FP.10 Combination of BIO101 with antisense oligonucleotide therapy demonstrates synergistic beneficial effects in severe SMA-like mice

Spinal Muscular Atrophy (SMA) is a neurodegenerative disease characterized by the loss of spinal motor neurons and progressive muscular atrophy, due to insufficient level of survival of motor neuron protein (SMN). SMA is defined as a non-cell autonomous disease, involving numerous tissues and cell-types, including skeletal muscles. In this context, strategies to overexpress SMN protein and approaches to maintain neuromuscular functions are currently developed and appear as promising long-term prospect for therapy in SMA. We evaluated the efficacy of Sarconeos (API BIO101), a Mas receptor activator, as monotherapy and in combination with ASO therapy in severe SMA-like mice (Smn^Δ7/Δ7; 2 copies SMN2^+/−). We showed beneficial effects of BIO101 as monotherapy on the entire motor unit with a complete protection of lumbar motor neurons, a limited muscular atrophy (-17% in the tibialis, -40% in the plantaris, and -12% in the soleus), an increased vascularization (+10% in the tibialis and the plantaris, +3% in the soleus), and an accelerated maturation of both muscular fibers and neuromuscular junctions. Interestingly, these benefits were independent of SMN expression. In combination with ASO therapy, BIO101 demonstrated synergistic effects on body weight (+1% with BIO101, +11% with ASO, +32% with ASO + BIO101 at 10 days after birth compared to vehicle) and increased survival (+5 days of median survival). Most importantly, the co-treated SMA-like mice improved their moving capacity (+40%) and their fatigue resistance (4,2-fold) compared to SMA-like mice treated only with ASO. These results provide strong evidence that BIO101, with beneficial effects on the entire motor unit, constitutes an efficient SMN-expression-independent therapy for improving muscle function and should be considered as a potential combinatorial option for a new therapeutic strategy in SMA patient.