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Effects of manipulating the immune system on dystrophin gene transfer and dystrophic phenotype in striated muscles of Duchenne muscular dystrophy model, mdx mouse

Eghtesad, Saman (2010) Effects of manipulating the immune system on dystrophin gene transfer and dystrophic phenotype in striated muscles of Duchenne muscular dystrophy model, mdx mouse. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Duchenne muscular dystrophy (DMD) is a fatal genetic disorder caused by mutations in the gene coding for dystrophin protein, which give rise to a dysfunctional protein in skeletal muscle. Dystrophic muscle progressively degenerates. In addition, necrotic muscle fibers undergo high levels of inflammation that in turn promote the pathology that is associated with this devastating disease. Therefore, treatments that 1) restore expression a functional dystrophin protein in dystrophic muscles, and 2) lower the ongoing inflammation in the necrotic muscle tissue, are both important in ameliorating DMD phenotype. Transfer of a functional dystrophin gene using a viral vector can help restore the missing dystrophin protein in dystrophic muscles. The host immune system, however, is a major barrier to successful vector-mediated dystrophin protein expression in a dystrophic host, as anti-dystrophin immune response leads to rejection of the protein. Here I show that temporal elimination of the host immune system by irradiation in the mdx mouse, a murine model of DMD, prior to vector-mediated dystrophin gene delivery, leads to a delayed and diminished host anti-dystrophin immune response. These findings are important for a better evaluation of anti-dystrophin immunity in a dystrophic host. In the case of lowering inflammation in dystrophic muscles, I investigated the effects of rapamycin, a potent immunosuppressant, on both dystrophic phenotype and dystrophin gene transfer in mdx mice. Treatment of adult mdx muscles with rapamycin lead to significantly lower levels of muscle fiber necrosis and reduced effector T cell infiltration in dystrophic muscles. These events correlated with a difference in activation of the mammalian target of rapamycin (mTOR) in the diaphragm muscle, but not the TA muscle, suggesting a differential regulation of mTOR activation in the two tissues. Rapamycin treatment, however, did not allow for a higher level of vector-mediated dystrophin protein expression in treated muscles. In general, these findings shed more light on the effects of manipulating the immune system in a dystrophic host in terms of both reducing the inflammation that is associated with DMD and reducing anti-dystrophin responses following gene therapy, suggesting that regulation of the immune system is essential in ameliorating DMD.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Eghtesad, Samansae9@pitt.eduSAE9
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairClemens, Paula Rpclemens@pitt.eduPCLEMENS
Committee MemberGlabiati, Ferrucciofeg5@pitt.eduFEG5
Committee MemberRobbins, Paul Dprobb@pitt.eduPROBB
Committee MemberMorel, Penelope Amorel@pitt.eduMOREL
Committee MemberO'Doherty, Robert Modohertyr@dom.pitt.eduRMO1
Date: 15 December 2010
Date Type: Completion
Defense Date: 20 October 2010
Approval Date: 15 December 2010
Submission Date: 9 December 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biochemistry and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Duchenne muscular dystrophy (DMD); Gene Therapy; mdx mouse; Immunity; Rapamycin
Other ID:, etd-12092010-130005
Date Deposited: 10 Nov 2011 20:09
Last Modified: 15 Nov 2016 13:54


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