Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center

The mission of our Wellstone Center is to perform cutting-edge research that leads to transformative therapies
for myotonic dystrophy type 1 (DM1) and 2 (DM2). Our Center is based on a long history of creating and
maintaining exceptionally close research interactions between basic scientists at the University of Florida and
clinical researchers at the University of Rochester. For this proposed Wellstone Center, we will transition to the
University of Florida as the primary Project/Performance Site but will maintain a similar leadership structure.
All 3 projects are highly synergistic and center on 2 themes: 1) continuing to accelerate and support clinical trials
in the DM1 space, including preparing for a potentially imminent post-approval landscape; 2) accelerating both
basic science and translational efforts for DM2 so that DM2 can also rapidly advance to clinical trials. Project 1
focuses on two DM2 mouse models that we have recently generated, including the first human BAC transgenic
mouse multisystemic model for DM2 (CNBP-DM2) and a human skeletal muscle actin (HSA) transgenic model
(HSA-DM2) similar to the HSALR mouse model for DM1. Preliminary studies demonstrate these models
collectively reproduce characteristic features of DM2, including CCTG repeat instability, nuclear RNA foci,
MBNL sequestration, RNA mis-splicing and RAN translation. The detailed molecular, histological, and
physiological effects due to multisystemic expression of CNBP-DM2 and skeletal muscle expression of HSA-DM2
transgenes will be assessed and these studies will be used to test two therapeutic strategies. Project 2 focuses on
clarifying molecular mechanisms underlying several leading therapeutic approaches using a new Dmpk CTG
expansion knockin multisystemic model for DM1 that reproduces characteristic DM1 molecular and
pathophysiological features. Project 3 transitions to current clinical issues by analyzing a large DM1 cohort using
a remote assessment strategy to examine disease severity. A DNA Bank will also be established for
comprehensive analysis of expanded repeats and statistical models will be developed to study relationships
between repeat length, age, sex and disease severity. The hypothesis that variant repeat interruptions are
associated with reductions in disease severity, somatic expansion and mis-splicing will also be tested. For DM2,
remote patient assessments and targeted recruitment will facilitate studies designed to assess roles for RAN
translation and RNA toxicity. In combination with these projects, our Administrative Core will provide rigorous
oversight for all projects and cores and emphasize synergy between the projects and cores. We will continue to
expand our Shared Resource Core since this core is an essential resource for our Wellstone Projects but also
serves the broader research and clinical community focused on dominant muscular dystrophies. Our Training
Core is designed to attract and build competency in the next generation of basic and clinical investigators focused
on DM1 and DM2 by training in wet and dry lab settings and will provide training in communication skills needed
to effectively engage all DM stakeholders.