The human immune system presents a potentially serious barrier to treatment of Duchenne muscular dystrophy (DMD). Pre-existing T cell immunity to dystrophin has been observed in patients vi^ith DMD. Moreover, in subjects with large deletions in the dystrophin gene, sequences that are unique to a therapeutic dystrophin transgene can prime T cell immunity. Further complicating the picture are humoral and cellular immune responses to the AAV capsid that have the potential to interfere with vector-mediated transduction of muscle. This MD-CRC Center is structured to provide insight into cellular immune responses to dystrophin or AAV capsid proteins in DMD patients who are candidates for therapies that include gene replacement, exon skipping, and stop codon suppression. The Immunology Core has two objectives that support the proposed Center. The first is to provide access to well-established assays for standardized quantification of T cell responses to dystrophin and AAV capsid proteins in human subjects with DMD. The second objective is to adapt advanced technologies for monitoring immunity to the study of DMD. This includes methods for direct visualization of dystrophin-specific T cell responses in human subjects and to assess their function in target tissues like muscle.
The Immunology Core is designed to provide standardized, reproducible analysis of cellular immune responses to dystrophin humans with Duchenne Muscular Dystrophy (DMD). Facilitating the analysis of immunity in Projects 1 and 2 has considerable relevance to treatment of progressive muscular disease associated caused by DMD.
|Giesige, Carlee R; Wallace, Lindsay M; Heller, Kristin N et al. (2018) AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD. JCI Insight 3:|
|Mendell, Jerry R; Sahenk, Zarife; Al-Zaidy, Samiah et al. (2017) Follistatin Gene Therapy for Sporadic Inclusion Body Myositis Improves Functional Outcomes. Mol Ther 25:870-879|
|Eidahl, Jocelyn O; Giesige, Carlee R; Domire, Jacqueline S et al. (2016) Mouse Dux is myotoxic and shares partial functional homology with its human paralog DUX4. Hum Mol Genet 25:4577-4589|
|Sondergaard, Patricia C; Griffin, Danielle A; Pozsgai, Eric R et al. (2015) AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models. Ann Clin Transl Neurol 2:256-70|
|Mendell, Jerry R; Sahenk, Zarife; Malik, Vinod et al. (2015) A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol Ther 23:192-201|
|Heller, Kristin N; Montgomery, Chrystal L; Shontz, Kimberly M et al. (2015) Human ?7 Integrin Gene (ITGA7) Delivered by Adeno-Associated Virus Extends Survival of Severely Affected Dystrophin/Utrophin-Deficient Mice. Hum Gene Ther 26:647-56|
|Al-Zaidy, Samiah A; Sahenk, Zarife; Rodino-Klapac, Louise R et al. (2015) Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy. J Neuromuscul Dis 2:185-192|
|Yalvac, Mehmet E; Arnold, William David; Hussain, Syed-Rehan A et al. (2014) VIP-expressing dendritic cells protect against spontaneous autoimmune peripheral polyneuropathy. Mol Ther 22:1353-1363|
|Chicoine, L G; Montgomery, C L; Bremer, W G et al. (2014) Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol Ther 22:338-347|
|Chicoine, Louis G; Rodino-Klapac, Louise R; Shao, Guohong et al. (2014) Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin ?2 surrogates. Mol Ther 22:713-24|
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