 billion. In the roles of founder and director of numerous companies, I have been involved in identifying technology, recruiting people and raising capital. In most of my more recent companies, I have served as Chairman of the Board.

MC: David, one of your companies, Aegerion Pharmaceutical, operates in the ultra-orphan disease world. Can you tell us a bit about that company?

DS: Aegerion has developed a drug for a very rare disease present in only one in a million people: Homozygous Familial Hypercholesterolemia (HoFH). The disease causes very high bad cholesterol that confers high risk for cardiac events like strokes or heart attacks, even in individuals as young as teenagers, for those who are untreated. We are pursuing approval with both FDA and European regulatory authorities, and we have put in place management and commercial infrastructures in the US and Europe to make the drug available to patients in need, when there is the proverbial regulatory green light. As Chairman of the Board of this company, I have become quite interested in the area of rare diseases.

MC: Lately, pharmaceutical companies seem to all be starting rare disease initiatives. This is in stark contrast to the traditional focus on blockbuster and “me-too” drugs. What is driving this change?

DS: The traditional view has been if there are not enough patients, it’s not really worth developing a drug. However, pioneering companies such as Genzyme, BioMarin, and more recently, Alexion, have successfully developed life-saving drugs to treat rare diseases while providing a return on investment for their shareholders. In so doing, they have opened the eyes of people in the pharmaceutical industry. This shift holds clear potential for organizations working toward the development of therapies for rare diseases, such as the Rett Syndrome Research Trust.

I suspect that rare diseases may also provide an easier path for drug approval. Much of the cost of drug development comes at the end, during the extremely large and expensive clinical trials that are needed for blockbuster drugs. In the rare-disease space, due to the small population sizes, trials will be much smaller, and therefore less expensive. Also, the regulatory process may be fast-tracked for a rare disease, as the FDA recognizes the enormous unmet need and cooperates with sponsors and patient advocates to provide new agents sooner.

So interest in innovation in the rare disease category has turned bullish, which makes this an exciting time for someone engaged in your work, Monica, and frankly also for people like me who are really interested in efficient and effective development of new drugs.

MC: Are large pharmaceutical companies set up to tackle drug development for rare diseases?

DS: I think the answer depends on the drug company. The bulk of the rare-disease experience in drug development has traditionally come from innovative smaller companies. For example, Genzyme, which started off as an idea on the back of an envelope, became a multimillion-dollar pharmaceutical company with a large number of products in its portfolio, and was recently acquired by Sanofi-Aventis. Sanofi now has a franchise that is very capable and active in the rare-disease field. Other companies have either built from scratch, made smaller acquisitions, or are making partnerships or deals with companies that have assets or programs in rare-disease drug development. Pfizer and GlaxoSmithKline have done this, and both now have rare-disease units.
I think it is too early to predict the success of these larger companies. Can the big companies be as effective as some of the smaller companies have been? Will the entrepreneurial spirit of a Genzyme in the early days be retained or lost as part of a larger company? We shall see.

MC: How do FDA drug reviews for a rare disease differ from those for a common one?

DS: The FDA has really had to modify its approaches to adapt to the needs of the rare-disease community. In fact, there is an orphan-disease unit within the FDA that is specifically tasked to review rare-disease drugs. These people are very familiar with how to evaluate a drug through a very different lens than is ordinarily used. It is important to keep in mind that regulatory decisions are always based on a favorable risk-benefit relationship.

MC: The Rett community, including families, clinicians and researchers, is highly concerned—-and properly so—with rigorous validation of pre-clinical advances and the complexities of developing solid protocols for outcome measures. Though Rett patients are a small population, the range of symptoms is staggering, so there are many issues to address.

DS: There are no perfect drugs – even Tylenol can have dreadful side effects if taken in excess, such as liver failure. The FDA must balance the solemn task of making available new and important therapies, while ensuring that such agents demonstrate safety and efficacy commensurate with the condition being treated.

MC: You were only recently introduced to Rett. What have you found most interesting thus far?

DS: That it has attracted some very talented individuals. The scientists, thought-leaders, and patient advocates involved in Rett Syndrome research represent an incredibly impressive group. Perhaps this is because Rett Syndrome is believed to be scientifically very tractable. It certainly helps that it is a single-gene disorder. The number of chronic conditions that can be attributed to a single gene is relatively low. So if I may say this, those in need of therapeutics for Rett Syndrome, may be fortunate in that there is an important foundation for discovery of potentially novel, disease-modifying therapeutics.

MC: I think the 2007 proof-of-concept reversal has also helped put Rett on the map; it had been a much more obscure disorder before that breakthrough.

DS: I agree. Each year in my not-for-profit work, I organize and chair a conference in New Haven, in conjunction with Yale and the Long Wharf Theater, called Global Health and the Arts,. For the past four years, this conference has promoted examination of important disease topics in public health and global health. This past May, we explored the neuropsychiatric disease arena. We had a major scientific symposium, with some of the most well known academic and industrial thought leaders from around the world, who were able to give us an update on relevant areas of science and technology, drug development, genetics, genomics, and translational medicine. In the middle of this event we actually had several individuals comment on the importance of the work being done in Rett and related disorders.

Monica, you need to continue doing what you do so well: ensure you have the best information from scientists at the cutting edge of this field, and then position that knowledge in a way it can be most effectively translatable. The more quickly drug development gurus can bring their expertise to the table, the better the chances of a successful outcome. I am very much looking forward to help you achieve that success.

MC: Thank you, David, and on behalf of every Rett family, welcome.


Ever wondered why most labs use male Rett mice for their experiments even though the females are the better model? What human symptoms are replicated in the Rett mice? What are some of the surprises these mice have in store for us? What are the complexities of doing well-designed and executed trials in mice? What are some of the pitfalls that the Rett field needs to avoid? What is the potential for the newly unveiled Rett rat? Listen and find out….

This past week, more than 30,000 neuroscientists convened in New Orleans for the annual Society for Neuroscience meeting. Here are some of their interesting (unpublished) findings on Rett Syndrome.

Rett rats

Recent progress in genetic engineering has made it possible to model Rett Syndrome in rats – whose behavior is easier to study than mice. Researchers led by Richard Paylor from the Baylor College of Medicine in Houston, Texas, designed a set of behavioral tests to capture the animals’ social interest, anxiety, vocalizations and sensory and motor abilities. The team found that male rats whose Mecp2 (the gene that is missing or mutated in girls with Rett Syndrome) is disrupted were less active, showed impairments in a memory task, and behaved in a way that suggested they have disrupted connections between sensory and motor brain areas.

IGF-1 on trial

Researchers administered a full-length version of insulin-like growth factor 1 (IGF-1) — which is now under clinical investigation for treating Rett Syndrome — to mice lacking Mecp2. This particular form of IGF-1 boosted neuron-to-neuron signaling and the ability of neural connections to change in strength, compared with untreated mutant mice. According to a report by, however, treatment did not improve mutant mice’s performance on a task of motor coordination and learning.

In a separate study of mutant mice, led by Jeffrey Neul’s team at Baylor, scientists administered a slow-release form of IGF-1, or PEG-IGF1, finding that it only slightly lengthened lifespan but did not improve heart rate, body temperature, breathing, motor function, or behavior. And a higher dose of PEG-IGF1 cut the lifespan of mice, the group found.

Neul is planning a clinical trial in adult women with Rett with a shorter, tripeptide form of IGF-1, which in 2009 scientists found delayed the onset of several symptoms of the disorder in a mouse model.

Selective expression

In 2010, Huda Zoghbi and her colleagues at Baylor showed that neurons that dampen brain signals through their production of the inhibitory chemical GABA (gamma-aminobutyric acid) play an important role in the development of Rett.

For a preliminary study presented this week, Zoghbi’s group found that reactivating Mecp2 expression exclusively in GABA neurons well into adulthood (6 and 9 weeks) improved two symptoms of Rett — obesity and ataxia — in male mice missing Mecp2. Her group is also measuring cognitive and breathing symptoms after selectively reactivating the gene in GABA neurons.

Reprogrammed Rett cells

Alysson Muotri at the Scripps Research Institute in La Jolla and his collaborators took cells from human males with Rett and converted them into induced pluripotent stem (iPS) cells, which have the ability to form any other cell in the body.

The group found that several molecular signaling pathways differ between the iPS cells of healthy people and individuals with Rett as their cells begin to form neurons. These early changes may underlie neuronal features of Rett. The scientists are working to validate the biochemistry, but report that the new findings suggest that iPS cells derived from people with Rett may help identify new drug targets.

Progress on point mutations

Two years ago, researchers from the Barrow Neurological Institute in Phoenix, Arizona, described a new Mecp2 mouse — the A140V model —that reproduces a point mutation (meaning a single “letter” of the DNA code is replaced).

Male mice with the mutation survive, though they have X-linked mental retardation and show some brain abnormalities — such as less intricate neuronal branching and more tightly packed cells – compared with healthy mice. Unlike other mutants, however, the A140V has a normal lifespan and weight gain and no seizures or trouble breathing. The same group presented a detailed protocol to characterize the shape and size of brain cells of female mice that carry the mutation.

Monica Coenraads, Executive Director of the Rett Syndrome Research Trust, interviews David Katz, PhD about his Journal of Neuroscience paper published 10/3/2012 and entitled “Brain Activity Mapping in Mecp2 Mutant Mice Reveals Functional Deficits in Forebrain Circuits, Including Key Nodes in the Default Mode Network, that are Reversed with Ketamine Treatment.”

David Katz Interview from RSRT on Vimeo.

Yesterday (October 8) Shinya Yamanaka of the University of Kyoto, Japan, was awarded the 2012 Nobel Prize in Physiology or Medicine for his discovery that a person’s cells can be reprogrammed to pluripotency – meaning they have the ability to form most other cell types in the body. Yamanaka shares the prize with John B. Gurdon of the Gurdon Institute in Cambridge, UK, who is known as the “godfather of cloning.”

After stem cells were initially isolated from mice, Yamanaka’s team found four genes that, in combination, could be introduced to adult cells to turn them into embryonic-like cells. The resulting so-called induced pluripotent stem (iPS) cells could in turn be coaxed into mature cell types such as neurons and gut cells. Yamanaka’s findings, published in 2006, gave way to new cell-based models diabetes, Parkinson’s disease, and other disorders.

Yamanaka’s reprogramming technique has also allowed researchers to study the early development of neurons derived from people with Rett syndrome. In 2010, Alysson Muotri’s research group at the University of California, San Diego, turned skin cells from people with Rett into pluripotent stem cells using Yamanaka’s methods.

“The data is already revealing a new biology,” writes Muotri in an email. The group has uncovered differences between human Rett neurons and those derived from animal models of the disorder, for example. “I believe this is a complementary new tool that will allow us to understand the molecular and cellular mechanism leading to the Rett condition,” he adds.

Importantly, Yamanaka’s fundamental discovery and the subsequent iPS cell work on Rett syndrome will also speed drug discovery, by allowing researchers to test candidate medicines directly on human neurons, Muotri says. Yamanaka’s winning the prize was “well deserved,” he adds.