Mutations in IGHMBP2 cause a broad clinical spectrum of rare, autosomal recessive diseases characterized by degeneration of α-motoneurons and ganglion cells encompassing two disorders, Spinal muscular atrophy with respiratory distress type 1(SMARD1), characterized by distal muscle weakness with fatal respiratory distress/failure, and Charcot Marie Tooth Disease 2S-CMT2S, with sensory and milder motor neuropathies and lesser respiratory involvement. Patients can fall in the middle of the spectrum of both diseases, as there is no evidence of phenotype-genotype correlation. 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. Our group has designed and optimized a transgene cassette driving IGHMBP2 cDNA expression suitable for clinical vector production (AAV9.IGHMBP2). However, in order to move to clinic, we conducted multicenter blinded, dose-ranging IND-enabling efficacy studies. Our AAV9.IGHMBP2 construct was tested in three different mouse models comprising the whole SMARD1/CMT2S disease spectrum: EM3 (severe, SMARD1-like phenotype), nmd-2J (intermediate phenotype) and EM5 (mild, CMT2S-like phenotype). We demonstrated that a single, intracerebroventricular injection of ssAAV9.IGHMBP2 in EM3, nmd-2J and EM5 mice at post-natal day 1 resulted in widespread expression of IGHMBP2 with improvement in functional measures in a dose dependent manner. All three mouse models showed a marked and dose-dependent response to the treatment leading to improvement of body weight, strength, neuromuscular junction innervation and survival. In addition, we also saw an increase in CMAP and MUNE, potentially clinically relevant biomarkers indicating improved muscle innervation. Moreover, the treatment improved grip strength and weight , with high dose injected mice being indistinguishable from wild-type littermates. Bridging studies with research grade and clinical grade material confirmed the potency of the clinical material in a dose-dependent manner. Collectively, these studies resulted in FDA approval of the first in human phase I/II clinical trial for intrathecal administration of ssAAV9.IGHMBP2 in SMARD1/CMT2S patients that is currently ongoing at Nationwide Children’s Hospital. Several patients have been dosed and treatment was safe and well tolerated over an extended period of time.