Translational Research

Poster Number: 172


Andrea Sierra Delgado, MD, MSc, Nationwide Children's Hospital, Shibi Likhite, PhD, Nationwide Children's Hospital, Sarah Holbrook, The Jackson Laboratory, Vicki McGovern, PhD, The Ohio State University, Deepti Chugh, PhD, Ohio State University, Joseph Caporale, Nationwide Children's Hospital, Xiaojin Zhang, Nationwide Children's Hospital, Maura Schwartz, Megan Baird, Nationwide Children's Hospital, Chase Haubert, Nationwide Children's Hospital, Abuzar Kaleem, PhD, Nationwide Children's Hospital, Annalisa Haurtlaub, Nationwide Children's Hospital, Natalie Rohan, Nationwide Children's Hospital, Erin Ratzlaff, Nationwide Children's Hospital, Chris Pierson, MD, Nationwide Children's Hospital, Brad Bolon, DMV, Gem Path, Pablo Morales, DM, The Manheimer Foundation, W. David Arnold, MD, The Ohio State University, Arthur Burghes, PhD, The Ohio State University, Gregory Cox, PhD, The Jackson Laboratory, Kathrin Meyer, PhD, Nationwide Childrens Hospital

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.