Mutations in the IGHMBP2 gene lead to a spectrum of rare, autosomal recessive diseases characterized by degeneration of ?-motoneurons and ganglion cells. Patients present with a broad spectrum of clinical features ranging from distal muscle weakness with fatal respiratory distress/failure (SMARD1) to muscular issues without respiratory symptoms (CMT2S). Currently, only symptomatic treatments are available for SMARD1/CMT2S, which have no effect on disease progression. Thus, there is an urgent need to develop an effective therapy for SMARD1/CMT2S. In the current multicentered dose-ranging IND-enabling study, we evaluated the efficacy of Adeno-Associated virus Serotype 9 (AAV9)-mediated delivery of a functional IGHMBP2 gene in three different mouse models comprising the whole SMARD1/CMT2S disease spectrum (EM3 (severe), nmd-2J(intermediate) and EM5(mild)). Here, we show that a single, intracerebroventricular injection of ssAAV9.P546.IGHMBP2 in EM3 ,nmd-2J and EM5 mice at post-natal day 1 resulted in widespread expression of IGHMBP2 with improvement in body weight and significant extension in survival in the severe model in a dose-dependent manner. Moreover, ssAAV9.P546.IGHMBP2 treatment effectively ameliorated pathological phenotypes such as loss of grip strength, decreased muscle weight and loss of neuromuscular junction innervation that are hallmarks of IGHMBP2-related disorders in all mouse models. ssAAV9.P546.IGHMBP2 also showed a marked improvement on compound muscle action potential and motor unit number estimation, electrophysiological measures previously used in preclinical and clinical studies of Spinal Muscular Atrophy type 1. Importantly, ssAAV9.P546.IGHMBP2 had no adverse effects when administered in wild type mice. To further translate this approach to the clinic, we administered ssAAV9.P546.IGHMBP2 intrathecally to six cynomolgus macaques aged 1-6 years. ssAAV9.P546.IGHMBP2 treatment was safe and well tolerated in non-human primates with widespread transgene expression throughout the central nervous system up-to 6 months post-injection. Collectively, these studies provide a strong foundation for a phase I/IIa clinical trial for intrathecal administration of ssAAV9.P546.IGHMBP2 in SMARD1/CMT2S patients.