Defining the role of CD38 and its potential as a therapeutic target in SBMA

Philadelphia College Of Osteopathic Med, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY: Defining the role of CD38 and its potential as a therapeutic target in SBMA Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive, X-linked neuromuscular disease affecting men, and is caused by a polyglutamine expansion within the androgen receptor (AR). With no disease-modifying therapy, identifying potential therapeutic interventions for this patient population is pressing. Mitochondrial and metabolic dysfunctions are critical to pathogenesis. SBMA patients suffer severe fatigability of their musculature, but the field has yet to interrogate metabolism in SBMA patient skeletal muscle. Our studies outlined herein will fill this gap by using state of the art stem cell technology paired with CRISPR-corrected isogenic controls to investigate metabolic alterations in SBMA patient-derived iPSCs differentiated into skeletal muscles. One of the essential co-factors utilized to sustain energy by powering mitochondria and overall metabolism, NAD+, is substantially diminished in skeletal muscle of mice modeling SBMA. The mechanism(s) by which NAD+ is reduced and how to recover it has been elusive to the field. Cluster of differentiation 38 (CD38) is an ecto-enzyme that is expressed by immune cells, as well as other tissues including skeletal muscle fibers, and CD38 expression patterns in mice are similar to humans. CD38 is primarily a NAD+ glycohydrolase, and it is the main NAD+ catabolic enzyme. We performed metabolomics analyses of skeletal muscle samples from transgenic mice modeling SBMA (AR100Q) and it revealed a 2-fold increase of one the products of CD38’s hydrolysis of NAD+, ADPR, over wild-type mice. Pharmacologic inhibition of CD38 reduced ADPR and restored NAD+ to levels similar to those of wild-type mice. These data suggest that hyperactivity of CD38 may be one of the major mechanisms by which NAD+ is depleted and that inhibiting its activity may be a means to restore NAD+ in SBMA. CD38 inhibition also enhanced glycolysis, corrected TCA cycle activity, and improved motor function of these SBMA mice. In this proposal we will further interrogate the role of CD38 in SBMA pathogenesis in two mouse models of SBMA (AR100Q and AR113Q (knock in)), and we will test more clinically translational CD38 inhibitors. CD38 activity in either tissue resident immune cells or skeletal muscle fibers can impact NAD+ and metabolism in tissue. Thus, we have outlined studies in mice to evaluate inflammation in SBMA and determine the relative contribution of CD38+ immune infiltrate to NAD+ depletion in skeletal muscle tissue. Investigations using skeletal muscle cultures from SBMA patients will complement these CD38 studies in mice. Overall our proposal highlights the potential to correct metabolic and motor function in SBMA without untoward effects upon the normal function of AR that is critical for muscle function. CD38 inhibitors are in clinical development my multiple biotechnology companies and our studies have potential to establish a rationale for future trials in SBMA patients.