HDAC2 Inhibitors for the Treatment of Cognitive Deficits in Alzheimer's Disease

DESCRIPTION provided by applicant Alzheimerandapos s disease AD is one of the most significant public health problems of the st century with the number of patients in the US estimated to reach million by and an annual cost of care projected to reach $ trillion Current treatments for the disease including cholinesterase inhibitors and memantine have limited effect for a short duration There is a pressing need to develop better therapies to relieve the cognitive impairments of the disease reduce the cost of care and delay the institutionalization of AD patients The goal of the proposed studies is to test novel selective HDAC inhibitors for their potential in treating AD Rodin Therapeutics has compounds that were identified using biochemical and cell based assays for both potency to inhibit HDAC activity weaker or no activity on other class I HDACs and high residence time on HDAC vs HDAC The combination of potency and high residence time on HDAC has led to the identification of a unique chemical series of compounds selective for HDAC with drug like properties suitable for in vivo work Here we propose studies for efficacy to reverse the inhibition of synaptic function in a murine model of neurodegeneration Further we propose to demonstrate that HDAC selective inhibitors are free of the toxicity associated with currently available non selective Class I HDAC inhibitors The proposed project will demonstrate that newly discovered small molecule inhibitors of HDAC will not affect hematopoesis a side effect associated with liabilities of pan Class I HDAC inhibitors e g CI SAHA entinostat and yet effectively upregulate synaptic genes associated with cognitive function and improve cognitive behavior A novel HDAC inhibitor with the desired profile of cognitive enhancement upregulation of synaptic gene and no effect on hematopoietic endpoints would confirm that selective HDAC inhibitors have a wider therapeutic index than pan class I HDAC inhibitors currently available At the successful conclusion of this Phase SBIR we will be poised to select a compound to move forward into IND enabling studies to support human clinical trials Phase of the SBIR proposal will fund GLP toxicity studies in two species The proposed studies align with the mission of the institute to develop improved treatments for individuals with age related cognitive dysfunction secondary to Alzheimerandapos s disease PUBLIC HEALTH RELEVANCE Rodin Therapeutics Narrative Alzheimerandapos s disease with million afflicted in the US is an illness with enormous impact on patients families and the health care system The proposed studies will investigate in preclinical models the safety and potential efficacy of a new treatment for AD The work aligns with the mission of the institute to develop improved treatments for individuals with age related cognitive dysfunction secondary to Alzheimerandapos s disease