Duchenne muscular dystrophy (DMD) typically results from mutations in the DMD gene that
disrupt the open reading frame, resulting in no dystrophin protein, whereas the milder Becker
muscular dystrophy (BMD) typically results from mutations that allow expression of a partially
functional dystrophin protein. This observation has led to the development of therapies intended
to result in expression of internally-deleted, BMD-like dystrophin proteins. Despite the availability
of four such commercial therapies for a subset of patients, and the transformative promise of
microdystrophin gene therapies that are on the horizon, there are fundamental unanswered
questions about the relationship of partial dystrophin expression to patient function—questions
that bear on our ability to assess the benefits of therapies, to offer prognosis to families, and to
guide approaches to retreatment in gene replacement therapies, among other issues.
Furthermore, it will be critical to understand the distinctions between endogenous, lifelong
expression of partially functional dystrophins, and therapeutic dystrophins delivered postnatally.
Our long-term goal is to understand a fundamental question: How much dystrophin protein—and
what kind of partially functional dystrophin, expressed at what time—is enough? Our objective in
this project is two-fold. First, we seek to understand in finer detail the molecular parameters of
dystrophin expression that result in phenotype amelioration. Second, we seek to develop
methods for full-length dystrophin expression from the endogenous DMD gene, which is a
possibility for a for a subset of patients, and has the potential for improved outcomes in
comparison to microdystrophin. Our central hypothesis is that multiple mechanisms exist to
account for variations in disease severity, and that understanding these mechanisms will lead to
a better understanding of the durability and long-term benefits of dystrophin restoration therapies.
Our rationale is that a detailed exploration of these mechanisms will lead to a better understanding
of the long-term outcomes expected from novel gene therapies for DMD.