Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy: Prevalence and a Glucocorticoid Treatment Effect

Abstract

Duchenne muscular dystrophy (DMD) typically occurs as a result of truncating mutations in the DMD gene that result in a lack of expression of the dystrophin protein in muscle fibers. Various therapies under development are directed toward restoring dystrophin expression at the subsarcolemmal membrane, including gene transfer. In a trial of intramuscular adeno-associated virus (AAV)-mediated delivery of a therapeutic minidystrophin construct, we identified in two of six subjects the presence of a population of T cells that had been primed to recognize dystrophin epitopes before transgene delivery. As the presence of preexisting T cell immunity may have a significant effect on the success of therapeutic approaches for restoring dystrophin, we sought to determine the prevalence of such immunity within a DMD cohort from our Muscular Dystrophy Association clinic. Dystrophin-specific T cell immunity was evaluated in subjects with DMD who were either receiving the glucocorticoid steroid prednisone (n=24) or deflazacort (n=29), or who were not receiving steroids (n=17), as well as from normal age-matched control subjects (n=21). We demonstrate that increasing age correlates with an increased risk for the presence of anti-dystrophin T cell immunity, and that treatment with either corticosteroid decreases risk compared with no treatment, suggesting that steroid therapy in part may derive some of its benefit through modulation of T cell responses. The frequency of dystrophin-specific T cells detected by enzyme-linked immunospot assay was lower in subjects treated with deflazacort versus prednisone, despite similar overall corticosteroid exposure, suggesting that the effects of the two corticosteroids may not be identical in patients with DMD. T cells targeted epitopes upstream and downstream of the dystrophin gene mutation and involved the CD4⁺ helper and/or CD8⁺ cytotoxic subsets. Our data confirm the presence of preexisting circulating T cell immunity to dystrophin in a sizable proportion of patients with DMD, and emphasize the need to consider this in the design and interpretation of clinical gene therapy trials.

Complexity of immune responses to AAV transgene products – Example of factor IX

“…Here, pre-existing CD8 + T cell immunity has been reported in some patients, possibly resulting from intermittent expression of dystrophin antigen by revertant fibers in the context of tissue inflammation [6]. These investigations document the potential for T cell immunity to self- and non-self dystrophin epitopes, as well as effectiveness of immune suppression [111]. Another example is α 1 -antitrypsin deficiency.…”

“…Transient immune suppression with steroids or B cell depletion with anti-CD20 combined with rapamycin are among the approaches that have seen first clinical use to prevent unwanted immune responses in gene therapy for muscular dystrophy and storage disorders [77, 111, 114]. Going forward, critical questions for the new protocols will be: is immune suppression needed?…”

Recent advances in the management of Duchenne muscular dystrophy

“…These authors state that glucocorticoids (GCs) are currently the only drugs to help maintain muscle strength and function in children with DMD (table 2). The multiple pharmacological effects of GCs on dystrophic muscle fibres are not fully understood; they include stimulation of insulin-like growth factors and modulation of T-cell responses 16 17. GCs are tolerated relatively well despite their potential multisystem adverse reactions.…”

Viral vector-mediated gene therapies

“…There are also concerns with any genetic null allele disorder that the therapeutic transgene itself can trigger an immunogenic response that could target successfully transduced cells (21). One strategy to evade an immune response to micro-dystrophin is by intra-amniotic gene delivery, while the immune system is developing.…”