Three years ago, the National Institutes of Health launched an innovative Blueprint Neurotherapeutics Network to pair academic and industry scientists in an attempt to develop strategies to treat a range of disorders that affect the nervous system. Now, the NIH has awarded its next three grants, bringing the total number of active projects to ten. Two of the ongoing projects will soon be entering preclinical development. Four other grantees pulled out of the program because of technical hurdles that arose during the first two years, said Rebecca Farkas, PhD, a program director in the Office of Translational Research at the National Institute of Neurological Disorders and Stroke who manages the $50 million network.
“Simply receiving grants wasn't enough without experience in drug discovery or the infrastructure in place to conduct these studies,” said Dr. Farkas. “In this new approach, scientists can work with consultants and contract research organizations (CROs) in the network to carry out translational research that could ultimately lead to clinical trials.”
The goal, she said, is to help academic scientists and small biotech companies take a potential drug through to phase I clinical testing and to ultimately entice a pharmaceutical company or other private funder to move it forward through advanced clinical trial testing towards federal approval. Part of this novel approach is an agreement with the researchers and consultants in the network that the intellectual property remains with the principal investigator.
The latest three projects include development of therapies for Fragile X Syndrome, age-related macular degeneration (AMD), and nicotine addiction. The program focuses on rare diseases and novel approaches to new ones. “We don't want to pursue something big pharma would do,” added Dr. Farkas.
Al Robichaud, PhD, chief scientific officer at Sage Therapeutics, heard about the Blueprint grant and believed that it would provide the two-year old company with additional resources that were needed to develop and test novel compounds for patients with Fragile X Syndrome (FXS), an orphan genetic disorder. The company is interested in neuroactive steroids for a range of conditions and decided to pursue Fragile X, where there are no effective treatments. Citing a paper that was published in 2010 in the Journal of Neuroscience, he said that there is evidence of reduced activity of gamma-aminobutyric acid (GABA)-A receptors in the disease, and “molecules that could increase GABA-A activity could work to reduce some of the symptoms and have potential to impact the disease process itself.”
The investigators have identified and tested several molecules that “show improvement in receptor function” in animal models of the disease, he added. In particular, he said that increasing GABA-A could have an impact on reducing social phobia, anxiety, and dysfunctional social interactions that impact daily life for these patients and their families. Dr. Robichaud believes that targeting GABA-A will help reset the brain to effectively regulate neuronal excitability.
Being part of the network has provided access to chemical and pharmacokinetic resources to identify a compound that has the best of everything: low toxicity; ease of administration; and, most importantly, efficacy. “This program is extremely helpful in moving us towards our goal of identifying the right compound for patients desperately in need of beneficial treatments.” They are now searching for molecules that target GABA-A receptors. Dr. Robichaud said that they could have a molecule in hand to begin testing in patients in the next two years.
To remain in the network, scientists who receive funding have to meet certain critical milestones outlined by the program. “The hope is that this grant will enable us to accelerate our development of an innovative therapy designed to address the symptoms of Fragile X, and could potentially have a durable, disease-modifying effect, as well,” said Dr. Robichaud.
An award was also given to scientists at the Scripps Research Institute in Florida to develop therapies for nicotine addiction. Their work focuses on orexin 1 (OX1) receptors that play an important role in the stimulatory effects of nicotine. Paul J. Kenny, PhD, an associate professor of neuroscience, and his colleagues believe that orexin 1-receptor antagonists have the potential to effectively help people quit smoking.
Previous work from Dr. Kenny's group has shown that orexin-A (OXA) acts through OX1 in the brain's reward center (the amygdala). The molecule is made by a few thousand neurons in the hypothalamus. The group identified an intriguing molecule that safely blocks OX1 and reduces nicotine-seeking behavior in animals. The scientists want to develop it to help people stop smoking.
Dr. Kenny and his colleagues have had federal support from the National Institute on Drug Abuse to develop new compounds. They have been using high throughput screening to identify potential molecules that block OX1.
“This Blueprint network provides huge resources to enhance potential mechanisms,” said Dr. Kenny. “It has been great to have direct access to individuals with a lot of experience in drug development. We are learning a lot and the program is taking on a life of its own.” They have identified several compounds and are now looking for the best one to move forward into clinical testing. “This has been a tremendous opportunity,” he added.
AGE-RELATED MACULAR DEGENERATION
Another grant in this latest round of funding went to University of Utah cardiologist Dean Yaw Li, MD, PhD, who studies how blood vessels are affected by acute and chronic inflammation. He began studying the cardiovascular system but soon realized that it would also be relevant to diseases of the eye, like diabetic retinopathy and wet AMD. Dr. Li and his colleagues have found that inhibiting an inflammatory molecule called Arg6 could prevent AMD.
He started a biotech company in 2007 — Navigen — that is now designing drugs that work on the Arg6 pathway. Again, Dr. Li was hoping that the expertise at hand in the Blueprint network would help them fine-tune strategies to develop medicines that target this pathway. “We now have access to companies and scientists in the network that do different things than we can do in an academic setting or in a small company. An individual company usually doesn't get the attention of big companies, and this program allows you to be part of something big.”
The inflammatory process disrupts blood vessels and causes them to leak. It is the soggy vessels that can lead to blindness. If they can reduce vascular leakage without undermining the inflammatory response they think that they will be able to prevent blindness. They had a molecule but they were having problems getting it to work right and still be safe. It turned out that the molecule wasn't potent enough and they had to use so much that it was toxic. They are now working on strategies to make more potent compounds.
•. Olmos-Serrano JL, Paluszkiewicz SM, Martin BS, et al. Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of Fragile X syndrome. J Neurosci. 2010; 30:(29):9929–9938.
•. Hollander JA, Lu Q, Cameron MD, et al. Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci USA. 2008; 105:(49):19480–19485.