Rare Disease Drug Discovery and Development Under One Roof

From identifying the genetic causes of rare autonomic nervous system disorder called familial dysautonomia (FD) to developing a screening test to discovering a potential treatment, Susan Slaugenhaupt, a neurologist at Harvard University and Massachusetts General Hospital, has utilized NINDS funding for every step of her 23-year-long effort to combat the devastating disease. Now, with help from the NIH Blueprint Neurotherapeutics Network, Dr. Slaugenhaupt is developing a new therapeutic to treat FD with plans to advance into clinical trials.

We’ve written a lot in the past couple of years about the importance of basic neuroscience discoveries in laying the foundation for the development of therapies to treat diseases of the brain and nervous system. For many reasons, though, drug discovery and drug development are rarely carried out by a single investigator. A basic research discovery from one lab is usually translated into a potential treatment by a different lab, most likely in the pharmaceutical industry. It is more often the case that a researcher’s promising discovery languishes on a shelf because she does not have the expertise or the resources to develop the drug to the point that the biotech/pharmaceutical industry takes an active interest in pursuing it. More and more, though, scientists can bring under one roof the tools and personnel they need to advance the development of their discoveries, and NINDS is actively supporting these researchers.

Other notable BPN projects include efforts to translate basic science discoveries into treatments for:

Highlights of the BPN program can be found on the OTR website.

In 2011, the NINDS Office of Translational Research (OTR) in conjunction with the NIH Blueprint for Neuroscience Research launched the Blueprint Neurotherapeutics Network (BPN) to encourage the development of small molecule drug discovery. Knowing that the pharmaceutical industry is more likely to get behind a new potential therapy that has been clinically validated, NINDS, through the BPN, offers support ranging from hit-to-lead chemistry through phase 1 clinical testing and further clinical studies can be funded by industry partners or through the NINDS Office of Clinical Research. The network is currently collaborating with additional researchers seeking to design treatments for a range of conditions including Alzheimer’s disease, macular degeneration, and drug addiction. An update to the BPN program was launched in 2014, along with translational funding programs for developing biologic-based therapies (CREATE Bio) and devices (CREATE Devices).

One BPN project that highlights the success of NINDS in facilitating translational neuroscience focuses on familial dysautonomia (FD), also known as Riley-Day syndrome—a rare genetic disorder with no available treatment that affects the development and survival of the sensory and autonomic nervous systems. Over the past 23 years, NINDS-funded FD projects have identified: the gene responsible for FD; a genetic screen to identify at-risk populations; a molecule that could reverse FD’s symptoms; and a mouse model in which to test the drug. The majority of that work has been performed or led by a single investigator, Harvard University and Massachusetts General Hospital neurologist Susan Slaugenhaupt external link.

FD_skin cells

Human neurons derived from the reprogrammed skin cells of a familial dysautonomia patient. Credit, Mats Nilbratt, Harvard University, Massachusetts General Hospital

Problems related to FD first appear in infancy. Symptoms include poor muscle tone, poor growth, frequent lung infections, difficulty maintaining body temperature, and difficulty with feeding. Children with the disease can experience frequent vomiting, bone fractures, poor balance, and kidney and heart problems. In addition, roughly one third of children with FD have a learning disability. As patients grow into adulthood, their problems with balance increase and they often need assistance to walk. Sudden death occurs in half of FD adults by age 40. While extremely rare in the general population, FD occurs in about 1 in 3,700 individuals of Ashkenazi Jewish ancestry. Thanks to a genetic test for the disease, FD has been getting increasingly rare. Still, not all individuals at risk of having children with FD are aware of the risk or the genetic test, creating the need for a drug to treat this devastating condition.

Dr. Slaugenhaupt has been studying FD for her whole career. As a new faculty member at Harvard, she was a co-investigator on an NINDS R01 grant that resulted in the discovery in 2001 that FD is caused by a mutation resulting in the mis-splicing of the gene IKBKAP external link. This mutation reduces the production of the protein IKAP, which plays a role in gene transcription. Two years later, with the assistance of the NINDS Sponsored Neurodegeneration Drug Screening Consortium, she identified a plant growth hormone called kinetin that can restore proper splicing of IKBKAP external link, providing the first potential treatment for FD. Kinetin is currently being tested for safety and efficacy in a phase 2 clinical trial. Furthermore, Dr. Slaugenhaupt’s discovery that the oral ingestion of kinetin can target gene-splicing errors may contribute to treatments for other splicing-related diseases such as Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA).


Dr. Susan Slaugenhaupt. Image credit: MGH.

With a candidate for the treatment of FD in hand, Dr. Slaugenhaupt and her lab switched gears. Using a continuation of her NINDS R01 grant and her own NINDS R21 grant, she developed a genetic mouse model in which to test kinetin external link, which has been demonstrated to cross the blood brain barrier. Then, in 2010, she partnered with the NIH Chemical Genomics Center (NCGC) to screen dozens of kinetin analogues to find more effective compounds. Recognizing Dr. Slaugenhaupt’s drive to develop a treatment for FD patients, her proposal was judged highly meritorious by peer review and she joined the BPN network in 2012.

Susan Slaugenhaupt Basic Research to Drug Discovery_new.001

Timeline for NINDS-funded familial dysautonomia research.

BPN has provided assay development, chemistry, and PK (pharmacokinetics) expertise, which are combined with Dr. Slaugenhaupt’s FD biology expertise to form the team that is attempting to optimize the chemical structure of kinetin to make it a safe and effective treatment. Over the past four years, the Lead Development Team for Dr. Slaugenhaupt’s project has synthesized over 400 compounds as they perform the medicinal chemistry necessary to identify a clinical candidate. Their work has yielded compounds with significantly increased potency and efficacy. The team also worked to improve ADME (absorption, distribution, metabolism, and excretion) properties while maintaining the increased potency.

With a viable clinical candidate nearly at hand the team attracted outside interest. Dr. Slaugenhaupt and Massachusetts General Hospital teamed up with PTC Therapeutics external link in December 2015 to complete the development of, and commercialize, a treatment for FD that they plan to test in clinical trials in 2017. Dr. Slaugenhaupt hopes the treatment can be offered to patients within three to four years.

NINDS is thankful for Dr. Slaugenhaupt’s commitment to translating her scientific discoveries into treatments that can relieve the suffering of patient with this devastating disease and we are proud to sponsor her research. We look forward to the opportunity to use the BPN program to help Dr. Slaugenhaupt and other NINDS investigators bring their discoveries to patients in need.

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