The Time for DMD Gene Therapy is Now: A Chat with the MDA | BioSpace

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Originally published: Jul 29, 2020

After almost 15 years since the first gene therapy trial for Duchenne muscular dystrophy (DMD) began, the dream of a DMD gene therapy drug is getting closer to a reality.

BioSpace sat down with Sharon Hesterlee, Ph.D., chief research officer at the Muscular Dystrophy Association (MDA), to talk about the history and challenges of developing gene therapy for DMD and the DMD gene therapy field as a whole, including Pfizer’s and Sarepta Therapeutics’ latest clinical data.

Duchenne muscular dystrophy (DMD)

is a progressive muscle wasting disease caused by a genetic mutation. The mutated gene is on the X chromosome, making DMD an X-linked disease. This explains why it largely affects boys as they don’t have a backup copy of the gene (they only have one X chromosome).

The first signs of DMD appear as the young boys begin to walk and get more mobile, typically between the ages of 2 to 5. “They have trouble walking, aren’t walking as well as their peers, and can’t jump,” Hesterlee commented. “Most boys stop walking and need a wheelchair between 9 and 14 years old.”

But the disease doesn’t just affect their legs — it affects muscles all over their body. The most troublesome symptoms are breathing difficulties. Eventually, they will need ventilation to help them breathe.

The life span of boys with DMD has been growing steadily (from in their teens to early 30s) due to improvements in heart and respiratory care. Despite this progress, most DMD patients pass away in their 20s to 30s due to respiratory failure, infection, or cardiomyopathy (dilation of the heart due to overwork).

Discovering DMD’s cause

Although we now know DMD is a genetic disease, it wasn’t that long ago that researchers didn’t know why or how the disease came about.

“Back in the mid-1980s, the cause of DMD was still unknown — all we knew was that it ran in families, there were no genes associated with the disease yet,” Hesterlee explained. “MDA gave research grants to four labs tasked with finding the cause. One of those labs, Louis Kunkel’s lab, identified the dystrophin gene first .”

Dystrophin, the largest gene in the human body, encodes a muscle protein responsible for keeping muscle cells from pulling themselves apart when the muscle is working, like a “shock absorber for the cell,” as Hesterlee described. Without dystrophin, the muscle cells suffer from microtears, leading to their demise and progressive muscle wasting.

“Once we identified the culprit gene, we thought ‘Oh great! We know what’s wrong, we’ll fix it!’” Hesterlee added. “But it took another 30 years to be able to apply this knowledge to develop effective drugs.”

Although corticosteroids can slow the progression of DMD to some extent, they don’t address the underlying issue — the lack of functional dystrophin. “Corticosteroids help dampen down inflammation,” said Hesterlee. “They can help slow down disease progression, but tackling inflammation only addresses one downstream effect.”

Fixing the mutated gene (through gene editing) or providing cells with a new healthy copy of the gene (through gene therapy) would provide the best benefit, possibly even leading to a lifelong cure.

Gene therapy for DMD

As the name suggests, gene therapy involves delivering a healthy copy of a mutated gene (in DMD’s case dystrophin) into cells. The tricky part is getting the gene inside the cell. This is accomplished using a ‘vector,’ usually a virus or nanoparticle, as a trojan horse to sneak the healthy gene into the cell.

“Viruses are very well evolved to get into cells,” commented Hesterlee. “Take out the viral genes required to make copies of itself and put in the healthy copy of dystrophin, then the virus can get inside cells but not replicate.”

Adeno-associated viruses (AAVs) are commonly used because they don’t naturally cause disease or many immune system side effects in humans. But there is a limit to how much cargo you can stuff inside these tiny viruses, about 5 kb for AAV. The whole dystrophin gene — over 440 times as big — is too large to fit inside any AAV.

Throughout the late 1990s and early 2000s, researchers tinkered with the dystrophin gene, figuring out what parts were needed and how much they could trim out to still have a functional protein. They finally found the perfect balance, naming the shortened genes ‘microdystrophins.’

“Sometimes called minidystrophins, there are slight variations between different versions of these shortened genes, but the key is they are all small enough to fit into AAV,” explained Hesterlee.

Other hurdles of developing a DMD gene therapy

Now that the dystrophy gene was brought down to a useful size, the next challenge researchers faced was getting the gene therapy from the blood stream into the muscle.

“Could we use histamine? What about a tourniquet and pressure? Or higher doses to drive the virus into the muscles?” Hesterlee added. “But we were cautious after the high profile death of Jesse Gelsinger in 1999.”

That’s why the first DMD gene therapy trial in the US, which began in 2006, involved injecting the gene therapy directly into the biceps of the children who participated. That allowed researchers to test the gene therapy proof-of-concept in DMD patients without worrying about systemic administration right off the bat. Subsequent gene therapy trials have moved to intravenous (IV) administration — typically only requiring one fairly quick dose.

“The trick was using higher doses and the right serotypes of AAV to move the vector out of the bloodstream and into muscle,” Hesterlee added.

Now, researchers had to find the best time during the course of the children’s disease to test the therapy.

“The earlier you treat, the better, but it’s hard to measure benefit if the children are not yet manifesting a lot of symptoms, so you want to test the children at a stage when they’re progressing,” said Hesterlee. “Also, if you were to treat infants, it’s important to remember that they will be making new muscle cells without the modified gene in them, so there is a balance of when to treat.”

Children with DMD tend to get stronger between 3 to 7 years old, then start to decline, Hesterlee explained. This is why many Duchenne drug studies traditionally haven’t involved children younger than 7 years old.

“Testing the children when they are starting to lose the ability to walk can avoid the natural history noise,” Hesterlee added. “You can compare outcomes to natural disease due to a rich natural history of DMD. In recent years, we’ve gotten much better at detecting benefits in the boys even when they are in the early stages and improving, so trials have started to skew younger, including children as young as 4 years old.”

Another challenge hinges on the fact that the gene is delivered using a virus, making the gene therapy an immunization in a way. The patient’s body will react to the viral vector just like it would any other virus, creating antibodies to hunt and destroy the gene therapy viruses. This not only quickly diminishes the amount of therapeutic virus in the body, but it could also mean the patient would only be able to get one dose of therapy — any subsequent doses would be destroyed too quickly by the body or, worse, potentially cause a severe immune reaction.

AAVs are also common viruses — some people have already been exposed to AAVs naturally and would never know because they cause no symptoms.

“Anywhere from 10 to 80 percent of DMD patients, depending on the serotype in question, have preexisting antibodies against AAVs, meaning they are not eligible for gene therapy,” Hesterlee elaborated. “Antibody status can be quite divisive in the DMD community.”

DMD gene therapies in development

Despite all the challenges faced over the years, there are a handful of gene therapies being developed for DMD currently, with a few pivotal Phase III trials close on the horizon. There are currently three companies with competitive trials in the US: Solid Biosciences, Sarepta Therapeutics, and Pfizer (who bought the DMD platform in 2016 from AskBio, a company involved in early DMD gene therapy trials).

Top DMD Gene Therapies in Development

Solid Biosciences’ therapy, called , involves a microdystrophin gene carried by an AAV9 viral vector. is a type of AAV that is particularly good at getting into muscle cells.

The company recently presented a clinical update at the virtual American Society of Gene and Cell Therapy (ASGCT) meeting in May. Microdystrophin expression was seen via muscle biopsies 90 days after treatment (at a dose of 2E14 vg/kg), which stabilized dystrophin-associated proteins and restored activity of a key enzyme (called neuronal nitric oxide synthase, or nNOS) in the muscles. Unfortunately, their Phase I/II trial (IGNITE DMD) is still on hold by the FDA.

“All three companies are using different versions of minidystrophin,” explained Hesterlee. “Solid’s is different because it contains the binding spot for an enzyme called nitric oxide synthase — both Sarepta and Pfizer cut that portion out.”

Sarepta Therapeutics has two DMD gene therapies Micro-dystrophin and (Nationwide Children’s), in clinical trials and one therapy, Micro-dystrophin (Genethon), in preclinical development. SRP-9001 includes a different serotype of AAV, called (which also gets into muscle and heart cells well), and a microdystrophin gene.

SRP-9001 (2E14 vg/kg dose) is currently being investigated in open-label Phase I/II study (Study 101). In mid-June, Sarepta announced that preliminary results from four boys ages 4–7 years were published in JAMA Neurology. SRP-9001 was safe and well-tolerated up to one-year post-administration. At 12-weeks post-treatment, the mean percent of dystrophin expressed in muscles was a whopping 95.8 percent. All functional improvement the boys gained (measured by the NorthStar Ambulatory Assessment (NSAA) rating scale) was also maintained for at least one year post-treatment. Importantly, there were no serious adverse events (only mild to moderate events).

“Sarepta had higher dystrophin gene expression and no serious adverse events, like Pfizer saw,” Hesterlee added.

SRP-9001 is also being studied in a randomized, placebo-controlled Phase II trial (Study 102) in 41 boys ages 4–7 years with results expected in . In fact, the FDA recently granted SRP-9001 Fast Track designation.

Instead of delivering the dystrophin gene, GALGT2 delivers the GALGT2 gene, which is also important for muscle function. It is currently being investigated in a Phase I/II study in six boys ages 4 and up.

While they aren’t gene therapies, Sarepta also has two FDA-approved genetic medicines: Exondys51 (eteplirsen) and Vyondys53 (golodirsen). Both employ exon skipping, redirecting DNA processing inside the muscle cells to create minidystrophin right in the cells — much like the researchers did in the lab, but directly in the children themselves. They also have 12 other exon skipping-based genetic medicines in their pipeline.

“The problem is exon skipping, in its current form, is not very efficient and each therapy only works in a subset of children with certain gene mutations,” Hesterlee commented. “Gene therapy is more efficient and covers everyone, regardless of genetic mutations, but it’s still good to have options while new therapies are in development.”

Pfizer’s gene therapy drug, called PF-06939926, is an AAV9 virus carrying a minidystrophin gene. The company’s most recent Phase Ib results were released in May at the ASGCT meeting (abstract no. 617). Although the Phase I trial is not placebo controlled, they can compare treated children to the known natural history of DMD. According to the company’s press release, preliminary data from nine boys with DMD (ages 6–12) showed the therapy was well-tolerated during intravenous infusion.

At 12 months post-injection, the boys had sustained, significant improvement in minidystrophin expression and improved muscle function (measured via the NSAA rating scale). The three patients receiving the low dose (1E14 vg/kg) had a mean percent dystrophin expression in muscles of 28.5 percent at two months and 21.2 percent at 12 months, compared to the six patients receiving the high dose (3E14 vg/kg) had 48.4 percent dystrophin expression at two months, three of whom had 50.6 percent at 12 months.

Three serious adverse events (SAEs) occurred, but they fully resolved within two weeks. Pfizer plans to begin a Phase III study with PF-06939926 by the end of 2020.

“Both Sarepta and Pfizer have collected some promising functional data,” commented Hesterlee. “It is very likely that one or both of these gene therapies could be approved.”

“This opens up the door for combination therapies, such as gene therapies to stabilize the muscle and small molecule drugs to deal with downstream events like fibrosis and inflammation,” Hesterlee concluded. “It could convert this disease from a devastating diagnosis to a manageable disease in the next 10 years.”

Check out the MDA’s Facebook Live Q&A event “MDA Frontline COVID-19 Response: Back-to-School in the Midst of COVID-19 — Concerns for the Neuromuscular Disease Community with Dr. Christopher Rosa and Justin Moy.” Tune in live this Friday, July 31 at 3pm ET to join the discussion.

Originally published at

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Explore the latest exciting advances in medicine.

Chelsea Weidman Burke, M.S.

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Biochemist turned science journalist. Alzheimer’s, immunology, immunotherapy, genetics, cancer. Follow my publication!

Chemically Inquisitive

Explore the latest exciting advances in medicine with a biochemical flair. A collection of my stories about viruses, immunotherapy, Alzheimer’s, genetics, and cancer.

Chelsea Weidman Burke, M.S.

Written by

Biochemist turned science journalist. Alzheimer’s, immunology, immunotherapy, genetics, cancer. Follow my publication!

Chemically Inquisitive

Explore the latest exciting advances in medicine with a biochemical flair. A collection of my stories about viruses, immunotherapy, Alzheimer’s, genetics, and cancer.

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