This year’s Bernard Sachs Lecturer is Jerry R. Mendell, MD, Professor of Pediatrics and Neurology at Nationwide Children’s Hospital and The Ohio State University College of Medicine in Columbus, Ohio. He also holds the Juanita Curran and Dwight Peters Chair of Pediatric Research at the Abigail Wexner Research Institute. Dr. Mendell has published over 400 journal articles, most of them focusing on neuromuscular disease, along with books on myopathies, peripheral nerve disorders, and gene therapy. He has done seminal studies on the use of gene therapy for individuals with neuromuscular disease.
Dr. Mendell graduated from the University of Texas in Austin before entering the University of Texas Southwestern Medical School in Dallas. Following medical school graduation in 1966, Mendell became a neurology resident at Columbia University’s New York Neurological Institute. After completion of his residency, he completed a three-year post-doctoral fellowship in the Medical Neurology Branch of the National Institutes of Health. In 1972 Mendell was recruited to The Ohio State University College of Medicine and Nationwide Children’s Hospital (then Columbus Children’s Hospital). He was named the Helen C. Kurtz Professor and Chair of the Department of Neurology at Ohio State in 1992, a position he held until moving to the Nationwide Children’s Hospital Research institute in 2004.
Although gene therapies for neurological diseases have blossomed in recent years and hold enormous promise for individuals with numerous genetic diseases, many years of painstaking work by Dr. Mendell and others underpin these seemingly sudden recent successes. But starting early in his career, Mendell wanted to do more than quantify and categorize the neuromuscular diseases. He was determined to find treatments that would improve the lives of patients, and this steadfast resolve helped him overcome early disappointing results and solve once impossible barriers.
Dr. Mendell’s work with muscular dystrophy began during his post-doctoral fellowship in the Medical Neurology Branch at NIH in 1969. His early work in Duchenne muscular dystrophy (DMD) described the contribution of a vascular pathway using experimental pathology outcomes,1 work now confirmed by the molecular confirmation of nNOS binding sites on dystrophin. Additional efforts to support this hypothesis seemed encouraging, but clinical trials to promote blood flow were disappointing.2;3 This was merely the first step of an extensive journey to find a treatment for neuromuscular disease, pursued over many decades. In the mid-1970’s, Dr. Mendell joined an exceptionally talented group of muscle disease researchers to begin addressing some of the basic questions regarding clinical trials design, leading to the birth of the Clinical Investigation of Duchenne Dystrophy (CIDD) group in 1979. Over the next several years, this group introduced and recommended standardized methods for clinical trials, defined the natural history of DMD, determined sample size based on power calculations, and reinforced the importance of intra- and inter-rater reliability scores. In 1989, the CIDD group defined corticosteroids as the first treatment to be effective for DMD.4 This study has been confirmed multiple times, and corticosteroid therapy is now the standard of care for DMD.5
Mendell’s research continued as the entire field embraced molecular biology as a tool for research. An attempt to transfer the gene using skeletal muscle stem cells (myoblasts) was disappointing considering that the method had been highly touted.6 The unraveling of the highly complex sequence of the dystrophin gene by the Kunkel Lab at Boston Children’s Hospital facilitated efforts to treat muscle disease by direct gene transfer. In 1999 Dr. Mendell performed the first ever AAV gene transfer for skeletal muscle for limb girdle muscular dystrophy type 2D. There were early indicators of gene expression, but the trial was catastrophically interrupted by the highly publicized death of Jesse Gelsinger during a trial using adenovirus to transfer the OTC gene. Further attempts at gene transfer came only after Mendell’s recruitment as the Director of the Translational Neuromuscular Gene Therapy Center at Nationwide Children’s Hospital in 2004.
In March 2007, Dr. Mendell again initiated gene therapy for muscular dystrophy in the Center for Gene Therapy. His team’s study of limb-girdle muscular dystrophy type 2D confirmed sustained gene expression for more than six months, importantly demonstrating the potential of this approach.7 A similar gene therapy study for DMD, with colleague Christopher Walker, demonstrated that expressing the gene into deleted domain of an endogenous gene was likely to result in rejection of the gene product because of transgene immunity.8 A recent trial has confirmed this concern.
An additional important contribution by the Mendell team was the development of the two-tier system for detection of DMD in the newborn. On the dried blood spot taken for detection of inheritable diseases, both CK and DNA are tested simultaneously. This seminal study of nearly 40,000 newborn males throughout Ohio showed the now acknowledged incidence of DMD at birth to be 1:5000.9 This important study laid the groundwork for the implementation of newborn screening for DMD and early gene transfer to benefit the boys with DMD.
Dr. Mendell also led the Center in clinical trial(s) on exon skipping – noteworthy because it was the first therapeutic agent to show increased dystrophin expression in DMD and now more than a decade later dystrophin expression levels are still increasing and follow-up, long-term exon skipping outcomes demonstrates slowing in disease progression.10;11 Eteplirsen is now approved by the FDA for commercial use, along with other exon skipping agents including casimersen and golodirsen.
A major milestone for gene therapy was the clinical trial and published article on SMA gene therapy showing unequivocal efficacy.12 This was a milestone achievement because it saves the lives of infants when the gene is delivered in AAV9 in very high dose by intravenous administration. In addition, an important finding was that pre-administration of prednisone 1 day prior to delivery with extension for 30-60 days significantly controls hepatotoxicity. Use of corticosteroids has now become standard in gene therapy trials. SMA gene therapy has now been approved by the FDA for clinical therapy as onasemnogene abeparvovec. In addition, based on the efficacy of SMA gene therapy, newborn screening for this severe disorder is now established in at least 38 states throughout the country. Treatment in the newborn period not only saves lives but results in normal to near normal milestones.13
Currently Dr. Mendell is investigating the systemic delivery of micro-dystrophin for DMD, and he recently published the first study to demonstrate its efficacy.14 Of interest, the DMD trial used a different virus serotype, AAVrh74, for gene transfer; this virus induced some adverse effects, but far fewer than other trials using high dose of virus or other AAV serotypes. The exceptional team at the Center for Gene Therapy is playing a leading role in establishing safety and efficacy in other childhood diseases. Clinical trials have now demonstrated excellent gene expression and functional improvement in limb-girdle muscular dystrophy.
A life of such singular accomplishment is typically accompanied by widespread recognition and numerous tributes, and Dr. Mendell has more such honors than can be mentioned in a short biographical sketch. To name a few, he was awarded the 1989 Presidential Award for Outstanding Research by the American Neurological Association, the 2017 Science Magazine Breakthrough Achievement Award, given in recognition of the most influential science article of the year in any journal, the 2018 Clinical Research Forum Distinguished Clinical Research Achievement Award by the National Press Club, and the 2019 Lifetime Achievement Award from the Limb Girdle Muscular Dystrophy Foundation. In 2020, he was elected to the National Academy of Medicine, and the American Society of Gene and Cell Therapy created the Jerry Mendel Translational Science Award in his honor.
The seminal contributions by Dr. Mendell and his Nationwide Children’s Hospital colleagues over the last 16 years have improved the lives of many infants and children with heritable neuromuscular disease. Importantly, the techniques they developed can now be applied to other genetic diseases. A lifetime of dogged determination to make a difference in the lives of children has paid wonderful dividends.
(1) Mendell JR, Engel WK, Derrer EC. Duchenne muscular dystrophy: functional ischemia reproduces its characteristic lesions. Science 1971;172:1143-1145.
(2) 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;239:522-524.
(3) Parker JM, Mendell JR. Proximal myopathy induced by 5-HT-imipramine simulates Duchenne dystrophy. Nature 1974;247:103-104.
(4) 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;320:1592-1597.
(5) 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.
(6) Mendell JR, Kissel JT, Amato AA et al. Myoblast transfer in the treatment of Duchenne’s muscular dystrophy. N Engl J Med 1995;333:832-838.
(7) 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;66:290-297.
(8) Mendell JR, Campbell K, Rodino-Klapac L et al. Dystrophin immunity in Duchenne’s muscular dystrophy. N Engl J Med 2010;363:1429-1437.
(9) Mendell JR, Shilling C, Leslie ND et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol 2012;71:304-313.
(10) Mendell JR, Rodino-Klapac LR, Sahenk Z et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 2013;74:637-647.
(11) Mendell JR, Goemans N, Lowes LP et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol 2016;79:257-271.
(12) Mendell JR, Al-Zaidy S, Shell R et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017;377:1713-1722.
(13) 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.
(14) 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;77:1122-1131.