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Friday, June 29, 2018

Vanderbilt licenses compound to Nashville’s Appello to advance Parkinson’s therapies

By Heidi Hall   Jun. 29, 2018






Vanderbilt University has signed a licensing agreement with Nashville-based start-up Appello Pharmaceuticals, Inc. to advance novel compounds developed by researchers in the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) for the treatment of Parkinson’s disease.
The drug-like molecules bind to mGluR4, a glutamate receptor that is highly expressed in areas of the brain directly relevant to Parkinson’s disease. Called positive allosteric modulators (PAMs), they adjust receptor activity—and thus the brain’s activity of the neurotransmitter glutamate—like a dimmer switch in an electrical circuit.
The molecules were developed with major support from The Michael J. Fox Foundation for Parkinson’s Researchand with the help of the Nashville-based Atticus Trust, a private foundation overseen by the family of Betty and Martin Brown.
“The Michael J. Fox Foundation placed a major investment in this program from its earliest stages,” said P. Jeffrey Conn, founding director of the VCNDD and the Lee E. Limbird Professor of Pharmacology in the Vanderbilt University School of Medicine.
“Also, we are especially indebted to the Brown family, who provided more recent support for key studies that were needed to bring the program to a point where it was ready for partnering with Appello,” Conn said.
Appello was established with major investment from New York-based Deerfield Management, which specializes in accelerating drug development projects at universities and other private, non-profit institutions.
Under the terms of the agreement, Appello will have the right to develop and commercialize products resulting from Vanderbilt’s research program. In turn, Vanderbilt University will obtain an equity interest in Appello as part of the consideration for the license.
“Appello is the perfect vehicle to accelerate the translation of our mGlu4 PAMs to Parkinson’s disease patients,” said Craig W. Lindsley, director of medicinal chemistry for the VCNDD, University Professor and William K. Warren Jr. Professor of Medicine.
“The center has advanced multiple programs through licenses and philanthropy,” Lindsley said, “but the opportunity to work with investors and build a company focused on a non-dopaminergic treatment for Parkinson’s disease was a golden opportunity to ensure our compounds get to patients.”
“Strategic collaborations are key to accelerating the impact of the great basic biomedical research we do at Vanderbilt” said Padma Raghavan, vice provost for research at Vanderbilt University. “This particular collaboration with Appello serves as an essential bridge toward improving patients’ lives.”
An estimated 1 million Americans have Parkinson’s disease, a progressive brain disorder characterized by resting tremor, rigidity and slowness of movement, as well as a battery of non-motor symptoms. It is caused by the death of nerve cells in a specific brain region that produce the neurotransmitter dopamine.
Dopamine replacement therapy, today’s gold-standard treatment for Parkinson’s, relieves some motor symptoms of the disease, but over time it causes debilitating side effects such as involuntary, uncontrollable movements, called dyskinesia.
It is believed that dyskinesia is caused at least in part by the ebb and flow of dopamine levels in the brains of people who are receiving dopamine replacement therapy. Current Parkinson’s treatments also provide less and less benefit to patients as the disease worsens over the long term.
The Vanderbilt compounds work in a fundamentally different way from dopamine replacement therapy, by bypassing the dopamine system altogether and instead modulating another of the brain’s neurotransmitters, glutamate.
The compounds represent an approach to correct the dysregulated signaling observed in Parkinson’s disease. When given systemically in a preclinical model of Parkinson’s disease, they reach the brain and relieve motor symptoms, including rigidity and akinesia, a “freezing” of certain motor muscles.
In this way they pharmacologically mimic a surgical procedure that has been successful in alleviating symptoms of Parkinson’s disease.
Conn and Lindsley’s colleagues in this effort include: Carrie Jones, assistant professor of pharmacology and director of behavioral pharmacology in the VCNDD; Colleen Niswender, research professor of pharmacology and director of molecular pharmacology in the VCNDD; Jerri Rook, research assistant professor of pharmacology (behavioral pharmacology); and Annie Blobaum, research assistant professor of pharmacology (drug metabolism and pharmacokinetics).
Media inquiries
Liz Entman, (615) 322-NEWS
Liz.Entman@Vanderbilt.edu

https://news.vanderbilt.edu/2018/06/29/vanderbilt-appello-parkinsons-therapies/

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