Abstracts / Neuromuscular Disorders 30 (2020) S166–S171 S167 LBO 3 Expression of apparent full-length dystrophin in skeletal muscle in a first-in-human gene therapy trial using the scAAV9.U7-ACCA vector Dr. Megan Waldrop 1,2 , Dr. Michael Lawlor 3 , Tatyana Meyers Vetter Dr. 1 , Emma Frair 1 , Margaret Beatka 3 , Dr. Hui Meng 3 , Megan Iammarino 1 , Brenna Powers 1 , Johan Harris 1 , Maryann Kaler 1 , Dr. Tabatha Simmons 1 , Dr. Nico Wein 1 , Dr. Kevin Flanigan 1,2 1 Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, United States; 2 Departments of Pediatrics and Neurology, Ohio State University Wexner Medical Center, Columbus, United States; 3 Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, United States Exon duplications that cause Duchenne muscular dystrophy (DMD) are promising candidates for exon skipping therapies because skipping a single exon copy should result in wild-type transcript and full-length dystrophin expression. We developed a therapeutic exon skipping viral vector (scAAV9.U7-ACCA) comprising four copies of a modified U7snRNA containing antisense sequences targeting the splice donor (2 copies) and splice acceptor (2 copies) of the DMD exon 2, the most commonly duplicated exon. Following dose finding studies in Dup2 mice and after demonstrating lack of toxicity in non-human primates, we initiated a first-in-human clinical trial (NCT04240314). We present the planned 3-month post-infusion data in the first 2 subjects treated with 3.0 × 10^13 vg/kg. Both boys tolerated the treatment well, with only transient nausea and vomiting. No SAEs have been experienced to date and no biochemical measures of hepatic or other toxicity were seen. Muscle biopsy at 3 months shows expression of apparently full- length protein, quantified by Western blot at levels of >6% in the younger (9.0 yrs) subject and ∼1-2% in the older (13.7 yrs) subject, possibly reflecting differences in myofiber transfection due to differing degrees of dystrophic skeletal muscle changes. Consistent with dystrophin expression, serum CK decreased from 13,495 u/L to 560 u/L at 3 months post-injection in subject 1 and from 5,103 u/L to 947 u/L at 3 months in subject 2. Functional outcome measures remained stable or improved. These findings represent the first therapeutic expression of apparent full-length dystrophin in a human gene therapy trial and support continued clinical investigation. http://dx.doi.org/10.1016/j.nmd.2020.09.008 LATE BREAKING NEWS E-POSTER PRESENTATION LBP 1 From mouse- to patient-relevant models: Using CRISPR activation to upregulate a compensatory disease-modifying gene in LAMA2-CMD Dwi Kemaladewi 2 , Annie Arockiaraj 1 , Jia Qi Cheng-Zhang 1 , Salah Daghlas 2 , Caleb Kim 2 1 Dept. of Human Genetics, Graduate School of Public Health, Univ. of Pittsburgh, Pittsburgh, United States; 2 Div. of Medical Genetics, Dept. of Pediatrics, Univ. of Pittsburgh School of Medicine and UPMC Children’s Hospital of Pittsburgh, Pittsburgh, United States LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD or MDC1A) is caused by mutations in the LAMA2 gene encoding the LAMA2 protein, resulting in muscle degeneration and peripheral neuropathy in patients. There are >650 pathogenic mutations identified in patients worldwide, therefore, individualized correction of LAMA2 mutation would be an extremely challenging and expensive undertaking. In contrast, the attenuation of disease pathogenicity by targeted modulation of the expression of disease modifier genes would be beneficial to all individuals affected with LAMA2-CMD. We previously reported the feasibility and therapeutic benefit of a CRISPR activation-based approach to postnatally upregulate a disease modifier gene Lama1, which is structurally and functionally similar to Lama2, in a mouse model. Here, we bridge the translation of this strategy from the mouse- to patient- relevant models. We treated fibroblasts obtained from >10 patients with LAMA2-CMD with optimized CRISPR activation components to upregulate human LAMA1. We observed robust upregulation of LAMA1 in all patient cells, irrespective of the mutation types and locations. Subsequently, we analyzed these treated cells for their mitochondrial respiration profiles. Our data showed that the treated cells have improved bioenergetic profiles, including basal respiration, ATP production, maximal respiration, and spare respiratory capacity. Finally, we showed that migration impairment caused by the lack of LAMA2 was rescued upon LAMA1 upregulation. Collectively, our data demonstrate the therapeutic benefit of CRISPR activation to modulate a disease modifier gene, which opens an entirely new treatment strategy for LAMA2-CMD patients and many other neuromuscular conditions. http://dx.doi.org/10.1016/j.nmd.2020.09.009 LBP 2 COVID-19 Myopathy: Persistence of Viral Particles in the Skeletal Muscle Dr. Dubravka Dodig 1 , Dr. Jian-Qiang Lu 2 , Katerina Gordon 2 1 UHN/University of Toronto, Toronto, Canada; 2 McMaster University, Hamilton, Canada A 36-year-old man presented with 3-day fever and no other associated symptoms. He was tested positive for COVID-19 virus (SARS-CoV- 2 real-time PCR assay from a nasopharyngeal swab/SARS Coronavirus 2 ORF1ab/2019 Novel Coronavirus E Gene.) On day 3, he became asymptomatic. On day 11, he developed myalgias and progressively worsening weakness. On day 25, he was non-ambulatory and serum creatine kinase (CK) level exceeded 11000 IU/L (normal 35-190 IU/L). Neurological examination demonstrated dense bilateral proximal muscle weakness. Electro-diagnostic testing revealed markedly myopathic features. Treatment with IV fluids and Lasix did not render clinical improvement and CK remained persistently elevated above 7800 U/L. Only after infusion of IV IG 2g/kg, the patient’s condition started to improve and CK trended down. On day 31, repeat COVID-19 testing was negative. A biopsy from the right vastus lateralis muscle was done. Pathological examination revealed features of necrotizing myopathy (figure) with inflammatory cell infiltrates predominantly CD68+ macrophages with rare CD4+ or CD8+ T-cells and no CD20+ B- cells. Electron microscopy (EM) identified viral particles (size: 50-200 nanometers in diameter; morphologically consistent with COVID-19) in the subsarcolemmal regions and endothelial cells of the endomyisal/perimysial capillaries. Our case is the first description of COVID-19 myopathy and EM demonstration of viral particles in the muscle to our knowledge. COVID- 19 viral particles persisted in the muscle fibers and vascular endothelial cells 5 weeks after the initial infection and repeat testing for COVID-19 was negative. COVID-19 myopathy, demonstrating features of immune-mediated necrotizing process, is a novel entity and future studies are required. http://dx.doi.org/10.1016/j.nmd.2020.09.010 LBP 3 Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease Julius Rönkkö, MSc 1 , Svetlana Molchanova, PhD 1,2 , Anya Revah- Politi, MSc, CGC 3,4 , Elaine Pereira, MD 5 , Mari Auranen, MD, PhD 6 , Jussi Toppila, MD, PhD 7 , Jouni Kvist, PhD 1 , Anastasia Ludwig, PhD 8 , Julika Neumann, MSc 9,10 , Stephanie Humblet-Baron, MD, PhD 10 , Geert Bultynck, PhD 11 , Adrian Liston, PhD 9,10,12 , Anders Patau, MD, PhD 13 , Claudio Rivera, PhD 8,14 , Matthew Harms, MD 15 , Henna Tyynismaa, PhD 1,8,16 , Emil Ylikallio, MD, PhD 1,6