Motor outcomes to validate evaluations in pediatric fshd (move peds) - the primary goal of this proposal is to hasten therapeutic development by validating outcomes and refining clinical trial…

Motor outcomes to validate evaluations in pediatric fshd (move peds) - the primary goal of this proposal is to hasten therapeutic development by validating outcomes and refining clinical trial strategies for pediatric-onset fshd. Cross sectional studies have suggested an association between a younger age of onset and greater clinical severity. They also show that having 1-3 D4Z4 repeats is associated with extra-muscular complications in pediatric fshd. Prospective studies in early-onset fshd to date have been limited by small number of sites and low ability to recruit and follow patients. Rationale: fshd is caused by the aberrant expression of a normally silenced gene, DUX4, which causes a toxic gain-of-function and may be a target for therapy. The key abnormality in fshd is particularly amenable to molecular knock- down or silencing of DUX4, making strategies like the use of antisense oligonucleotide or RNA interference possible. Several pharmaceutical companies have active programs for targeted treatments in adult fshd, and many more are planned and on the horizon over the next five years. Early-onset pediatric fshd is a population of high interest to drug companies for the following reasons: 1) early-onset pediatric fshd results in more significant disease burden than in adults; 2) treating fshd at earlier ages may have a more lasting and profound effects; and 3) smaller body size and faster rates of progression may make AAV delivered gene therapies more feasible. The fshd clinical trials research network (ctrn) will be utilized and is comprised of international academic centers, which has leveraged support from key stakeholders to create infrastructure for study coordination, evaluator training, and data management/statistical support. The study will be a prospective 24-month study of 80 pediatric fshd participants (at least half meeting criteria for early-onset fshd) and will validate the pediatric fshd composite functional measure (fshd-COM peds), reachable workspace (RWS), and quantitative MRI (qmri) measures intra-muscular FAT content, which have shown to be responsive to disease progression or treatment in adults with fshd and correlated to performance. The study proposes the following aims. Aim 1 will determine the validity of the pediatric fshd COM and RWS as a primary clinical outcome assessment (COA) for fshd clinical trials. Also, will determine multicenter test-retest reliability, cross sectional associations to other fshd disease measures, responsiveness to fshd disease progression, predictive baseline clinical characteristics for trial planning, and minimal clinically important changes. Aim 2 will determine the validity of qmri as a prognostic or monitoring biomarker for fshd clinical trials. Similar to aim 1, this determines the convergent validity, responsiveness to disease progression, and baseline cut offs useful for trial planning. At the completion of this study, the fshd-COM peds, RWS, and qmri will be validated for use in pediatric fshd clinical trials and will investigate differences between the early-onset and childhood and adolescent onset fshd for trial planning purposes.