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Follistatin Gene Therapy for the Treatment of Muscular Dystrophy

Handy, Chalonda Renee
http://rave.ohiolink.edu/etdc/view?acc_num=osu1259090498

Abstract Details

2009, Doctor of Philosophy, Ohio State University, Integrated Biomedical Sciences.
The muscular dystrophies (MDs) represent a group of inherited myogenic disorders characterized by persistent muscle wasting and progressive functional decline. To date, there are no optimal therapies for MD. Most potential treatments have been targeted towards improving conditions in Duchene Muscular Dystrophy where loss of dystrophin is responsible for the muscle defect. However, a number of emerging therapies are currently under review with particular attention being paid to factors that enhance muscle growth. The myostatin inhibitor follistatin, which results in enhanced muscle growth and function appears to offer substantial promise. The efficiency of follistatin lies in its ability to bind myostatin thus preventing its receptor binding that would normally allow for the downregulation of genes responsible for myoblast proliferation and differentiation. Follistatin is effective in that it not only circumvents the muscle inhibitory effects of myostatin, but is also able to operate outside of the myostatin pathway to offer muscle protection and improve pathology during instances of muscle wasting. Here, we highlighted the unique muscle enhancing effects of adeno-associated virus (AAV) delivery of follistatin (FS344) by using rodent models and non-human primates. We saw that in young as well as aged dystrophin deficient mdx mice, follistatin was able to improve muscle conditions and decrease dystrophic symptoms. The relatedness of follistatin to muscle disease was also seen in both local and systemic administration of follistatin gene therapy to severely dystrophic laminin-alpha2 deficient mice that closely recapitulate Merosin Deficient Congenital Muscular dystrophy. To investigate if follistatin was equally effective and safe in larger animals, in that this is an important criterion for clinical evaluations in humans, we administered a one-time injection of an AAV bearing follistatin into the quadriceps muscle of Cynomolgus macaques. Like our observations in mice, we saw significant improvements in muscle size and function as assessed by a physiological measure of muscle strength. To understand the possible mechanism for these follistatin induced changes, we performed a series of binding experiments as well as microarray analysis to study at the protein and transcriptional level the effects of muscle follistatin overexpression. Although not conclusive, these characterization studies set the stage for continued investigations into the follistatin mediated muscle response. Taken together this study not only provided evidence for the ability of follistatin to enhance muscle size and strength in both normal and dystrophic conditions, but also provides new starting points for understanding the molecular and functional relevance of myostatin inhibition by follistatin overexpression.
Brian Kaspar (Advisor)
Paul Martin (Committee Member)
Douglas McCarty (Committee Member)
Kevin Hackshaw (Committee Member)
154 p.
Biomedical Research
follistatin; gene therapy; muscular dystrophy; myostatin

Recommended Citations

Citations

  • Handy, C. R. (2009). Follistatin Gene Therapy for the Treatment of Muscular Dystrophy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1259090498

    APA Style (7th edition)

  • Handy, Chalonda. Follistatin Gene Therapy for the Treatment of Muscular Dystrophy. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1259090498.

    MLA Style (8th edition)

  • Handy, Chalonda. "Follistatin Gene Therapy for the Treatment of Muscular Dystrophy." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1259090498

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.