Therapeutic approaches in spinal bulbar muscular atrophy (SBMA): exploiting the alternative AR-A isoform to mitigate the toxicity of the mutant androgen receptor that drives the disease

SBMA is an untreatable neuromuscular disease affecting about 2/100,000 individuals over the world. Recent studies suggested that this prevalence may have been greatly underestimated. The disease is due to a mutant androgen receptor with an elongated polyglutamine tract (ARpolyQ). The ARpolyQ becomes toxic to affected cells only after its activation with androgens. Thus, most proposed therapeutic approaches in SBMA, are based on testosterone production and/or activity inhibition, as well as on ARpolyQ downregulation. Unfortunately, these approaches have severe side effects due to androgenic function loss in males, with important endocrine consequences poorly tolerable for patients. Here, we will explore novel genetic and pharmacologic approaches to induce alternative initiation of AR translation to skip the insertion of the elongated polyQ tract into AR, abolishing its toxicity. The advantage is that we will preserve AR activity in SBMA patients, favouring the production of a not toxic AR protein (the AR-A). The AR-A retains all critical functional AR domains and heterodimerizes with the endogenous mutant ARpolyQ, preventing its toxic conversion. To enhance AR-A production in SBMA affected cells, we will take advantage of our preliminary data showing that AR-A is produced using the same template utilized for ARpolyQ, but starting after the region encoding the toxic polyQ. Thus, we will test different molecules (like antisense oligonucleotides, SINEUP, etc.) for their ability to re-route the use of the AR template to generate AR-A instead of ARpolyQ. If successful, these approaches may provide novel and safe therapeutic approaches for SBMA.