Optimization of AAV9 gene therapy for Spinal Muscular Atrophy with respiratory distress Type 1 using in vivo disease models

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive motoneuron disease with infantile onset. It is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene, which lead to a deficient amount of the encoded protein. The main clinical symptoms are distal muscular atrophy and diaphragmatic palsy which requires supportive ventilation. Currently there are no effective therapies available. Recently, we demonstrated that adeno‐associated virus 9 (AAV9)-mediated gene therapy showed promising results in preclinical models. To refine this approach, we compared the efficiency of two AAV9-IGHMBP2 vectors, carrying different promoters, by administering them intracerebroventricularly (ICV) in SMARD1 mice model (nmd), during the presymptomatic phase at post natal day 1. Expression analysis demonstrated a significant increase in the IGHMBP2 protein expression level compared to control. Treatments resulted in an extended survival time, higher body weight and improvement of the motor behaviours, with an amelioration of the performance in the hindlimb splay and rotarod tests. Histopathological analysis, performed on mice muscle, showed an increased number of innervated neuromuscular junctions, usually morphologically altered and reduced in nmd mice. Finally, to support the translatability of the therapy, we assessed the lack of a significative alteration of the toxicity biomarkers after the treatment. Although further experiments are needed these results provided a promising starting point for the development of an effective treatment for SMARD1 patients.