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.
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…
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…
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.
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.
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.”…
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.”…
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…
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.
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