In Duchenne, Solving Dystrophin Immunogenicity May Be Key

The quest to find a permanent solution to Duchenne muscular dystrophy (DMD) may depend on gaining a better understanding of how anti-dystrophin immune responses affect treatment, according to a new article.

Dariusz C. Górecki, Ph.D.

Writing in the journal Gene Therapy, corresponding author Dariusz C. Górecki, Ph.D., and colleagues, argue that understanding immune responses to re-expressed dystrophin should be considered a key piece of the therapeutic puzzle. Górecki is a professor of molecular medicine at the University of Portsmouth, in the United Kingdom.

The authors noted that DMD is linked with an absence of dystrophin, which leads to a wide range of effects and symptoms, including progressive muscle degeneration and wasting.

Górecki and colleagues identified three main strategies for addressing this problem. The first is related to the view that dystrophin loss in the myofibers is the key to solving DMD. That has led to the development of therapies that promote ribosomal readthrough of premature stop codons in patients with certain mutations.

The second strategy is based on insights from a similar disorder, Becker muscular dystrophy (BMD), the mutations of which preserve the transcript reading frame and result in mini- or micro-dystrophin proteins that are still semi-functional. Patients with BMD tend to have later onset and slower progression of symptoms, they noted.

“Drugs that induce exon skipping are intended to convert out-of-frame mutations in DMD into in-frame mutations, thereby promoting widespread re-expression of internally truncated but semi-functional mini- and micro-dystrophins,” they wrote.

Yet, as with the first strategy, induction of exon-skipping only works for subsets of patients with particular mutations.

The limitations of those first two strategies — along with the development of gene-editing technology — has led to the development of new gene therapies that use viral vectors to re-express dystrophin. This strategy, Górecki and colleagues noted, has the potential to “convert” DMD into a milder, BMD-like condition. It also has the potential to work on all patients with DMD. Yet, that high potential also comes with a major challenge — the immunogenicity of both viral vectors and the re-expressed dystrophin protein, the authors said.

The immunogenicity of viral vectors has been well-documented and investigated, but Górecki and colleagues said the more pressing and more complex issue is the immunogenicity of the re-expressed dystrophin.

“Unfortunately, this aspect has not been given sufficient attention until now,” they wrote.

The authors explained that therapeutically expressed dystrophin appears to cause an immune response in DMD patients because the proteins “contain antigenic epitopes that were not present when [the] patient’s immune system developed.” Thus, to the immune system, the new dystrophin appears to be foreign. At least, that’s the simple explanation. Górecki and colleagues said the actual explanation is “much more layered and complicated.”

In the article, the authors go on to explain the factors involved in anti-dystrophin responses and the variable outcomes associated with treatment-enhancing therapeutic strategies. They also outline questions they say still need to be resolved.
“Key questions include the underlying mechanisms of immunity induction by antigenic epitopes of the re-expressed dystrophin, the impact of such responses on the therapeutic efficacy, and the role of patient-specific risk factors, such as preimmunization due to revertant fibers, chronic muscle inflammation, pre-existing T lymphocytes reactive to dystrophin, which avoided deletion in dystrophic thymus, or antigen cross-reactivity.”

The investigators argue that assessing patients’ immune status prior to any therapy might be an important step in deciphering how to mitigate any anti-dystrophin responses. That assessment might also warrant the development of new testing and therapeutic approaches to pair with immune assessment.

Although Górecki and colleagues say better understanding dystrophin immunogenicity is a significant challenge, they also argue that it is a major opportunity. Successful dystrophin re-expression therapies could have major impacts on the lives of older patients, but since the disease is diagnosable at birth, these strategies could potentially lead to early intervention that could prevent damage and possibly induce neonatal tolerance.