by 10%. Overall, patients also had an improved sense of well being with very few adverse side effects. doi:10.1016/j.ymgme.2018.12.208 193 Antisense oligonucleotide treatment targeting glycogen synthase (GYS1) in a mouse model of Pompe disease Virginia Kimonis a , Lan Weiss a , Michele Carrer b , Howard Yu a , Nina Raben c , Tamar Grossman b , a UC Irvine, Orange, CA, United States, b Ionis Pharmaceuticals, Carlsbad, CA, United States, c National Institutes of Health, Bethesda, MD, United States. Pompe disease is a progressive myopathy resulting from the deficiency of acid α-glucosidase (GAA). The standard of care is ERT with recombinant human (rh) GAA. ERT works well in alleviating the cardiomyopathy however, many patients continue to have progres- sive muscle weakness from muscle glycogen accumulation produced by muscle glycogen synthase (GYS1). Previous studies have shown that inhibition of GYS1 reduced lysosomal glycogen. Knockdown of GYS1 mRNA by phosphorodiamidate morpholino oligonucleotide conjugated with a cell penetrating peptide however wasnephrotoxic. Antisense Oligonucleotides (ASO) technology has emerged as a powerful therapeutic alternative for the treatment of genetic disorders by targeting RNA. In order to impart specificity for the muscle variant of GYS1, we propose the use of ASO-mediated gene silencing through the RNaseH1 dependent degradation mechanism. Most recently therapy for spinal muscular atrophy has been successful using ASOs, and our hope is that ASO technology will be successful in Pompe disease. Over 150 ASOs were designed and screened in vitro to identify the most efficacious ASO for testing in wild type mice. The lead from the screen were validated in a dose response study and the top 10 ASOs were screened in vivo. The 2 ASOs (GYS1 ASO#1 and GYS1 ASO#2) showed the best tolerability and efficacy profile leading to knock down of GYS1 mRNA by approximately 50% of control. We have performed a pilot study of the efficacy of two GYS1 ASOs in Pompe mice as monotherapy and have reduced muscle GYS1 mRNA levels versus PBS and a mismatch ASO. ASO#2 resulted in weight loss of the mice. We will present the results of the study of the effect of the GYS1 ASOs on muscle glycogen, histology, GYS1 RNA and muscle function in Pompe mice. These preliminary studies provide proof of principle for a promising adjunct treatment for Pompe disease. doi:10.1016/j.ymgme.2018.12.209 194 Feasibility of quantifying behavior in early progressive MPS II Kelly E. King a , Elsa G. Shapiro a , Chester B. Whitley a , Joseph Muenzer b , Julie B. Eisengart a , a University of Minnesota, Minneapolis, MN, United States, b University of North Carolina, Chapel Hill, NC, United States Hunter syndrome is a rare X-linked lysosomal disorder associated with progressive multisystem involvement. Ages of onset vary, as do disease course and phenotypic severity. The early progressive phenotype involves delayed developmental milestones with worsening intellectual impairment and regression. Disease progres- sion creates dramatic neurobehavioral symptoms, including hyper- activity, inattention, behavior difficulties, sleep disturbance, and others. These behaviors are highly disruptive, distressing to families, and significantly impact quality of life. But these symptoms have been difficult to measure. Existing pediatric behavioral assessment tools do not capture the unique constellation of symptoms, nor variability of expression. To address this problem, we are developing a Hunter-specific caregiver rating scale of neurobehavioral symp- toms. The goal is to create a valid, reliable tool that detects change in neurobehavioral profile, informing natural history and therapeutic response. A first step involves drafting a tool using methods of scale development for another MPS type with neurobehavioral impair- ment, the Sanfilippo Behavior Rating Scale. Item sets are informed by coded video recordings of: 1) semi-structured play in small groups of affected boys and 2) focus groups with caregivers literature review and review of existing tools. Inclusion criteria include: 1) confirmed diagnosis of early progressive Hunter syndrome 2) age 4 to 9 years 3) able to ambulate. Findings aligned with the literature’s descrip- tions of diverse symptoms, with considerable differences in presen- tation within-child, dependent upon internal and external factors (e.g., fatigue, hunger, novelty of a setting). Caregiver reports indicated a need for a behaviorally anchored scale that assesses frequency of symptoms and context rather than severity. Next steps will involve piloting the draft scale and soliciting caregiver feedback. Future directions include validating the measure in a larger multi- center study. Support: Shire pharmaceuticals, NIH U54NS065768, National MPS Society, UMN Center for Neurobehavioral Develop- ment doi:10.1016/j.ymgme.2018.12.210 195 Safety and efficacy of VAL-1221, a novel fusion protein targeting cytoplasmic glycogen, in patients with late-onset Pompe disease Priya Kishnani a , Robin Lachmann b , Tahseen Mozaffar c , Crista Walters a , Laura Case a , Matt Appleby d , Vincenzo Libri d , Manisha Kak c , Marie Wencel c , Hal Landy e , a Duke University, Durham, NC, United States, b National Hospital for Neurology and Neurosurgery, London, United Kingdom, c University of California, Irvine, Orange, CA, United States, d UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, United Kingdom, e Valerion Therapeutics, LLC, Concord, MA, United States Disease progression in Pompe Disease, a lysosomal storage disorder, occurs despite enzyme replacement therapy ERT, and is characterized by cytoplasmic accumulation of glycogen, presumably due to rupture or seepage of glycogen from lysosomes, defects in autophagy and the targeting of conventional ERT only to the lysosome. VAL-1221 is a fusion protein comprising the Fab portion of a cell-penetrating antibody utilizing the nucleoside transporter ENT-2 to gain access to the cytosol, and recombinant human acid alpha glucosidase (rhGAA), which enters lysosomes via mannose-6- phosphate receptors (M6PRs). Thus, VAL-1221 targets both cytosolic and lysosomal glycogen. 30 mg of VAL-1221 contains 20 mg of rhGAA. We performed a 3-month Phase 1/2 repeat dose, dose- escalation study of VAL-1221 with an rhGAA (Myozyme/Lumizyme) control to assess its safety and preliminary efficacy. 12 adults with late-onset Pompe disease (LOPD) treated with rhGAA for at least one year were randomized (1:3) to rhGAA (20 mg/kg qow) or to VAL- S85 Abstracts / Molecular Genetics and Metabolism 126 (2019) S17–S156