FDA APPROVAL: Gene Therapy Comes of Age

FDA APPROVAL: Gene Therapy Comes of Age 1024 575 Abbie Miller
Colorful illustration of gene therapy in action
UPDATED: May 2019
On May 24, 2019, the FDA approved Zolgensma (formerly AVXS-101), a first-of-its-kind gene therapy for spinal muscular atrophy.

In the 13 months that have passed since this article first posted, the long-term outcomes of gene therapy for spinal muscular atrophy (SMA) have continued to bolster the community’s hope for the treatments.

Now, the FDA has approved Zolgensma (formerly AVXS-101) for pediatric patients less than 2 years of age with SMA, including those who are pre-symptomatic at diagnosis. Jerry Mendell, MD, principal investigator in the Center for Gene Therapy at the Abigail Wexner Research Institute, led the Phase 1 clinical trial that was the first to study gene therapy for spinal muscular atrophy type 1 (SMA1), the most severe form of SMA.

Black and white photo; Dr. Jerry Mendell Environmental Portrait

The FDA’s decision is validation of my team’s decades of work to develop a treatment that alters the course of this unforgiving condition and provides a therapeutic option for the families and infants with SMA.

When you see one of the clinical trial participants – now four years old and running, jumping and dancing – it is incredible.

— Jerry Mendell, MD

Original Article from April 2018

Harnessing the ability of a virus to deliver genetic material to a cell to treat, cure or prevent disease has been the long-time goal of researchers working in gene therapy. Over the past 30 years, the journey to gene therapy has been fraught with challenges and roadblocks. But in 2017, after countless starts and stalls along the road, the field experienced many breakthroughs.

No breakthrough received more attention than when researchers from Nationwide Children’s Hospital and The Ohio State University published the astonishing results of the phase 1 clinical trial of gene therapy for spinal muscular atrophy type 1 (SMA1) in the New England Journal of Medicine.

The SMA1 early phase trial, led by Jerry Mendell, MD, principal investigator in the Center for Gene Therapy in The Research Institute at Nationwide Children’s, demonstrated extended survival and increased achievement of milestones previously unseen in the natural course of the disease — a devastating, progressive neuromuscular disease that typically results in death by age 2. An intravenous injection of AVXS-101, a modified adeno-associated virus serotype 9 (AAV9), delivered the survival of motor neuron (SMN) gene.

The trial builds on nearly 30 years of foundational research and collaboration. Arthur Burghes, PhD, of The Ohio State University, created the SMA mouse model that remains the standard by which all therapies are initially tested. Brian Kaspar, PhD, senior vice president and chief scientific officer at AveXis, a clinical-stage gene therapy company developing treatments for patients suffering from rare and life-threatening neurological genetic diseases, during his appointment at Nationwide Children’s, discovered that the AAV9 vector can cross the blood-brain barrier when injected into the vascular system and can deliver genes directly to motor neurons. That landmark study was published in Nature Biotechnology in 2009.

“None of this would have been possible without the seminal discovery that AAV9 crosses the blood-brain barrier,” says Dr. Mendell, also a professor of Pediatrics, Neurology, Pathology, and Physiology and Cell Biology at The Ohio State University College of Medicine.

AAV9 vectors are promising gene delivery tools for long-term transduction in a wide range of tissues — perhaps most notably central nervous system tissues and muscle tissues.

Researchers at Nationwide Children’s and across the country are building on the current AAV9 gene therapy successes to offer hope for patients and families with neuromuscular diseases.

“Beyond SMA, we are working on gene therapy solutions for myriad neuromuscular and neurologic diseases — Charcot-Marie-Tooth disease, Batten’s disease, and muscular dystrophies to name a few,” says Kevin Flanigan, MD, director of the Center for Gene Therapy at Nationwide Children’s. “And as we find the genetic causes for more and more rare diseases, we are going to see these efforts grow.”

Dr. Kevin Flanigan; Black and white environmental portrait photo in lab coat


Gene therapy for a specific disease is not a one-and-done scenario. Several different types of mutations can affect a given gene or set of genes that regulate a protein or cellular process.

Sanfilippo Syndrome

Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, is the target of one of the programs led by Dr. Flanigan, who is also director of the Center of Research Translation (CORT) in Muscular Dystrophy Therapeutic Development at Nationwide Children’s. CORT was established through a $7.5 million grant from the National Institutes of Health’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Four different genes may be involved, resulting in MPS types IIIA through IIID. Vectors originally developed at the Center for Gene Therapy for patients with MPS types IIIA and IIIB are currently in trials at Nationwide Children’s, led by Dr. Flanigan and sponsored by Abeona Therapeutics.

“Similar to the SMA1 trial, these AAV9-mediated gene therapy products targeting the central nervous system (CNS) are delivered intravenously, and so far appear to be quite well tolerated,” says Dr. Flanigan.

Limb Girdle Muscular Dystrophy

“Limb girdle muscular dystrophy (LGMD) is a fantastic example of how complicated developing gene-specific therapies can get,” says Louise Rodino-Klapac, PhD, principal investigator in the Center for Gene Therapy in The Research Institute at Nationwide Children’s.

Dr. Rodino-Klapac is also the chief scientific officer of Myonexus Therapeutics, a clinical-stage gene therapy company developing first-ever treatments for LGMD types 2D, 2B, 2E, 2L and 2C based on research at Nationwide Children’s. Many forms of LGMD result from a problem in the dystrophin-associated complex. Each of the approximately 20 subtypes of LGMD has a prevalence ranging from 1 in 100,000 to 1 in 200,000 and is caused by a unique mutation. Therefore, each subtype needs its own gene therapy approach. In the Rodino-Klapac lab, gene therapies for six of the different forms of LGMD2 are currently under investigation. The therapy for LGMD2E aims to correct a beta-sarcoglycan mutation and is the first approved for clinical trial. The trial is scheduled to begin enrolling patients in 2018.

“The preclinical results have blown us away,” says Dr. Rodino-Klapac, who is also an associate professor of Pediatrics at The Ohio State University College of Medicine. “Normally, we’re happy if 50 percent of the muscle fibers treated express the gene. In all of our preclinical studies, an excess of 95 percent of muscle fibers are expressing the gene. This makes us really hopeful about what the drug will be able to do for patients.”

Dr. Rodino-Klapac says there may be multiple reasons why the rate of expression has been so high in these preclinical studies, but she speculates that using self-complementary AAV (which was also used in the SMA1 trial) and the small gene size may be important factors. Self-complimentary AAV (scAAV) vectors contain complementary sequences that spontaneously anneal – or recombine – upon infection of the host cell. This technique works best for transfecting small genes, such as the SMN gene used in the SMA1 trial and the betasarcoglycan gene targeted in the LGMD2 trial, as the maximum gene length for scAAV is 2.4 kilobases (kb).


But what about large genes?

While AAV gene therapy is limited by the vector’s capacity — only 4.8 kb — the research community is not deterred from tackling a gene therapy solution for the largest known human gene. Errors in the gene coding for dystrophin lead to Duchenne muscular dystrophy (DMD), one of the most well-known muscular dystrophies. The DMD gene’s cDNA is about 11.5 kb — roughly 2.5 times larger than the vector’s capacity.


While the DMD gene is too large to insert in the vector, in two recently opened clinical trials, researchers are using a miniature version of the gene — microdystrophin.

“The idea is that the smaller version of the gene will enable the cells to produce dystrophin that is ‘close enough’ to wild-type to dramatically improve the symptoms and survival of boys with Duchenne muscular dystrophy,” explains Dr. Mendell.

One trial at Nationwide Children’s, led by Drs. Rodino-Klapac and Mendell, will test the efficacy of Sarepta Therapeutics’ microdystrophin gene therapy product. Another trial, led by Barry Byrne, MD, PhD, director of the Powell Gene Therapy Center at the University of Florida, looks at a slightly different version of microdystrophin produced by Solid Biosciences.

“In our preclinical work, the micro-dystrophin has been effective in producing a near wild-type phenotype,” says Dr. Rodino-Klapac. “We are hoping for a profound effect in the phase 1 clinical trial, but we will have to see how effective the minigene is compared to the full-length one.”

“To this point, we’ve had very little to offer these families,” says Dr. Mendell. “For 50 years, our only approved treatment for Duchenne muscular dystrophy has been prednisone. Our research aims to see if gene therapy is a safe and effective option for these patients and others with rare neuromuscular diseases in the future.”

The Nationwide Children’s clinical trial of microdystrophin for DMD will be the first use of intravenous (IV) gene therapy for any muscular dystrophy, according to Dr. Rodino-Klapac. “We’ll be starting with children aged 4 to 7 years old. This is still early in the disease process, and we hope that by intervening early, we can halt the progression of the disease. A second cohort, with children aged 3 months to 3 years, will enable us to see if we can prevent the onset of symptoms through the gene therapy.”

The team will be administering doses that were effective in preclinical studies. A control group of DMD patients will receive a placebo and be followed for one year. They will be offered treatment in the second year of the trial. The University of Florida trial, currently recruiting participants, is open to children aged 4 to 17 years and utilizes a control group.

“Our study design for this trial allows us to have matched controls in addition to the treatment group,” says Dr. Byrne, also a professor of Pediatrics and Molecular Genetics & Microbiology at the University of Florida. “The control patients will have the opportunity to receive the treatment later, based on the delayed start design. This provides a reasonable comparator of adverse events and benefits.”

Surrogate Gene Therapy

Another gene therapy strategy to treat DMD ignores the DMD gene entirely.

This is the surrogate strategy: Provide genes, delivered via viral vector, that encode proteins that can functionally compensate for the proteins that are missing in diseases. In the case of DMD, the GALGT2 genes are not in the right place in the muscle cell normally to take on that role, but by directing overexpression through gene therapy, they can.

In 2009, Paul Martin, PhD, investigator in the Center for Gene Therapy at Nationwide Children’s and professor of Pediatrics and Physiology and Cell Biology at The Ohio State University showed that GALGT2 overexpression in skeletal muscle prevents injury in both mdx (muscular dystrophy pathology) and wild-type mice. Since then, researchers at Nationwide Children’s in cooperation with Sarepta Therapeutics have developed the technology into a product that is currently in a phase 1/2a clinical trial, which is the first arterial gene therapy trial in DMD.

“GALGT2 overexpression compensates for the lack of dystrophin in the context of DMD,” says Dr. Flanigan, leader of the clinical trial for GALGT2 at Nationwide Children’s. “By overexpressing synaptic dystroglycan binding partners in the skeletal muscles, such as utrophin, the muscles can function normally — even when dystrophin is absent.”

The GALGT2 surrogate approach offers a particular benefit that many gene therapies lack. This single substitute is expected to treat the majority of dystrophin gene mutations responsible for DMD, as well as potentially having applications in other muscular dystrophies.

Could Two Vectors Be Better Than One?

Like the DMD gene, the gene for dysferlin (DYSF) is too large to package in an AAV vector. However, using dual vector technology to increase the packaging capacity of AAV, researchers have developed dysferlin overlaps. This technique relies on homologous recombination to piece two plasmids delivered in separate vectors back together upon infection of the target cell.

Dr. Rodino-Klapac; black and white environmental portrait photo in lab; former Nationwide Children's employee

“The gene of interest, in this case, DYSF, is divided between two transfer plasmids with substantial sequence overlap,” says Dr. Rodino-Klapac. “When administered together, both vectors enter the cell and the plasmids recombine and express the full-length gene.”

The broad scope of preclinical work with this technology for other genes shows mixed results, with the main concern being low efficiency of recombination.

However, researchers hope that it will be an effective solution for some genes. In the case of DYSF, it has worked remarkably well, says Dr. Rodino-Klapac.

Dr. Rodino-Klapac is leading an intramuscular trial using a dual vector approach for dysferlinopathy — a muscular dystrophy affecting patients in their late teens or early 20s, with approximately one-third of patients becoming wheelchair-bound within 15 years of diagnosis. LGMD2B and Miyoshi myopathy are the two most common forms of dysferlinopathy. She is hopeful that an intravenous clinical trial could open in 2019.


“One consideration that is critical with these clinical trials is that, at present, the dose is a one-time thing for these kids. Currently, they won’t have a chance for another stronger dose. Once they are injected with vector, they build up an immunity to it and future doses won’t be effective,” says Dr. Mendell.

Likewise, if someone has environmental exposure to AAV9, they may have antibodies that would exclude them from the trial because of the likelihood that the therapy would be unable to get past the immune system.

“It’s heartbreaking to exclude patients from a trial because they have antibodies to AAV,” says Dr. Rodino-Klapac. “Our hope is that we will have a strategy to offer the therapy safely and effectively to patients who have had environmental exposure to the virus.”

Drs. Mendell and Rodino-Klapac and their colleagues at the Center for Gene Therapy at Nationwide Children’s have had success in using apheresis and immunotherapeutic mediations in animal models. The next step will be to design a clinical trial to test the process in patients.

“Solving the problem of re-dosing is vital to offering the best possible outcomes for patients and their families,” says Dr. Mendell. “Developing a solution is the right thing to do.”

Another step on the road to the future of gene therapy is newborn screening. Newborn screening identifies many genetic diseases that gene therapy aims to treat. And as more gene therapies become available, the number of genetic diseases on the screening list is likely to increase. So, when should gene therapy be given?

“We believe the sooner the child can get treatment the better the outcome,” says Dr. Mendell. “In our trial, those patients with SMA1 who were treated early are reaching milestones never seen in the natural history of the disease.”

When the gene therapy has the ability to not only stop the progression of a disease but — if given early enough — stop the onset of symptoms entirely, the question seems to have a clear answer. However, given the lack of long-term studies for these new therapies, researchers don’t yet know how long the effects will last.

“That’s part of the re-dosing conversation,” adds Dr. Byrne. “As later onset diseases are identified in early life, no one is sure what to do with that information. But it seems likely that earlier intervention will lead to better outcomes.”

Treating smaller children also requires less vector. For the SMA1 trial, researchers gave the gene therapy to infants. In the upcoming DMD and LMGD trials, participants will be in the 4-to-12-year-old range.

“The requirements of using AAV gene therapy related to DMD in older, larger kids is stretching the resources of the exisiting technology,” says Dr. Byrne.

While researchers have shown safety and efficacy of AAV9 in numerous preclinical studies, and in the handful of early-phase clinical trials, the limits of the technology have yet to be defined. In a recent study published in Human Gene Therapy, James Wilson, PhD, and colleagues report severe toxicity in large animal models following high-dose IV administration of the AAVhu68 vector expressing human SMN. During the Nationwide Children’s SMA1 trial, four patients had asymptomatic elevated liver enzymes attenuated with a course of prednisone. Dr. Mendell notes that no other side effects were observed during the trial.

Two factors may explain the marked difference in the results of the two studies. First, the vector used in the Wilson study is an AAV9 mutant, and while it is only two base pairs different from the AAV9 serotype, it hasn’t gone through the same testing as AAV9, says Jaysson Eicholtz, director of GMP (Good Manufacturing Processes) Operations at Nationwide Children’s. Additionally, different methods were used to quantify concentrations of vector in the gene therapy products produced at each clinical manufacturing facility (CMF).

“We don’t have an industry standard for this process, but at Nationwide Children’s we use a manual process that has been consistent across all research, preclinical, toxicology and clinical lots,” says Eicholtz. “The digital droplet PCR method used on the products in the Wilson paper could result in concentrations of vector four times higher than the method we at Nationwide Children’s use for dosing.”

Dr. Byrne suggests that developing better and more consistent ways to measure concentrations across the industry will be an important step in bringing gene therapy to the clinic.

“In a theoretical sense, you can do the math on the scale up… but until you actually do it, there’s a lot that you don’t know,” he says. “We still have a lot of work to do in developing analytics for bioavailability and potency. Those questions have been sorted out in the small molecule world, but we don’t yet have consistency for those tests in the gene therapy world.”


In today’s political and economic climate, every medical advancement is greeted first with excitement and optimism, followed quickly by the question “How much is this going to cost?”

A month after approval, for example, Spark Therapeutics revealed it would charge $850,000 for a one-time dose of its vision-loss gene therapy. This hefty price tag makes it the most expensive medication sold in the United States. Of course, negotiations with insurance companies take the pricing conversation further, including outcomes-based rebates.

“These are extraordinarily expensive therapies to produce,” says Dr. Flanigan, who is also a professor of Pediatrics and Neurology at The Ohio State University College of Medicine. “We’re going to have to figure out whether our model for this works in the long run. As we accumulate more and more rare diseases treatable by gene therapy, costs upwards of $1 million per dose may not be sustainable.”

Directly contributing to pricing is the challenge to commercialize and mass-produce the products. Scalability and manufacturing are key points in conversations with industry partners, says Dr. Rodino-Klapac. “It’s a bit different to make enough vector for hundreds of patients compared to a dozen patients in a trial.”

As vector products move into the marketplace, industry partners will be required to address the challenges of scale and distribution.

“I’m optimistic that we’ll meet the challenges that we’ve had. When I first came to Nationwide Children’s, we had to figure out how we could possibly make enough vector to do an IV clinical trial. Well, now we’re here, and we’re doing it. It’s not insurmountable,” Dr. Rodino-Klapac says. “If the science is there, and the drug is effective, we’ll find a way … How could we not?”

This article appeared in the Spring/Summer 2018 print issue. Download a PDF copy now.

See also: Can Gene Therapy Treat Dominantly Inherited Disorders?


  1. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytesNature Biotechnology. 2009 Jan;27(1):56-65.
  2. Hinderer C, Katz N, Buza EL, Dyer C, Goode T, Bell P, Richman LK, Wilson JM. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an AAV vector expressing human SMNHuman Gene Therapy. 2018. [Epub ahead of print]
  3. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L’Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK. Single-dose gene-replacement therapy for spinal muscular atrophyThe New England Journal of Medicine. 2017 Nov 2. [Epub ahead of print]
  4. Potter RA, Griffin DA, Sondergaard PC, Johnson RW, Pozsgai ER, Heller KN, Peterson EL, Lehtimaki KK, Windish HP, Mittal PJ, Albrecht DE, Mendell JR, Rodino-Klapac LR. Systemic delivery of dysferlin overlap vectors provides long-term gene expression and functional improvement of dysferlinopathyHuman Gene Therapy. 2017 Jul 13. [Epub ahead of print]
  5. Xu R, DeVries S, Camboni M, Martin PT. Overexpression of Galgt2 reduces dystrophic pathology in the skeletal muscles of alpha sarcoglycan-deficient miceAmerican Journal of Pathology. 2009 Jul;175(1):235-247.

Image credits: Nationwide Children’s

About the author

Abbie (Roth) Miller, MWC, is a passionate communicator of science. As the manager, medical and science content, at Nationwide Children’s Hospital, she shares stories about innovative research and discovery with audiences ranging from parents to preeminent researchers and leaders. Before coming to Nationwide Children’s, Abbie used her communication skills to engage audiences with a wide variety of science topics. She is a Medical Writer Certified®, credentialed by the American Medical Writers Association.