July 28 2014
Posted July 15, 2013
SAN DIEGO, July 16, 2013 – Confirming an enzyme in the serine hyrdrolase family as a therapeutic target to slow and potentially reverse the effects of Down syndrome and Alzheimer’s disease is the goal of new research announced today by Abide Therapeutics, in collaboration with researchers at the University of California, San Diego School of Medicine and funded by a grant from the Cure Alzheimer’s Fund.
The principle investigator (PI) for the grant is Alexander Kleschevnikov, Ph.D., and the co-PI is William Mobley, MD Ph.D., who are both from the Department of Neurosciences and Down Syndrome Center for Research and Treatment at UC San Diego.
The grant will support early stage development research to evaluate a serine hydrolase inhibitor to delay or prevent a mouse model of Down syndrome. Pioneering innovative approaches to selectively target the serine hydrolase enzymes group with collaborators at UC San Diego, Abide has created novel small molecule inhibitors of its target enzyme, monoacylglycerol lipase (MAGL) of the serine hydrolase family through the company’s selective targeting technology.
“The results of this study will help better fit the pieces of the Alzheimer’s puzzle together,” said Tim Armour, president and CEO of the Cure Alzheimer’s Fund.
Down syndrome is caused by chromosome 21 trisomy, which contains genes involved in Alzheimer’s disease, such as amyloid precursor protein (APP). By age 40, people with Down syndrome have significant levels of Alzheimer’s type neuropathology, including plaques and tangles considered to be hallmarks of the disease. Down syndrome mouse models exhibit similar abnormalities in brain structure and cognition observed in people who have Down syndrome and Alzheimer’s disease and can be used to study both diseases.
“Foundational research from Dr. Cravatt and two independent groups have shown monoacylglycerol lipase (MAGL), a serine hydrolase family member, plays a significant role in Alzheimer’s disease progression and beta-amyloid accumulation,” said Alan Ezekowitz, MBChB, D.Phil., president and CEO of Abide Therapeutics. “As we know, serine hydrolases are involved in many human physiological processes and have been implicated and successfully targeted to treat major diseases. However, they still have been largely unexplored as a complete class of drug targets, and we are very interested in interrogating this particular serine hydrolase as a therapeutic target for Alzheimer’s disease.”
Work from the laboratory of Ben Cravatt, one of the scientific co-founders of Abide Therapeutics and professor at The Scripps Research Institute, illustrated the link between endocannabinoid pathways and the generation of proinflammatory eicosanoids in the brain (Nomura, et al. Science 2011). The key regulator of these pathways is the MAGL enzyme. Two independent groups built on this observation by showing that genetic and or pharmacological inactivation of MAGL reversed many features Alzheimer’s disease in mice (Piro et al. Cell Reports 2012; Chen et al. Cell Reports 2012).
Dr. Ezekowitz continued, “These foundational findings prompted us to collaborate with the Mobley group at UC San Diego to explore whether these findings might extend to models of Down syndrome. Then based on our own encouraging preliminary results we sought support from Cure Alzheimer’s Fund to continue the Abide and UC San Diego collaboration.”
“We are extremely grateful for the Cure Alzheimer’s Fund for supporting this project, which has the potential to benefit patients with Down syndrome and if successful, will have a direct application to patients with Alzheimer’s disease,” said Dr. Mobley.
About Serine Hydrolases
The large family of serine hydrolases are validated but largely under explored as drug targets. These enzymes play a key regulatory role in human physiological processes, such as regulating CNS signaling, digestion, metabolism, inflammation, blood clotting, and life cycle of viruses and pathogens. Thus, the ability to target serine hydrolases has broad therapeutic applications. The proprietary Abide technology platform provides a unique highly selective small molecule collection that specifically targets the common catalytic site of serine hydrolases. The technology provides a rapid and effective method for target identification and validation.
About Abide Therapeutics
Abide Therapeutics is focused on developing innovative medicines that target serine hydrolases, one of the largest enzyme classes in nature with validated but mostly untapped therapeutic potential. Serine hydrolases play important regulatory roles in human physiology and disease. Abide has created a proprietary platform, based on technology developed at The Scripps Research Institute by Professors Ben Cravatt and Dale Boger, that specifically targets serine hydrolases with selective small molecules. The ability to target and modulate serine hydrolases has potential to develop new medicines in many therapeutic areas. Abide is located in San Diego. To learn more, visit www.abidetx.com.