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Did Sarepta Therapeutics Just Unveil a Breakthrough?

The leading gene therapy developer just bolstered its technology platform.

Delivery is important. It matters for e-commerce, the space economy, pizza night, and especially drug development. That's what makes a recent announcement from Sarepta Therapeutics  (SRPT)  worth a closer look by investors.

As one of the leading genetic medicine companies on the planet, Sarepta Therapeutics is on the forefront of many nerdy advances. It was the first drug developer to earn U.S. Food and Drug Administration (FDA) approval for products treating Duchenne muscular dystrophy (DMD), a rare genetic disorder impacting muscle development. That portfolio is expected to generate full-year 2022 net revenue of at least $825 million. 

Meanwhile, Sarepta Therapeutics currently boasts over 37 pipeline programs, including 21 assets in gene therapy alone. The most important in the eyes of Wall Street, SRP-9001, is now expected to be submitted for regulatory approval ahead of schedule. 

Simply put, there are many moving parts to the company, and many are moving in the right direction.

Although the latest announcement focuses on a tool in early-stage development, it could give the company a significant advantage when it comes to delivering gene therapies.

How Are Gene Therapies Delivered?

A gene therapy aims to restore the function of a gene causing a disease or health ailment. The most common type of gene therapy tries to deliver working copies of a replacement gene into a patient's cells. This approach doesn't touch the patient's DNA, but instead parks a delivery shuttle within the cell. The replacement gene packaged inside the delivery shuttle is read by the cell's machinery to produce functional copies of the encoded protein, thus treating a disease.

The most common delivery shuttles are hollowed-out viruses, sometimes called viral capsids or vectors. These vectors cannot make a patient sick, but they can be fine-tuned to end up in certain organs and body tissues. That's important because some diseases are caused by mutated genes in the liver, while others are caused by mutated genes in the lung, and so on.

Although viral capsids make for pretty good delivery shuttles, there are significant drawbacks.

  • Small capacity: The most common viral capsid, adeno-associated virus (AAV) vectors, have a small capacity. That forces scientists to find or create miniaturized versions of genes to stuff inside. It would be better to deliver a full-length, human copy of a gene.
  • Immune triggering: Many viral capsids currently used in drug development trigger a strong reaction from the immune system. This can neutralize a high number of the delivery shuttles, which forces scientists to increase the dose to ensure enough make it into a patient's cells. It can also lead to life-long immunity to the vector after a single dose. This is why many gene therapies are one-and-done treatments – not because they're a cure. Ideally, gene therapies could be dosed multiple times to drive responses in all patients.
  • Safety concerns: Many viral capsids currently used in drug development have significant side effects. This is due to a confluence of factors, such as the high doses required to sneak past the immune system, the follow-on effects of activating the immune system, and less-than-perfect targeting to certain organs and body tissues. For example, an AAV gene therapy aimed at muscle tissues could also accumulate in the liver, causing liver toxicity and even death.

The global industry is well aware of these challenges. Some are ditching viral capsids as delivery shuttles. Some are searching for viruses that are safer in humans. Some are trying to engineer safer viral vectors.

Sarepta Therapeutics has adopted an all-of-the-above approach in its quest for solutions, but the most promising to date relies on engineering better AAV vectors.

Will This Gene Therapy Tool Represent a Breakthrough?

The genetic medicine leader has been working with the Broad Institute, one of the world's leading research labs and one of the pioneers behind CRISPR gene editing, to develop a suite of next-generation delivery shuttles named MyoAAV. 

After corroborating the collaborator's work inside its own laboratories, Sarepta Therapeutics has hailed the tools as a potential breakthrough in precision genetic medicines.

A press release highlighted four primary improvements of MyoAAV delivery shuttles compared to natural AAV vectors, as measured in preclinical studies in non-human primates:

  • An up to 50x improvement in gene expression within muscle tissues.
  • An up to 15x improvement in gene expression within cardiac tissues.
  • Reduced delivery to and accumulation in the liver (an "off-target" tissue for diseases in the company's pipeline).
  • The potential to be used at up to 10x lower doses. Gene therapy doses are determined on an exponential scale, so this isn't as impressive as it sounds. Nonetheless, this could provide meaningful improvements in safety, cost, and manufacturing.

Sarepta Therapeutics secured an exclusive license to use MyoAAV delivery shuttles for five different diseases, including DMD, with options for additional targets. The license appears to span both gene therapy and gene editing payloads.

Will the next-generation tools represent a true breakthrough? The early preclinical data certainly look promising. Of course, it's important to acknowledge the careful wording of the press release.

Many of the improvements were expressed as "up to," while a closer parsing of the scientific literature and competitive landscape show comparisons to natural AAV capsids may be misleading. A handful of well-funded start-ups are engineering next-generation AAV capsids, which would provide a more apt comparison. Then again, Sarepta Therapeutics forged partnerships across the landscape and appears to have chosen MyoAAV for clinical trials.

It's also important for investors to acknowledge one unaddressed drawback: MyoAAV delivery shuttles will still have a relatively low capacity. That will force Sarepta Therapeutics to continue using miniaturized versions of replacement genes instead of full-length, human copies. Higher delivery efficiency should reduce the impact of this limitation, but the drawback looms.

MyoAAV won't be a major driver of Sarepta Therapeutics stock for the foreseeable future, but investors can be pleased that the company is narrowing its bets as it advances toward the clinic. Data reported in the next few years will determine if the bets pay off.