Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center

The mission of our Wellstone Center is to promote research that leads to transformative treatments for
autosomal dominant forms of muscular dystrophy. The main focus is on myotonic dystrophy type 1 and type 2
(DM1 and DM2). The Center unites two groups of investigators who have worked together on myotonic
dystrophy for two decades, namely, the team of clinical and translational researchers who study DM at the
University of Rochester, and the team of RNA scientists and geneticists who study DM at the University of
Florida. Together, this partnership is credited with establishing RNA gain of function as a genetic mechanism,
elucidating the role of MBNL proteins and CUG repeats as fundamental drivers of RNA toxicity, developing the
first DM1 animal models showing RNA toxicity and MBNL insufficiency, accomplishing the first therapeutic
rescue of DM1 in animal models, developing clinical methods, natural history data, and biomarkers that are
needed to conduct clinical trials, and bringing the first targeted treatment to early-phase trials for DM1.
Continuing is this vein, the proposed studies are designed with three parallel objectives: to clarify disease
mechanisms, to strengthen the pipeline of preclinical therapeutic agents, and to generate the tools and
knowledge for conducting highly informative clinical trials. Each Project of the center involves close
collaboration of investigators at Rochester and Florida sites. Project 1 is focused on DM1, and will characterize
the first allelic series of mice having targeted insertion of highly expanded repeats at the murine DM1 locus. It
will also determine how splicing biomarkers respond to increments of toxic RNA, decrements of MBNL1
protein, and therapeutic interventions. Using a common set of models and methods, the investigators will
compare two leading strategies to mitigate RNA toxicity: post-transcriptional knockdown using antisense
oligonucleotides (ASOs), and transcriptional inhibition using small molecules. The ASO strategy will focus on
methods to improve drug delivery to muscle fibers. While substantial progress towards “trial readiness” has
been made for DM1, DM2 lags behind. Project 2 will initiate studies of natural history and clinical endpoints
for DM2. The transcriptome changes in DM1 and DM2 will be compared, and clinical steps of biomarker
development will be completed. Repeat-associated non-AUG (RAN) translation will be examined as a potential
mechanism for myopathy in DM2. Project 3 addresses animal models and mechanisms for DM2. The first
transgenic mouse model of DM2 will be characterized, and mechanisms for RNA toxicity by intronic vs. exonic
repeats, or CUG vs. CCUG repeats, will be compared. The new models will be used to develop ASO and small
molecule treatments for DM2. The Shared Resource core contains the National Registry for DM and FSHD. It
supports Projects of our Center but also serves the broader community of researchers who study dominant
forms of dystrophy. Taken together, the Center will continue to stimulate and support world-wide efforts to
develop effective treatments for DM1, DM2, and FSHD.