Spinal Muscular Atrophy with Respiratory Distress Type I (SMARD1) is a neurodegenerative disease defined by respiratory distress, muscle atrophy and sensory and autonomic nervous system defects. SMARD1 is a result of mutations within the IGHMBP2 gene. We have generated six Ighmbp2 mouse models based on patient-derived mutations that result in SMARD1 and/or Charcot–Marie-Tooth Type 2 (CMT2S). Here we describe the characterization of one of these models, Ighmbp2D564N (human D565N). The Ighmbp2D564N/D564N mouse model mimics important aspects of the SMARD1 disease phenotype including motor neuron degeneration and muscle atrophy. Ighmbp2D564N/D564N is the first SMARD1 mouse model to demonstrate respiratory defects based on quantified plethysmography analyses. SMARD1 disease phenotypes, including the respiratory defects, are significantly diminished by intracerebroventricular (ICV) injection of ssAAV9-IGHMBP2 and the extent of phenotypic restoration is dose-dependent. Collectively this model provides important biological insight into SMARD1 disease development.

1. Ownership: CLL is co-founder and chief scientific officer of Shift Pharmaceuticals. 2. Income: CLL has received in excess of $10,000 in income per annum from Shift Pharmaceuticals. 3. Research support. Research in the CLL and MAL labs have been supported by subawards from Shift Pharmaceuticals (as part of grants from the DOD, CMT Research Foundation and the NIH). 4. Intellectual property. CLL and MU share patents on novel compounds licensed by Shift Pharmaceuticals and planned patents for additional novel compounds. MAL and ZCL are associated with Shift by family relation. SAH was formerly employed by Shift Pharmaceuticals. KS is chief scientific officer for Sanctum Therapeutics Corporation. 1. Ownership: KS is chief scientific officer of Sanctum Therapeutics Corporation. 2. Income: KS has received in excess of $10,000 in income per annum from Sanctum Therapeutics Corporation. 3. Intellectual property. KS and MU share patents on novel compounds licensed by Sanctum Therapeutics Corporation and planned patents for additional novel compounds.

Metastasis of uterine leiomyosarcoma to the pancreas is rare. A 46-year-old woman was diagnosed with uterine leiomyosarcoma and underwent surgery. Thereafter, recurrences in the lung and subsequently in the pancreas were diagnosed. These lesions were resected and diagnosed as metastasis of uterine leiomyosarcoma. We report a rare case of uterine leiomyosarcoma with metastasis to the lung and pancreas, both of which were resected using aggressive surgery.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disorder that develops in infancy and arises from mutation of the immunoglobulin helicase μ-binding protein 2 ( IGHMBP2 ) gene. Whereas IGHMBP2 is ubiquitously expressed, loss or reduction of function leads to alpha motor neuron loss and skeletal muscle atrophy. We previously developed a gene therapy strategy for SMARD1 using a single-stranded AAV9- IGHMBP2 vector and compared two different delivery methods in a validated SMARD1 mouse model. An important question in the field relates to the temporal requirements for this or any potential treatment. To examine the therapeutic window, we utilized our recently developed SMARD1 model, FVB/NJ- Ighmpb2 nmd-2J , to deliver AAV9- IGHMBP2 at four different time points starting at post-natal day 2 (P2) through P8. At each time point, significant improvements were observed in survival, weight gain, and motor function. Similarly, treatment improved important hallmarks of disease, including motor unit pathology. Whereas improvements were more pronounced in the early-treatment groups, even the later-treatment groups displayed significant phenotypic improvements. This work suggests that an effective gene therapy strategy could provide benefits to pre-symptomatic and early-symptomatic individuals, thereby expanding the potential therapeutic window for SMARD1.