Genetic Targets Invigorate Research for Duchenne Muscular Dystrophy

NeurologyLiveFebruary 2019
Volume 2
Issue 1

Over the past several years, scientific teams have developed investigational methods for delivering a gene to correct a mutation in the DMD gene which causes DMD by creating dysfunction in a patient’s dystrophin production.

Over the past several years, scientific teams have developed investigational methods for delivering a gene to correct a mutation in the DMD gene which causes Duchenne muscular dystrophy (DMD) by creating dysfunction in a patient’s dystrophin production. These gene therapies have become progressively more effective as delivery methods and the corrected genes have been improved.

Recently, the success of these therapies in patients with DMD has been related to the use of a shorter DMD gene, which produces a smaller completely functional protein, micro-dystrophin. Investigators have used antisense oligonucleotides to mask the deletion of exons in the coding of the DMD gene. This has been shown to be successful in preclinical studies as well as in humans.

“I’m absolutely thrilled to be seeing this hopeful technology come to fruition,” Crystal Proud, MD, a pediatric neuromuscular neurologist at Children’s Hospital of The King’s Daughters (CHKD) in Norfolk, Virginia, told NeurologyLive. “I’m a reasonably young neuromuscular neurologist, and it’s such a fantastic time to be in this specialty.”

With a number of gene therapies and exon-skipping therapies being evaluated in ongoing clinical trials, clinicians treating muscular dystrophies have begun to discuss the potential clinical implications of applying these therapies for patients with DMD.

The State of Gene Therapy

One of the treatments in development, suvodirsen, previously known as WVE-210201, has been designed by Wave Life Sciences for the 13% of patients with DMD who have a specific type of mutation in the DMD gene that makes them amenable to exon 51 skipping treatment. The safety, tolerability, and plasma concentrations of ascending doses of WVE-210201 are being assessed in an ongoing, multi-dose, open-label extension trial for boys with DMD aged 5 to 18 who carry the gene mutation amenable to exon 51 skipping.

Preclinical experiments showed that suvodirsen was associated with a 52% increase in the levels of dystrophin protein compared with normal skeletal muscle tissue.1 As well, it was granted both orphan drug and rare pediatric disease designations from the FDA, following its orphan drug status granted by the European Commission.

In December 2018, Wave Life Sciences announced that its investigational candidate produced positive results in phase 1 testing for boys with DMD who are amenable to exon 51 skipping. Based on the 4 (undisclosed) doses already tested, 1 has been selected to be used in an upcoming planned phase 2/3 trial. The phase 1 trial assessed 4 primary outcome measures of safety in 40 patients: the number of patients with adverse events (AEs), the severity of those AEs, the number of patients with serious AEs (SAEs), and the number of patients who withdrew due to AEs. Secondary outcomes consisted of the maximum observed concentration (Cmax) at day 1 day 2, and day 8; the time to Cmax (Tmax) at day 1, day 2, and day 8; and the area under the plasma concentration-time curve (AUC0-t) at day 1, day 2, and day 8.2

In January, the FDA selected the treatment’s upcoming phase 2/3 trial as the first to be part of its Complex Innovative Trial Design (CID) pilot program, based on innovative features of the trial design and the therapeutic needs. The application to the program by Wave included its plan to leverage historical control data for DMD to augment the placebo arm of the phase 2/3 trial.3

“It’s amazing to see the change that I have seen in just the past few years. Being able to offer patients more hope than we’ve ever been able to offer in the past has been just a phenomenal thing,” Proud said. “We’re really seeing the technology apply to many areas of neuromuscular medicine. For me, I get to see it not only in DMD, but in other neuromuscular conditions as well.”

Another treatment in development is Sarepta Therapeutics’ rAAVrh74.MHCK7.micro-dystrophin, a micro-dystrophin gene therapy candidate under evaluation in a phase 1/2 clinical trial (NCT03375164). This shorter gene provides instructions for the production of a smaller form of the dystrophin protein and is delivered via a viral vector.

As of this publication, positive results from the trial show that rAAVrh74.MHCK7.micro-dystrophin is able to improve the functional performance of boys with DMD, without causing SAEs. Ultimately, the therapy showed robust expression of transduced micro-dystrophin, as measured by immunohistochemistry, in 4 patients. The mean gene expression for the study, as measured by the percentage of micro-dystrophin positive fibers, was 81.2%, and the mean intensity of the fibers was 96.0% compared with normal control.4

As measured by Western blot, the levels of micro-dystrophin were reported as 74.3% compared with normal using Sarepta’s method, equivalent to 95.8% compared with normal pursuant to Nationwide Children’s quantification of Sarepta’s method, which adjusts for fat and fibrotic tissue.

“We at Parent Project Muscular Dystrophy [PPMD] are very optimistic about the dystrophin restoration and replacement programs that are on the horizon, exon skipping and gene therapy delivering micro-dystrophin,” Abby Bronson, the senior vice president of research strategy at PPMD, told NeurologyLive. “All these dystrophin restoration programs are as important as gene therapy is, even still in the early stages. Although, it continues to also show potential.”

Additionally, Solid Biosciences has developed its own micro-dystrophin gene transfer therapy, SGT-001. Recent data from its phase 1/2 dose-ascending IGNITE-DMD clinical trial found that there were low levels of micro-dystrophin protein expression in 3-month biopsies from 3 patients dosed with 5E13 vg/kg of the treatment. As a result, the company is planning to move forward with the dose escalation as soon as possible.5

Potential Clinical Issues

A potential confusion for these therapies is that they are mutation-specific—there is not a clear and efficient pathway for approval for exon-skipping drugs for additional mutations using the same backbone, so patients must have a particular DNA change to qualify for a gene therapy. There are additional considerations for which patients may be indicated and when, and what the duration of treatment could be.

“A lot of patients are not going to have that specific indication,” Proud explained. “We want to be able to utilize the drug with optimal efficacy at just the right moment.”

Proud detailed a number of questions which still need to be answered for these treatments, including the specifics about when to initiate treatment and what the specific threshold for initiation should be. Additionally, Proud posited that because many of the viral vector delivery systems in development permit a 1-time dose, there is some speculation about when and if the treatment will run its course, and if it were to only last a certain amount of time, it becomes paramount to decide when the best opportunity to give a treatment will be.

“Is that going to be when these boys are declining between the ages of 7 and 10? Is it going to be when they’re little and they’re still quite strong, so maybe 4 or 5 years old? And are there other combination therapies that we can continue to utilize to maintain that strength,” Proud said. And these unanswered questions may not be resolved by the time these treatments come before the deciding regulatory authorities.

“I still think we’re several years off from FDA approval,” she said. “Those are the things that we as neuromuscular neurologists are thinking about because we obviously want to be able to offer guidance to families on what’s best for their child. There are, right now, a lot more questions than there are answers. We’re still gathering a lot of data and we still have a lot of questions in the neuromuscular community.

“But we’re very hopeful,” she added.

Immune Response Considerations

Once suitability for gene therapy is determined for a patient with DMD, the determination of efficacy at the time of infusion, post-infusion, and in the subsequent weeks following infusion will be a vital step in the treatment plan. Immune response to DMD gene therapies is being taken into consideration, as the FDA has been both cautious and diligent about evaluating for potential AEs.

“When we’re thinking about the type of treatment, we believe that the highest risk, at least that we’re aware of, is during infusion and the next couple of weeks following infusion is for the systemic and inflammatory response that can happen in the body,” Proud said.

Recommendations for mitigating inflammatory response include a month-long dosage of an oral steroid (i.e., prednisolone) prior to infusion and monitoring the liver. A baseline aspartate aminotransferase (AST) and alanine aminotransferase (ALT) measurement and trending over time can help to ensure that those levels are not increasing and demonstrating that inflammation is not reducing.

“It’s my understanding that with steroid treatment before infusion, inflammatory response has been kept under control, and this is continued after therapy as well,” Proud explained. “With many of these gene therapies, whether we’re talking about DMD, spinal muscular atrophy, or limb-girdle dystrophy, typically we’re talking about a premedication with an oral steroid medication for about a month before you would use the viral vector. It has been demon­strated that this has been hopeful to reduce inflammation and, ultimately, that steroid is slowly weaned and reduced in dosage over several weeks while following certain laboratory parameters to ensure that the body’s inflammation is under control.”

She noted that immune and inflammatory response is some­thing to be taken into consideration with these treatments, and that so far, the manufacturers and the clinical investigators have been thoughtful in their approaches to it.

Bronson clarified that currently, there is some concern about the introduction of this new dystrophin—generated from exon skipping or gene therapy—into the body will cause an immune response that will render the therapy less effective.

“Understanding this response is very important for optimizing the therapy,” Bronson said. “PPMD appreciates companies continuing to explore and enhance both exon skipping and gene therapy, and we are hopeful that both treatments will continue to broaden the number of patients they can treat.”

PPMD recently awarded a $329,000 grant to Kanneboyina Nagaraju, MD, PhD, and his team at Binghamton University’s School of Pharmacy and Pharmaceutical Sciences in New York, to explore this concern. The researchers will examine the body’s immune response to the production of new dystro­phin protein resulting from exon-skipping and gene therapy treatments.6

To evaluate the role of the immune system on dystrophin resto­ration, Nagaraju will explore the combination of exon-skipping or micro-dystrophin gene therapy with an immunosuppressive treat­ment. They plan to utilize 1 of the following 3 tactics in combination with treatment: rituximab, an anti-CD20 antibody used to treat auto­immune disorders and cancer, to block antibodies to newly produced dystrophin; abatacept (also known as CTLA4ig) to halt an anti-dystro­phin immune response; or either prednisolone, vamorolone, or epler­enone to test the respective reduction in inflammatory and anti-dys­trophin immune response. These considerations are necessary to determine how to sustain the gene therapy and exon skipping.

“When you do gene therapy, there is an immune response to dystrophin,” Nagaraju, a professor and founding chair of the Department of Pharmaceutical Sciences at the School of Pharmacy and Pharmaceutical Sciences at Binghamton University, told NeurologyLive. “You have an antigen that the body has never seen. The biologics are pretty advanced in treating protein diseases, so the question becomes, ‘Which biologic to use?’ By specifically targeting B cells, we may be able to reduce antibody response. Whether the responses are pathogenic or not, we know they’re there. Now, [do we have to] block T cell responses because they come first? It is better, probably, to block both.”

Potential Logistics in Practice

Proud explained that for the majority of physicians in the neuro­muscular community, expectation if and when these treatments make it to market is that they’ll be used in combination.

“I would love to see these kids treated by one medication, but I don’t know how realistic that is,” she said. “The majority of us believe that combination therapy is the most realistic option, and it’s a matter of finding those components to make the most appro­priate cocktail to being able to help support dystrophin produc­tion, particularly in these boys with DMD.”

There are a number of pathological points within DMD that can be targets of these treatments, she said. Within the disorder, there is a need to produce dystrophin to a level that allows for muscle strength to be maintained, as well as a need to reduce muscle breakdown that would otherwise continue through the course of the patient’s life. Proud also expressed concern with how muscle membrane stabilization will occur. Ultimately, it appears that even the best option won’t be a magic bullet.

“Where we see things going in general with particular drug aiming at each of those points of vulnerability in pathophysiology of disease,” she explained. “Perhaps it’s going to gene therapy in combination with an anti-myostatin, or in combination an anti-inflammatory. But I do think the most likely thing is combination therapy aiming at a different piece of the puzzle.”

One area of important focus for Proud is biomarkers. Currently, the easiest to use and most available biomarker is creatine phosphokinase (CPK), which has been observed to decline in prelim­inary data of the gene therapies in development. This, Proud said, “is extremely hopeful” as it has not been seen with any other treat­ment modalities.

“The question that most of us have is whether that will persist,” she said. “But that is certainly a useful biomarker to follow. Perhaps that will become part of our routine clinical practice after a patient has received gene therapy for treatment of their DMD. Perhaps part of our routine laboratory work will be to monitor that CPK level and if it declines, that to a certain extent, indicated efficacy, as do the clinical assessments that we do.”

She said that she anticipates that, regardless of the treatment, physicians will continue to pursue those assessments using a multidisciplinary approach, with those outcomes and measure­ments dictating the efficacy of these interventions.

“Our clinical practice of monitoring these parameters will be continued; I don’t think their functional outcomes are going anywhere,” Proud explained. “We just may be adding more observa­tion to our repertoire to follow the boys’ responses to this treatment.”

Managing Care Today and Tomorrow

The introduction of genetics into treatment has also included benefits from genetic testing. At CHKD, the ability to evaluate each patient who is clinically diagnosed with a neuromuscular disorder is being able to characterize them molecularly. The opportunities that clinicians have to pursue genetic testing have rapidly expanded in the last decade, and typically, Proud said she is able to offer many of her patients a diagnosis of neuromuscular disease with genetics.

“Furthermore, for patients with DMD, we’re able to characterize their genetic change and consider them for participation in clin­ical research trials if that’s within the family’s wishes,” she noted. “We’re able to pursue all of the FDA-approved molecular-specific treatments. We’re able to say, ‘when this particular type of tech­nology comes along in the future, this is the one that will apply to you.’ It allows me to really help prepare patients and families for potential opportunities down the line.”

With ongoing in-human clinical trials and potential FDA-approved treatments down the line, physicians are bringing genetics into the conversation more than ever before. For Proud, these treatments are discussed in almost every clinic visit. These treatments, even prior to approval, have offered her patients an option they never had. Whether patients choose to participate in clinical trials or not, Proud said she is having conversations about 3 to 5 years from now, when treatments may be approved, including what may or may not applicable to a specific patient.

Being able to offer enrollment in trials is one of the most important pieces of care for Proud. It’s something she described to NeurologyLive as part of her duty as a physician to propose partic­ipation in clinical trials.

“Many families of boys with DMD are quite savvy and eager and interested to find something that may help their child in any way,” she said. “Part of my dedication to them is being able to offer them that option, and part of that also becomes being knowledgeable about the opportunities that are out there. When a patient comes to see me in clinic, yes, we’re talking about how they’re doing, we’re doing an assessment, but I’m also able to discuss with them the options that are available to them at CHKD or around the country.”

“That’s a critical piece of have in a neuromuscular clinic, being able to offer families opportunities because those are opportuni­ties of hope for them,” she added.


1. M. Wood, J. Zhang, K. Bowman, et al. WVE-210201, an investigational stereopure oligonucleotide therapy for Duchenne muscular dystrophy, induces exon 51 skipping and dystrophin protein resto­ration. Neuromuscular Disord. 2017;27(2):S217. doi: 10.1016/j.nmd.2017.06.442.

2. Wave Life Sciences announces positive phase 1 results for WVE-210201 in Duchenne muscular dystrophy (DMD) [press release]. Cambridge, MA: Wave Life Sciences; December 6, 2018. wave­­tive-phase-1-results-wve-210201. Accessed Janu-ary 28, 2019.

3. Wave Life Sciences Duchenne muscular dystrophy clinical trial selected for FDA Complex Innovative Trial Designs Pilot Program [press release]. Cambridge, MA: Wave Life Sciences; January 3, 2019.­cular-dystrophy-clinical-trial. Accessed January 28, 2019.

4. Sarepta Therapeutics announces that at the 23rd International Congress of the World Muscle Society, Jerry Mendell, M.D., presented positive updated results from the four children dosed in the gene therapy micro-dystrophin trial to treat patients with Duchenne muscular dystrophy [press release]. Cambridge, MA: Sarepta Therapeu-tics; October 3, 2018. news-release/2018/10/03/1601085/0/en/Sarepta-Therapeutics-Announces-that-at-the-23rd- International-Congress-of-the-World-Muscle-Society-Jerry-Mendell-M-D-Presented-Positive- Updated-Results-from-the-Four-Children-Dosed.html. Accessed January 28, 2019.

5. Solid Biosciences Announces Preliminary SGT-001 Data and Intention to Dose-Escalate in IGNITE-DMD Clinical Trial for Duchenne Muscular Dystrophy [press release]. Cambridge, MA: Solid Biosciences; Published February 7, 2019.­ences-announces-preliminary-sgt-001-data-and-intention-to-dose-escalate-in-ignite-dmd-clini­cal-trial-for-duchenne-muscular-dystrophy-1. Accessed February 7, 2019.

6. Parent project muscular dystrophy awards $329,000 grant to Binghamton University to examine the role of the immune system on dystrophin restoration [press release]. Hackensack, NJ: PPMD; December 19, 2018.­ton-university-to-examine-the-role-of-the-immune-system-on-dystrophin-restoration-300768740.html. Accessed January 28, 2019.

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