NEW YORK—In a partnership that has already made "incredible progress," according to the principal investigator at Mount Sinai School of Medicine (MSSM), the New York-based institution and Medisyn Technologies have announced a collaboration to develop novel , -amyloid (Ab) lowering drugs as a treatment for Alzheimer's disease (AD). An estimated 4.5 million Americans currently suffer from Alzheimer's disease—a number that has doubled since 1980 and is expected to reach 12 million to 16 million by 2050. There are currently no drugs that prevent or cure the disease.
The research began with MSSM screening some 2,000 FDA-approved drugs for activity against AD. The goal, according to MSSM's Dr. Giulio Maria Pasinetti, Professor of Psychiatry and Neuroscience and Geriatrics and Director of the Alzheimer's disease Translational Research Laboratory in the Department of Psychiatry, was to discover novel compounds that would not just ameliorate symptoms of the disease but modify its progression.
"That's when we started communicating with Medisyn about their topological methodology," Dr. Pasinetti relates. "At the time, it was a highly novel approach, never done before in neurogenerative disorders, certainly not in Alzheimer's disease. We have since been through a series of iterations to reduce toxicity, enhance penetration of the blood-brain barrier and improve activity in order to get to clinical studies." The partners hope to complete in vivo efficacy validation of the novel drug candidates by the end of 2007.
David Land, president of Medisyn Technologies, describes Medisyn's topological approach as differing markedly from traditional molecular descriptions that are based on bonds and bond angles. Instead, Medisyn takes compounds that are known to be bio-active and compares them to an inactive training set, examining differences mathematically to develop a template. "By next applying our Forward Engineering discovery engine to MSSM's pre-clinical in vivo work and therapeutic expertise, we anticipate rapid identification of new validated in vivo leads to build a diverse preclinical pipeline of drug candidates for treating AD," he states.
Land notes that Medisyn's approach describes "the social interaction of atoms in the molecule," and that this abstract mathematical description ensures that it is unbiased. The technology captures 1,400 different mathematical descriptions or topological indices. Proof of the pudding, he adds, is the company's current roster of 35 active projects, 22 of which are partnered.
Applied to the MSSM lead set, previously shown to be effective in reducing the generation of endogenous Ab1-40 and Ab1-42 peptides in primary neuron cultures, the Medisyn topological methodology created a template of the specific molecular features of the lead compounds, which was then used to identify 24 diverse new lead compounds. From this set, 21 compounds tested active for lowering Ab1-40 and 16 compounds tested active for Ab1-42 peptides. To date, 10 compounds meet all parameters for potency and low toxicity, with two showing a 10-fold increase in potency over the best performing compounds in the MSSM lead set.
Ongoing activity-based topological studies will provide clarification of the molecular features responsible for Ab-lowering activities in vivo including the absence of hypotensive side effects, low toxicity, high bioavailability and high penetration across the blood-brain barrier. Validated and characterized lead compounds will be out-licensed to pharmaceutical companies for further clinical development. Commercialization rights will be shared between MSSM and Medisyn Technologies.