PROJECT SUMMARY Congenital Myasthenic Syndromes (CMS) are a group of clinically similar neuromuscular transmission disorders that differ in their underlying genetic mutation. While some phenotypical variation exists, CMS are commonly characterized by muscle weakness (myasthenia) that worsens with physical exertion. Defects in Collagen Q (ColQ), a multidomain functional protein of the Neuro Muscular Junction (NMJ) responsible for AChEticholinesterase (AChE) anchoring and Muscle specific Kinase (MusK) phosphorylation, lead to endplate AChE deficiency and ColQ CMS. ColQ CMS is a severe, pediatric orphan disease with a prevalence of approximately 1,600 people in the major developed countries. Severe ColQ CMS can result in early death and causes decreased Quality of Life due to extreme fatigability, dependency on intermittent respiratory support, and/or tube feeding, which occurs in 2/3 of patients by early adulthood. No cure nor standardized treatment has been yet developed for ColQ CMS. While some CMS subtypes are managed via administration of AChE inhibitors, ColQ CMS is refractory and can deteriorate if treated with AChE inhibitors. Best available care involves chronic administration of ?2-adrenergic receptor agonists, which only provide modest symptomatic improvements. Amplo Biotechnology is developing treatments for CMS, seeking to streamline the process of testing new adeno-associated virus (AAV) by applying a platform approach whereas, by using the same gene delivery system and manufacturing methods, subsequent indications can be targeted by changing the animal model and the transgene delivered. This approach will save time, money and will ultimately allow to address the unmet needs of smaller patients’ populations where traditional drug development investments cost are commercially unviable. AMP-201, is the first gene therapy product for ColQ CMS, based on an AAV8 vector carrying the human ColQ gene. The development pathway presented has been based on regulatory (pre-IND, pre-CTA) and scientific advice (TACT, Treat-NMD) provided for a closely related gene therapy that Amplo is developing for Dok-7 CMS (Fast-track SBIR recently awarded). Preliminary results in a ColQ CMS mouse model show that intra-venous injection of a AAV8-COLQ is able to correct the pathological signs of AMP-201 in the ColQ -/- mice model which recapitulates the phenotype of ColQ CMS. AMP-201 will enable a shift in the current clinical practice from chronic administration of drugs to alleviate symptoms to a one-off treatment allowing physicians to treat the entire affected population, curing adult disease, and stopping disease progression in children. The goal of this STTR Fast-Track project is to validate the efficacy and safety of using AMP-201 for ColQ CMS. Amplo will use Phase I activities to perform a pre-clinical dose-finding and efficacy study in ColQ -/- mice. The outcome of Phase I activities will be used to direct toxicity studies in mice and pivotal DMPK/ADME and toxicology in non-human primates (NHP) in Phase II. Manufacturing, quality, and stability procedures will also be defined.

NARRATIVE ColQ CMS is a rare neuromuscular disorder with no cure associated. Severe limb-girdle pattern of weakness, choking spells, respiratory insufficiency, severe scoliosis present early on during the disease progression with early death not uncommon among these patients. This project aims to validate the safety and efficacy of a new gene therapy product for ColQ CMS able to transform clinical practice from chronic administration of drugs to alleviate symptoms to a one-off, non-pharmacological treatment, administered through a single intravenous injection. The project is expected to unveil important insights on the mechanism of action of Neuromuscular Junction as well to explore the existence of a shared gene therapy development pathway for CMS.