Modulation of PDE4B by Aptamers for the Treatment of Alcohol Use Disorder

Project Summary Alcohol use disorder (AUD) affects over 14 million Americans, causing significant physical, emotional, and social harm, and contributing to over 178,000 deaths annually. Current medical treatments for AUD, such as naltrexone, acamprosate, and disulfiram, demonstrate limited efficacy. Recent genome-wide association studies (GWAS) have identified phosphodiesterase 4B (PDE4B) as a significant genetic risk factor for alcohol consumption and AUD. This suggests that PDE4B plays a crucial role in the predisposition to substance abuse by regulating cAMP levels in brain regions involved in reward processing and addictive behaviors. Our company, EnvisBio LLC, aims to develop novel therapeutic agents targeting PDE4B to treat AUD. Specifically, we propose to identify aptamers that regulate PDE4B activity. Aptamers are single-stranded oligonucleotides that fold into defined conformations to bind their targets. They offer several advantages over traditional small molecule inhibitors and large biomolecules, including ease of chemical synthesis, lack of immune response, and the potential for modification to enhance stability and blood-brain barrier penetration. We propose two Specific Aims in this Phase I SBIR. Aim 1 involves multiple parallel approaches to screen and identify aptamers that bind to PDE4B in humans and rats. In Aim 2, we will test the function of aptamers in cell-based assays. By achieving these aims, we will identify PDE4B-specific aptamers with high specificity that are negative allosteric modulators. A subsequent Phase 2 SBIR project will allow us to test the in vivo effect of these modulators in rat models of alcohol self-administration, with the ultimate goal of advancing them into human clinical trials for treating AUD.