The overall goal of this project is to develop reliable and valid clinical outcome assessments (COAs) for limb girdle muscular dystrophy 2A (LGMD2A) to hasten therapeutic development. LGMD2A is an autosomal recessive form of LGMD due to a loss of function in muscle structural gene CAPN3. This loss of function leads to progressive weakness of the shoulder and hip girdle muscles and therefore progressive disability, including loss of ambulation or the ability to maintain a job. There are no FDA approved treatments for LGMD2A, which represents a large unmet medical need. LGMD2A is amenable to gene replacement therapies; and in recent years, a systemic gene therapy has been approved for spinal muscular atrophy, and is in development for LGMD2E. At least three companies have gene-targeted therapies in development for LGMD2A ? creating a situation where therapeutic development has outstripped our ability to prepare for clinical trials. The rationale for this study is that defining a core set of COAs for LGMD2A which are reliable, related to key areas of LGMD2A disease impact, and responsive to disease progression, and determining the size of change in the COAs which would be clinically meaningful would hasten therapeutic development and allow for properly powered clinical trials. We propose the following Specific Aims: 1) To define a common set of pelvic and shoulder girdle COAs, and COAs useful for capturing phenotypic diversity; 2) To determine the sensitivity to longitudinal disease progression of our COAs; and 3) To refine clinical trial strategies based on baseline and longitudinal phenotypic characteristics. To achieve our aims, we plan to leverage an existing LGMD Clinical Research Network to conduct a 12 month longitudinal observational study of 50 clinically affected and genetically defined LGMD2A indivdiuals at eight sites on our LGMD Research Network. We hypothesize that COAs representing the major areas of shoulder and pelvic girdle functional burden will be amenable to multi- site training, reliable, related to patient-identified areas of disease impact, and useful for power and sample size planning for forthcoming clinical trials. In addition, we hypothesize that certain baseline clinical characteristics related to age, functional status, or mutation may be useful for refining trial planning strategies. At the completion of this study, we will have: defined the phenotypic variation across LGMD2A; determined which COAs are most appropriate for therapeutic trials; and established the variability in these COAs for power and sample size planning. Given the significant progress in therapeutic development for LGMD2A, the development of appropriate COAs for this population is an urgent need.
Limb girdle muscular dystrophy 2A (LGMD2A) is a common muscular dystrophy due to loss of function of a muscle structural gene called CAPN3, which causes progressive weakness and disability, has no treatments, but is amenable to approaches to gene replacement therapy or therapies with other muscle therapeutics. Developing a common set of tools for measuring change in shoulder, arms, and pelvic girdle function will help the LGMD2A community prepare for forthcoming clinical trials, and ensure that clinical trials do not reject potentially useful drugs due to poor planning or lack of robust clinical outcome tools. We propose to validate a number of clinical trial outcome tools by performing a 12-month study of 50 individuals with LGMD2A at eight sites in an existing LGMD Clinical Research Network to help hasten therapeutic development.
