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  • Updated 02.15.2022
  • Released 03.30.2022
  • Expires For CME 02.15.2025

Perspectives: Dr. Jerry Mendell discusses Duchenne muscular dystrophy and gene therapy

Interview questions

[01:40] Tell us about your life prior to medical school. What got you interested in medicine? What got you interested in neurology and academic medicine?

[09:50] Tell us about how you decided to go to the National Institutes of Health for your post-doctoral fellowship? Did you have a particular area of research in mind? How did your fellowship influence your thinking and plans? Did a mentor play a role?

[15:20] You served as Chair of Neurology for The Ohio State University College of Medicine. How did this happen? How was your experience as Chair valuable for you?

[21:44] What brought about your move from Ohio State to Nationwide Children’s Hospital? Did you have a mandate to accomplish certain goals at Children’s?

[24:35] In what ways has the Duchenne field progressed since then, and what were your key contributions? What does the future of Duchenne muscular dystrophy look like over the next 10 to 20 years?

[33:40] You have been at Children’s now for nearly 18 years; what was it like building a program, and what were the major milestones that led to recent high-impact successes?

[38:01] Most recently you have carried out important work related to spinal muscular atrophy. Tell us about the field and your contributions to it? What are their implications for patients with spinal muscular atrophy?

[36:35] What are your goals for the future?

[41:05] Do you have career development and satisfaction guidance for students?

Biography

Dr. Jerry R Mendell is an attending neurologist at Nationwide Children’s Hospital, the Dwight E Peters and Juanita R Curran Endowed Chair in Pediatric Research at the Abigail Wexner Research Institute at Nationwide Children’s Hospital, and a professor of pediatrics and neurology at Nationwide Children’s and The Ohio State University. He has been elected to the National Academy of Medicine and was the first recipient of the Translational Medicine Award from the American Society of Gene and Cell Therapy. This award was named in his honor and will be awarded yearly to future recipients.

Dr. Mendell graduated from the University of Texas, attended UT Southwestern Medical School, and did neurology residency at Columbia University’s New York Neurological Institute. His postdoctoral fellowship at the Medical Neurology Branch of the National Institutes of Health (NIH) launched his career in neuromuscular disease and inspired his next 50 years in academic medicine to improve the lives of patients with neuromuscular disease. Upon leaving the NIH, he was recruited to The Ohio State University and Nationwide Children’s Hospital, where he has spent his entire career. He has published more than 400 articles focusing on neuromuscular disease and authored books on skeletal muscle disease, peripheral nerve disorders, and gene therapy.

Duchenne muscular dystrophy research

Early work in Duchenne muscular dystrophy described a vascular pathway responsible for muscle damage (03; 04; 12). The translational importance of this pre-molecular work has now been confirmed by the nNOS binding site of the DMD gene. Beginning in 1979 and for several years to follow, important clinical contributions were related to participation with an exceptionally talented group of muscle disease researchers known as the Clinical Investigation of Duchenne Dystrophy (CIDD). The CIDD group took on new challenges for clinical trials, including standardizing approaches that could refine existing safety and efficacy measures. Targets included defining the natural history of Duchenne muscular dystrophy, introducing reliable testing methods validated by intra- and interrater reliability scores, demonstrating the importance of sample size based on power calculations, and applying statistical methods of analysis to outcomes to ensure precision. The value of separating the responsibilities of a principal investigator from the evaluators (PTs) was introduced and is still the gold standard today.

The first significant breakthrough in treatment was described in 1989, with a demonstration of the efficacy of corticosteroids in Duchenne muscular dystrophy (07). The importance of prednisone or one of its corticosteroid variants with different dosing regimens has been confirmed multiple times and is now the standard of care for Duchenne muscular dystrophy. This has dramatically influenced the protocols for clinical trials. Virtually every new approach to treatment for Duchenne muscular dystrophy includes testing the potentially novel therapy while the patient remains on corticosteroid treatment. With corticosteroids in place, Mendell’s research moved toward molecular-based strategies. This was made possible by the Kunkel Lab at Boston Children’s Hospital, which unraveled the dystrophin gene’s highly complex 2.4 million-base pair DNA sequence. The discovery of the DMD gene had an enormous impact on treatment efforts for muscle disease that influenced approaches in hopes of changing the natural history of Duchenne muscular dystrophy. A highly touted early effort to transfer the DMD gene used skeletal muscle stem cells (myoblasts). This approach was disappointing for the Mendell research team (06). In 1999, the first in-human clinical trial using adeno-associated virus for gene transfer to skeletal muscle was performed in LGMD2D/R3. This SGCA gene for this disease was chosen instead of DMD gene transfer, given that the alpha-sarcoglycan cDNA would fit the packaging restrictions of the adeno-associated virus. At the same time that LGMD2D/R3 gene transfer began, the highly publicized death of Jesse Gelsinger occurred during a clinical trial attempting to transfer the OTC gene in adenovirus. This signature event changed all subsequent translational efforts in gene delivery for muscle disease, emphasizing the potential safety of using the adeno-associated virus as the delivery vehicle.

In 2004, Dr. Mendell became Director of The Translational Neuromuscular Gene Therapy Center at Nationwide Children’s Hospital. In March 2007, reinitiation of LGMD2D/R3 gene therapy for muscular dystrophy was highly rewarding and launched a path to follow for many years. This SGCA clinical trial demonstrated sustained gene expression for more than 6 months, an important milestone for the field (08). In a similar gene therapy approach for Duchenne muscular dystrophy, one of the cardinal lessons of gene therapy was established. Transgene immunity was elicited following expression of the packaged cDNA into a deleted domain of the gene, resulting in rejection of the gene product (02). A recent trial has confirmed this concern and its potential risk. The illustrated principle serves as a guide to investigators designing current gene therapy clinical trials.

While working on treatment strategies, the Mendell Lab developed the two-tier system to detect Duchenne muscular dystrophy in newborns using the dried blood spot for both CK and DNA testing. This seminal study established the global incidence of Duchenne muscular dystrophy at birth at 1:5000 (11). Other newborn screening studies have also confirmed this birth incidence. Implementation of newborn screening for Duchenne muscular dystrophy could lead to early gene transfer, significantly benefitting boys with Duchenne muscular dystrophy.

Dr. Mendell also led the Center for Gene Therapy at Nationwide Children’s Hospital in clinical trials on exon skipping--noteworthy because it was the first therapeutic agent to show increased dystrophin expression in Duchenne muscular dystrophy. More than a decade later, dystrophin expression levels have been maintained, and outcomes demonstrate a slowing in disease progression (09; 05). Eteplirsen (exon 51) is now approved by the United States Food and Drug Administration for commercial use, along with other exon-skipping agents, including casimersen (exon 45) and golodirsen (exon 53).

Dr. Mendell led the Phase 1 clinical trial that proved to be the first effective gene therapy for spinal muscular atrophy type 1, reversing the most severe form of spinal muscular atrophy that typically results in death by 2 years of age. The study, published in the New England Journal of Medicine was the People’s Choice for Science Magazine’s 2017 Breakthrough of the Year Award (01). In May 2019, the United States Food and Drug Administration approved onasemnogene abeparvovec (Zolgensma®) for spinal muscular atrophy in pediatric patients younger than 2 years of age. Based on approval, newborn screening for spinal muscular atrophy was approved in most states, permitting gene therapy treatment in the newborn period and making a huge difference in the function and life expectancy of children with spinal muscular atrophy.

Currently, Dr. Mendell is actively engaged in systemic delivery of microdystrophin in a Duchenne muscular dystrophy gene therapy; validation of efficacy was published in JAMA Neurology (10). Motor function improved, and continued follow-up has shown sustained improvement for 4 years. Duchenne muscular dystrophy gene therapy is now in a Phase 3 trial with the unambiguous goal of attaining Food and Drug Administration approval.

The seminal contributions reflect the continued effort, hard work, and determination by Dr. Mendell, who has achieved recognition for contributions of the Center for Gene Therapy at Nationwide Children’s Hospital. Dr. Mendell has also achieved recognition as a translational clinician-scientist, using available tools over many decades to improve the lives of patients with neuromuscular disease.

References

01
Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017;377(18):1713-22. PMID 29091557
02
Mendell JR, Campbell K, Rodino-Klapac L, et al. Dystrophin immunity in Duchenne's muscular dystrophy. N Engl J Med 2010;363(15):1429-37. PMID 20925545
03
Mendell JR, Engel WK, Derrer EC. Duchenne muscular dystrophy: functional ischemia reproduces its characteristic lesions. Science 1971;172(3988):1143-5. PMID 5574520
04
Mendell JR, Engel WK, Derrer EC. Increased plasma enzyme concentrations in rats with functional ischaemia of muscle provide a possible model of Duchenne muscular dystrophy. Nature 1972;239(5374):522-4. PMID 4563024
05
Mendell JR, Goemans N, Lowes LP, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol 2016;79(2):257-71. PMID 26573217
06
Mendell JR, Kissel JT, Amato AA, et al. Myoblast transfer in the treatment of Duchenne's muscular dystrophy. N Engl J Med 1995;333(13):832-8. PMID 7651473
07
Mendell JR, Moxley RT, Griggs RC, et al. Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. N Engl J Med 1989;320(24):1592-7. PMID 2657428
08
Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, et al. Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol 2009;66(3):290-7. PMID 19798725
09
Mendell JR, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 2013;74(5):637-47. PMID 23907995
10
Mendell JR, Sahenk Z, Lehman K, et al. Assessment of systemic delivery of rAAVrh74.MHCK7.micro-dystrophin in children with duchenne muscular dystrophy: a nonrandomized controlled trial. JAMA Neurol 2020;77(9):1122-31. PMID 32539076
11
Mendell JR, Shilling C, Leslie ND, et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol 2012;71(3):304-13. PMID 22451200
12
Parker JM, Mendell JR. Proximal myopathy induced by 5-HT-imipramine simulates Duchenne dystrophy. Nature 1974;247(5436):103-4. PMID 4809132
13
Aartsma-Rus A, Ginjaar IB, Bushby K. The importance of genetic diagnosis for Duchenne muscular dystrophy. J Med Genet 2016;53(3):145-51. [Free full text] PMID 26754139
14
Al-Zaidy SA, Mendell JR. From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1. Pediatr Neurol 2019;100:3-11. [Free full text] PMID 31371124
15
Annexstad EJ, Lund-Petersen I, Rasmussen M. Duchenne muscular dystrophy. Tidsskr Nor Laegeforen 2014;134(14):1361-4. [Free full text] PMID 25096430
16
Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol 2018;17(3):251-67. Erratum in: Lancet Neurol 2018. [Free full text] PMID 29395989
17
Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol 2018;17(4):347-61. [Free full text] PMID 29395990
18
Carter BJ. Adeno-associated virus and the development of adeno-associated virus vectors: a historical perspective. Mol Ther 2004;10(6):981-9. [Free full text] PMID 15564130
19
Chamberlain JR, Chamberlain JS. Progress toward gene therapy for Duchenne muscular dystrophy. Mol Ther 2017;25(5):1125-31. [Free full text] PMID 28416280
20
Duan D. Systemic AAV micro-dystrophin gene therapy for Duchenne muscular dystrophy. Mol Ther 2018;26(10):2337-56. [Free full text] PMID 30093306
21
Elangkovan N, Dickson G. Gene therapy for Duchenne muscular dystrophy. J Neuromuscul Dis 2021;8(s2):S303-16. [Free full text] PMID 34511510
22
Emery AE, Emery ML. The History of a Genetic Disease: Duchenne Muscular Dystrophy or Meryon's Disease. 2nd ed. New York: Oxford Univ Press, Inc. 2011. [Free full text]
23
Falzarano MS, Scotton C, Passarelli C, Ferlini A. Duchenne muscular dystrophy: from diagnosis to therapy. Molecules 2015;20(10):18168-84. [Free full text] PMID 26457695
24
Keeler CE. Gene therapy. J Hered 1947 ;38(10):294-8. [Free full text] PMID 18900293
25
Lim KR, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther 2017;11:533-45. [Free full text] PMID 28280301
26
Miller NF, Alfano LN, Iammarino MA, et al. Natural history of steroid-treated young boys with Duchenne muscular dystrophy using the NSAA, 100m, and timed functional tests. Pediatr Neurol 2020;113:15-20. [Free full text] PMID 32979653
27
Rare Disease Advisor . Duchenne muscular dystrophy. Available at: www.rarediseaseadvisor.com. Accessed March 1, 2022. [Free full text]
28
Ryder S, Leadley RM, Armstrong N, et al. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet J Rare Dis 2017;12(1):79. [Free full text] PMID 28446219
29
Sun C, Shen L, Zhang Z, Xie X. Therapeutic strategies for Duchenne muscular dystrophy: an update. Genes (Basel) 2020;11(8):837. [Free full text] PMID 32717791
30
Yiu EM, Kornberg AJ. Duchenne muscular dystrophy. Neurol India 2008;56(3):236-47. [Free full text] PMID 18974549

Contributors

Author

  • JMendell1

    Jerry R Mendell MD

    Dr. Mendell of Nationwide Children’s Hospital and The Ohio State University received honorariums and consulting fees from AveXis, Novartis, and Sarepta Therapeutics.

    See Profile

Editor

  • Aprr

    Raymond P Roos MD

    Dr. Roos serves on the Scientific Advisory Board of Revalesio Corporation and received consulting fees from Best Doctors and Guidepoint Network. He also owns stock in Amgen, Express Script, Ionis, Merck, Pfizer, and Cigna.

    See Profile

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