Gene Therapies Hold Promise for Neuromuscular and Other Rare Diseases

Pharmacy Practice in Focus: Health SystemsJanuary 2024
Volume 13
Issue 1

Challenges remain, however, to therapy development for a limited patient population.

After decades of research, gene therapy strategies are finally being implemented into clinical practice. The FDA has approved 13 gene therapies, including 6 in 2023.1 In the neuromuscular disease (NMD) space, there are now 2 FDA-approved therapies available, both for rare diseases that affect fewer than 200,000 individuals in the US. The National Center for Advancing Translational Sciences estimates that 1 in 10 individuals (approximately 30 million) in the United States have a rare disease and that 95% of the approximately 10,000 known rare diseases lack an FDA-approved treatment.1 Many rare diseases are caused by single gene defects (monogenetic), making them potentially amenable to treatment with gene therapy, and providing hope for better and more durable treatments on the horizon.

Research for genomic medicine or gene therapy -- Image credit: RFBSIP |

Image credit: RFBSIP |

Benefits of Gene Therapy

Gene therapy typically works by introducing a new gene (known as a transgene) into cells, which restores or adds gene expression to treat a disease. In many cases, a defective gene may be replaced with DNA encoding a functional copy of the same gene, thereby addressing the root cause of the disease. These replacement genes are often delivered into cells using a viral-delivery system, such as adeno-associated virus (AAV). Most gene therapies are designed as a onetime treatment and are expected to correct underlying gene defects, leading to long-term, durable improvements in function and overall health.1

Gene Therapy Successes in NMDs

In May 2019, onasemnogene abeparvovecxioi (Zolgensma; Novartis) became the first FDA-approved gene therapy for patients with an NMD.2 It was approved to treat children younger than 2 years with a confirmed diagnosis of spinal muscular atrophy (SMA). In June 2022, Novartis reported the final results from its phase 3 SPR1NT trial (NCT03505099) of onasemnogene abeparvovec-xioi, which demonstrated that all 29 children with SMA who were treated before the appearance of symptoms achieved age-appropriate milestones, including sitting, standing, and walking.3 Additionally, none of the children required respiratory or nutritional support or experienced serious treatmentrelated adverse events (AEs) during the trial.

In June 2023, the FDA granted the accelerated approval of SRP-9001 minidystrophin gene therapy (delandistrogene moxeparvovec-rokl; Elevidys; Sarepta Therapeutics) to treat ambulatory children aged 4 to 5 years with Duchenne muscular dystrophy (DMD). This approval was based on positive results in this age range from several clinical trials, including the phase 1/2 SRP-9001-101 (NCT03375164), the phase 1/2 SRP-9001-102 (NCT03769116), and the phase 1 ENDEAVOR (SRP-9001-103; NCT04626674) studies.4 SRP-9001 was shown to increase the expression of the micro-dystrophin protein, which the FDA concluded was reasonably likely to predict clinical benefit.

Additionally, SRP-9001 was studied in the phase 3 postmarketing confirmatory EMBARK trial (SRP-9001-301; NCT05096221). In this trial, the study failed to meet its primary end point; however, SRP-9001 demonstrated robust evidence for a clinically meaningful benefit that was similar in magnitude and statistical significance across all age groups and across all key prespecified secondary end points, including time to rise (P = .0025) and 10-m walk test (P = .0048). According to a news release, the results support the submission of an efficacy supplement to the biologics license application, and the FDA has indicated an openness to reviewing the data for label expansion based on the evidence.5,6

Upcoming Gene Therapy Options for NMDs

These advances in SMA and DMD disease management hold promise for the development of gene therapies for other NMDs. Gene therapy treatments are being explored in clinical trials for a number of NMDs, including amyotrophic lateral sclerosis, limb-girdle muscular dystrophy, Pompe disease, the inherited giant axonal and Charcot-Marie-Tooth neuropathies, and myotubular myopathy. As of December 2023, 36 active or recruiting interventional clinical trials of gene therapies for neuromuscular diseases were registered on

Hurdles to Gene Therapy Development

Despite the promise of recent approvals, the development of new gene therapies is subject to a number of risks and challenges associated with implementation, including AEs, durability of treatments/need for redosing, and regulatory and commercial hurdles for ultrarare indications.7 One significant complication of many gene therapies is the immune response triggered by the capsid protein of the AAV-delivery vehicle. This response is influenced by a variety of factors, including the amount of AAV vector introduced (eg, high dosing), impurities in the drug preparation (eg, empty capsids), undesirable DNA content within the capsid (eg, DNA from the host cell or high CpG content in vector genome), as well as preexisting neutralizing antibodies in the patient. Theoretically, some individuals may have an underlying genetic predisposition for an increased inflammatory response to gene therapy, but more study is needed to determine whether this is the case. These factors can elicit or amplify the immune response to the introduced gene therapy, causing rejection of the therapy.

One capsid-triggered clinical manifestation that has been observed across several gene therapy trials is hepatotoxicity (liver injury). In August 2022, Novartis reported the deaths of 2 children from acute liver failure following treatment with onasemnogene abeparvovec-xioi.8 Serious liver toxicity also occurred in the phase 1/2 clinical trial ASPIRO (NCT03199469) investigating the X-linked myotubular myopathy drug candidate AT132 (Astellas). Despite the promising efficacy of AT132, 4 children experienced abnormal liver function, leading to death following treatment.9 In September 2021, Astellas paused the recruitment of new participants into the ASPIRO study to determine its next steps. The company now plans to license and develop a new gene therapy candidate that may be effective at a lower dose, decreasing the risk of hepatotoxicity.10

Another problem that can occur due to the immunogenicity of the AAV capsid during gene therapy delivery is thrombotic microangiopathy (TMA). In capsid-triggered TMA, the immune response to the AAV capsid (mediated by the complement system) can cause hemolytic anemia (destruction of red blood cells), low platelet counts, and microscopic blood clots, leading to damage to small blood vessels in the kidneys, brain, and other organs.11 This complication is thought to have occurred in several participants in Pfizer’s fordadistrogene movaparvovec (mini-dystrophin) gene therapy study that demonstrated serious AEs consistent with TMA. In December 2021, Pfizer paused its phase 3 CIFFREO trial (NCT04281485) of fordadistrogene movaparvovec in ambulatory boys aged 4 to 7 years with DMD, following the death of a participant in the phase 1b study of the therapy in nonambulatory boys.11,12 The affected boy died 6 days post treatment due to cardiac shock with rising troponin levels, which is a sign of heart attack, and without significant thrombocytopenia or systemic reduction of complement. Though the exact cause of death is under investigation, it is believed to be the consequence of an innate immune response in the heart that resulted in swelling and heart failure.12

The capsid is not the only part of a gene therapy that may elicit an immune response. In some cases, responses occur due to the introduced transgene itself. Transgene-triggered AEs have occurred in the DMD mini-dystrophin gene therapy trials.7,13 Some participants were shown to have at-risk genotypes because they expressed truncated dystrophin proteins lacking specific protein epitopes known as cross-reactive immunological material (CRIM), which allowed their immune system to produce anti-dystrophin antibodies specific for the missing epitopes. These antibodies ultimately reacted with the mini-dystrophin gene therapy containing the CRIM epitopes. Following identification of this problem, trial sponsors have moved to exclude CRIM-negative individuals from participating in future gene therapy trials until more is understood about the issue.13

Another challenge for the development of effective gene therapies is durability. Two follow-up studies of onasemnogene abeparvovec-xioi, START (NCT03421977) and LT-002 (NCT04042025), have shown relatively long-term durability and efficacy of the gene therapy.14 Data from START demonstrated that all treated children maintained their previously achieved motor milestones, and 3 treated children achieved a new milestone of standing with assistance at 7.5 years post treatment. In an interim analysis of the 15-year LT-002 study, presymptomatic and symptomatic children treated with onasemnogene abeparvovec-xioi also demonstrated maintenance of motor milestones.

However, investigators at the 2023 Muscular Dystrophy Association Conference in Dallas, Texas reported on a number of factors that can influence the duration of effect of a gene therapy. It was noted that durability cannot be easily predicted during the design of the gene therapy vector. The transgene that is introduced during gene therapy can be lost in several ways over time. The continuous degeneration and regeneration of muscle fibers that occur during the course of many neuromuscular diseases can lead to loss of the introduced transgene. Similarly, muscle growth in treated children can lead to the dilution of the introduced genetic material, leading to decreased efficacy over time. Another possibility is that cytotoxic T cells of the immune system may target transgene-expressing fibers, leading to destruction of corrected muscle tissues.7

Given this concern of waning efficacy, the question of redosing of gene therapies has arisen. Currently, individuals who have antibodies to AAV are not candidates for AAV-based gene therapy because the antibodies often neutralize the introduced vector before the transgene can be expressed. Similarly, individuals who have previously participated in a trial for an AAV-based gene therapy, and may therefore have developed antibodies to AAV, are no longer eligible to participate in future gene therapy trials. Approaches to modulate the immune response to allow for redosing are being explored but are not yet available. Understanding and appropriately managing the immune response will be critical to producing safe and effective gene therapies.7

To reach the next stage of commercial development of a new gene therapy, sponsors must gain marketing approval from the FDA. To receive approval for a new gene therapy in the US, investigators must first submit an investigational new drug application, which will be evaluated by the FDA’s Center for Biologics Evaluation and Research.15,16

Historically, it has been difficult to complete drug development and get approval for rare diseases, such as NMDs; drug sponsors and manufacturers must overcome a number of financial and regulatory constraints.17 The research and development involved in bringing a drug to market can be prohibitive. One study estimated this cost at between $318 million and $3 billion in 2018.18 It is important to note that the cost of developing a drug for a common disease is the same as developing a drug for a rare or ultrarare disease (< 50,000 affected individuals).

Additionally, the manufacturing of gene therapies is also challenging, requiring investment in sophisticated infrastructure and facilities, advanced genetic technologies, highly trained personnel, and sensitive biological materials. Furthermore, the FDA has required that manufacturers submit 3 commercial-grade batches of a new biologic product to validate the manufacturing and cleaning process before a new drug can be approved.19 In the case of rare and ultrarare diseases, the number of drug doses produced in these initial 3 batches may outnumber the number of individuals with a particular disease, which may discourage manufacturers from investing in such therapies.

For the drug development process to be viable, the costs associated with research and development and manufacturing must be recouped through sales. Many gene therapies, however, target rare or ultrarare diseases that affect a very small population. In fact, for some ultrarare diseases, there are fewer than 30 known affected individuals globally. It is therefore difficult to both find participants to enroll in clinical trials and to sustain profitability with such a small market. Furthermore, gene therapies are usually administered only once, requiring the full cost of the therapy to be paid upfront (over a few years), and not amortized over a lifetime. Approved gene therapies are therefore priced much differently than other medications (eg, $2.1 million for onasemnogene abeparvovec-xioi and $3.2 million for SRP-9001), which in turn confounds existing insurance payment models and limits access for patients who may greatly benefit from these therapies.20-22

Recognizing the need to incentivize therapeutic development for rare and ultrarare diseases, Congress passed the Orphan Drug Act of 1983, which provided the FDA with authority to grant orphan drug designation to a drug or biological product designed to prevent, diagnose, or treat a rare disease or condition.23 The Orphan Drug Act has helped to encourage the development of gene therapies, but longer-term solutions will likely require changes in how regulatory agencies review therapies for rare and ultrarare diseases.24 For example, there is a push for regulators to give marketing approval to therapeutic categories, such as antisense oligonucleotides and gene therapy vehicles as a single product, so that these strategies can be rapidly repurposed for new targeted therapies.24 This would reduce the amount of preclinical and toxicology studies required to initiate a human trial. Similarly, current FDA regulations provide a pathway to approve drugs for specific diseases, but not for broader disease classes. An alternative model would be to approve drugs for classes of rare diseases, such as diseases caused by related genetic mutations (ie, in the same gene or pathway) that also present similarly.24 Using this model, rare diseases fitting the broader disease class could potentially be added to the labels of previously approved therapies.

Ultimately, reducing the scientific, financial, and regulatory burdens of developing gene therapies is the only way to make the system more viable, enabling enhanced development of gene therapies with the potential to transform the lives of people with rare and ultrarare diseases.


1. Delivering hope for rare diseases. National Center for Advancing Translational Sciences. January 2023. Accessed November 30, 2023.

2. AveXis receives FDA approval for Zolgensma, the first and only gene therapy for pediatric patients with spinal muscular atrophy (SMA). News release. Novartis. May 24, 2019. Accessed June 20, 2023.

3. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the phase III SPR1NT trial. Nat Med. 2022;28(7):1381-1389. doi:10.1038/S41591-022-01866-4

4. Sarepta Therapeutics announces FDA approval of Elevidys, the first gene therapy to treat Duchenne muscular dystrophy. News release. Sarepta Therapeutics. June 22, 2023. Accessed August 19, 2023.

5. Meglio M. SRP-9001 fails to meet primary end point in phase 3 EMBARK study. NeurologyLive® October 31, 2023. Accessed December 1, 2023.

6. Sarepta Therapeutics announces topline results from EMBARK, a global pivotal study of ELEVIDYS gene therapy for Duchenne muscular dystrophy. News release. Sarepta Therapeutics. October 30, 2023. Accessed December 1, 2023.

7. Lek A, Atas E, Hesterlee SE, Byrne BJ, Bönnemann CG. Meeting report: 2022 Muscular Dystrophy Association summit on “Safety and Challenges in Gene Transfer Therapy.” J Neuromuscul Dis. 2023;10(3):327-336. doi:10.3233/JND-221639

8. Zolgensma acute liver failure update. News release. Novartis. August 11, 2022. Accessed August 19, 2023.

9. Fourth boy dies in trial of Astellas gene therapy candidate. Genetic Engineering & Biotechnology News. September 15, 2021. Accessed August 19, 2023.

10. Mast J. After gene therapy deaths, Astellas tries potentially safer approach. STAT. June 8, 2023. Accessed August 19, 2023.

11. Study to evaluate the safety and efficacy of PF-06939926 for the treatment of Duchenne muscular dystrophy. Updated August 31, 2023. Accessed November 19, 2023.

12. A study to evaluate the safety and tolerability of PF-06939926 gene therapy in Duchenne muscular dystrophy. Updated December 13, 2022. Accessed August 19, 2023.

13. Bönnemann CG, Belluscio BA, Braun S, Morris C, Singh T, Muntoni F. Dystrophin immunity after gene therapy for Duchenne’s muscular dystrophy. N Engl J Med. 2023;388(24):2294-2296. doi:10.1056/NEJMc2212912

14. Novartis shares Zolgensma long-term data demonstrating sustained durability up to 7.5 years post-dosing; 100% achievement of all assessed milestones in children treated prior to SMA symptom onset. News release. Novartis. March 20, 2023. Accessed August 20, 2023.

15. Investigational new drug (IND) application. FDA. Updated July 20, 2022. Accessed June 20, 2023.

16. Center for Biologics Evaluation and Research (CBER). FDA. Updated March 7, 2023. Accessed June 20, 2023.

17. Landfeldt E. Gene therapy for neuromuscular diseases: health economic challenges and future perspectives. J Neuromuscul Dis. 2022;9(6):675-688. doi:10.3233/JND-221540

18. Rennane S, Baker L, Mulcahy A. Estimating the cost of industry investment in drug research and development: a review of methods and results. Inquiry. 2021;58:469580211059731. doi:10.1177/00469580211059731

19. Process validation: general principles and practices. FDA. Updated August 24, 2018. Accessed June 20, 2023.

20. Stein R. At $2.1 million, new gene therapy is the most expensive drug ever. NPR. May 24, 2019. Accessed June 20, 2023.

21. Fidler B. Sarepta prices Duchenne gene therapy at $3.2M. BioPharma Dive. June 22, 2023. Accessed August 20, 2023.

22. Hampson G, Towse A, Pearson SD, Dreitlein WB, Henshall C. Gene therapy: evidence, value and affordability in the US health care system. J Comp Eff Res. 2018;7(1):15-28. doi:10.2217/CER-2017-0068

23. Designating an orphan product: drugs and biological products. FDA. Updated July 8, 2022. Accessed June 20, 2023.

24. Newton W. Drug development for ultra-rare diseases: what happens when N=1? Clinical Trials Arena. April 21, 2023. Accessed June 20, 2023.

About the Author

Sharon Hesterlee, PhD, is the chief research officer at the Muscular Dystrophy Association.

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