A few decades ago, the prospect of gene therapy seemed to belong in the realm of science fiction. Now, gene therapy has come of age, and is in the process of becoming a serious form of therapy for use in many diseases, including Duchenne muscular dystrophy (DMD). 

“Gene therapy.” In the minds of laypeople, this phrase might conjure up many images that might not necessarily be an accurate representation. Is it a one-stop cure that spells the end to some of the most complex diseases of our day? Or will it work in a more nuanced, long-term way? 

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In this article, we will discuss gene therapy in DMD based primarily on the work of Heslop et al, who have written an excellent piece carefully breaking down the various aspects of gene therapy for DMD. 

Understanding Gene Therapy 

Heslop and colleagues started their study commenting on the huge amount of interest, excitement, and expectation placed on gene therapy based on promising preclinical data, as well as its efficacy in similar neurodegenerative disorders such as spinal muscular atrophy

“However, it is also important to take an objective view of the realistic possibilities and limitations of [adeno-associated virus (AAV)] gene therapy for DMD as well as considering the likely barriers to clinical trials and the development of gene therapy as an approved and accessible treatment,” they cautioned. 

First things first: what is gene therapy? “AAV gene therapy is a way of treating or changing the progression of a disease by the introduction of genetic material into the cells of a patient. This may involve different approaches, but for DMD currently relies on delivery of genetic material by an AAV vector,” Heslop et al wrote, crediting Francesco Muntoni of the University College London and Great Ormond Street Hospital Trust with the simple explanation. 

To understand how gene therapy offers clinical benefits to patients, we need to understand something of the pathophysiology of DMD. Elangkovan and Dickson, in their study on the uses of gene therapy for DMD, wrote, “The disease is caused by mutations in the DMD gene that codes for dystrophin. Dystrophin is a structural protein that maintains the integrity of muscle fibers and protects them from contraction-induced damage. The absence of dystrophin compromises the stability and function of the muscle fibers, eventually leading to muscle degeneration.” 

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So, dystrophin levels are the key issue here. According to Heslop et al, gene therapy can offer a way in which shortened dystrophins are developed. It is possible to remove parts of the DMD coding sequence to identify the critical domains that permit the maximum function of the translated protein to be maintained. This would reduce their size sufficiency so that they can be accommodated by an AAV vector.

“The resulting micro and mini dystrophins have been compared and changes made to reach what is felt to be the optimum sequence,” Heslop and colleagues explained. 

However, these shortened dystrophins are still not as effective as wild-type dystrophins. Therefore, Heslop et al stressed this key point: “DMD gene replacement therapies, if successful, should not be seen as a cure for DMD. We should not either refer to ‘turning Duchenne into Becker’, as BMD patients are born with a truncated form of dystrophin and any new nuclei formed will be able to produce BMD protein.” 

Many of the experiments conducted on gene therapy in DMD cases involved the use of animal models. Elangkovan and Dickson wrote, “Whilst microdystrophin gene transfer using AAV vectors shows extremely impressive therapeutic success so far in large animal models of DMD, translating this advanced therapy medicinal product from bench to bedside still offers scope for many optimization steps.”

Perceptions of Patients and the Public

So what do we know about human patient perspective on gene therapy? Heslop et al devoted a section in their study to how DMD patients respond to this novel therapy. They learned that patients are generally optimistic about the prospects of gene therapy, outweighing any possible concerns on risk, uncertainties, or burdens. This is especially true for patients who have already become nonambulatory due to the disease. 

“Additionally, the study found a relatively high tolerance for mortality risk and that this tolerance increased with disease progression,” Heslop and colleagues wrote. Of course, patient opinions on any particular therapy can and do change. A UK survey indicated that young families want to have access to gene therapy in the UK, and that older patients are optimistic about the idea of being part of the solution by being recruited into clinical studies. 

It seems that the more the public is educated about the potential benefits of gene therapy, the more they are excited about its possibilities. Hence, constant education and dialogue are paramount to keep the DMD patient population and the wider public engaged. The mood, for now, is upbeat and optimistic. 

With all the theoretical possibilities of gene therapy, as well as the generally positive response from patients, it is now up to researchers and physicians to refine this form of therapy, generate sufficient clinical data, and slowly incorporate it into clinical practice, while keeping costs low. 

References

Elangkovan N, Dickson G. Gene therapy for Duchenne muscular dystrophy. J Neuromuscul Dis. Published online September 7, 2021. doi:10.3233/JND-210678

Heslop E, Turner C, Irvin A, et al. Gene therapy in Duchenne muscular dystrophy: identifying and preparing for the challenges ahead. Neuromuscul Disord. Published online September 8, 2020. doi:10.1016/j.nmd.2020.10.001