NeuroVoices: Aki Ko, on mRNA Therapeutics for Duchenne Muscular Dystrophy

Aki Ko

Duchenne muscular dystrophy (DMD), a severe, progressive, muscle-wasting disease, is caused by mutations in DMD (encoding dystrophin) that prevent the production of the muscle isoform of dystrophin. Over the years, the development of palliative therapies, including night-time assisted ventilation and cough assistance, anti-heart failure medications, and corticosteroids, have extended the average lifespan of patients.

More recently, the field has broken through with more true disease-modifying therapeutics, including 4 exon-skipping drugs and 1 adeno-associated viral (AAV)-microdystrophin drug that supplements a missing dystrophin protein with its shortened version. Despite these advances, many of the issues patients face remain, with a need for additional therapeutics. RNA therapeutics, which comprised a diverse group of oligonucleotide-based drugs, have been suggested as a potential option for neuromuscular conditions like DMD.

At the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-7, in Orlando, Florida, Elixirgen Therapeutics presented late-breaking analyses on the development of their mRNA therapeutic called Bobcat. Bobcat, which has enabled successful generation of mRNA encoding a full-length human dystrophin protein, was tested in the skeletal muscles of several mice models. The results were promising, with data indicating that the produced DMD proteins were stable and remained in the injection site for 3 weeks.

Aki Ko, chief executive officer at Elixirgen Therapeutics, sat down with NeurologyLive^® at the conference to discuss the promise behind the therapy and why it can be successful in treating DMD. As part of a new iteration of NeuroVoices, Ko provided insight on the mechanism of action of Bobcat and how it differs from previously approved therapies, the known safety and feasibility aspects of mRNA therapies, and whether they could be used as a complement or replacement for currently approved agents.

NeurologyLive: Discuss the origin of the Bobcat mRNA therapy and how it came about?

Aki Ko: We have worked in mRNA technologies for a very long time. As a company, we're looking into some of the big issues in RNA for its potential therapeutic applications, such as its transience and a lack of durability. This Bobcat mRNA was developed entirely in-house, not from an academic center or anything like that. We gave somewhat of a preview of this platform at the RNA Leaders Conference in September 2023. At MDA 2024, we're presenting for the first time that it's being used towards a disease, Duchenne muscular dystrophy, and dystrophin, the largest gene in the human genome, is a great way to showcase its abilities.

Although early, what potential advantages does your product have over previously approved therapies?

Obviously, early things you don't know until the data is out, and you may not know until the regulatory agencies review it. But with those caveats in mind, I think there are advantages in what's being delivered and how it's being delivered. If we go into the what with previous approaches, there's been groundbreaking work for the creation of micro and mini dystrophins to overcome some of the size limits of AAV (adeno-associated viral) vectors. Compared to that, a full length dystrophin has potential advantages in the stability of the protein and other potential functional effects.

For how it's being delivered, is the mRNA approach, which also has potential advantages over let's say, an AAV approach, which seems to be most common. One of them is that mRNA is not a virus. There are no considerations on that side for viral protein immunogenicity. For application of mRNA, again, not being a virus, there's no biosafety levels that are necessary. mRNA is redosable, so it's a therapy that you can keep taking. Also, it is simple to manufacture, especially considering the infrastructure that's been built for the COVID vaccine manufacturer. There is now a lot of capacity in the world to create mRNA, and Bobcat mRNA is not a special mRNA in terms of manufacture. It's a simple linear mRNA. The manufacture is equally simple.

What have you observed in preclinical models thus far?

One thing I'll add is that how we envision the application of this Bobcat mRNA encoding a full-length dystrophin is in a complementary context so that patients that have already undergone clinical trials, for example, would be able to potentially use this complimentary proposed treatment. It could be used to support other existing clinical trials and for current standard of care. We're thinking that it's going to be something that could be applied across the board.

mRNA in general has similar historical difficulties in the capacity, and its carrying capacity in the manufacture and expression of full-length dystrophin. Full-length dystrophin, roughly 11 kilobase, is very difficult to encode in one vector. But again, Bobcat mRNA is the technology in which we are enabling that for the first time.

What we're showing in our poster is the expression of human full-length dystrophin when injected into mouse skeletal muscle. We're showing a very typical pattern that you'll see in the literature with immunohistochemistry. The additional data is on the functional side. In DMD model mice, with some repeated local injection dosing to the mouse forearms, after six weeks of repeat injections, the DMD model mice had their function restored to no different than a wild-type mouse. Furthermore, we then tried to see how long can this work. How durable is it? This is what's being shown in the presentation. It's something that's ongoing as well. But what we're showing here is that after one injection, three weeks later, the functional restoration is still being had. This is a mouse muscle strength that's being measured with a forearm grip test, so the mice are gripping, and seeing how strong that they can pull. This is a known measurement.

What would be the next steps for this type of therapy?

We are currently actively in conversations with nonprofits, investors, and potential partners. We currently have a development plan, and if fully funded, would enable us to have to go beyond IND (investigational new drug) next year.

Considering the fact that a lot of the therapeutics that are currently in use are either exon-skipping or antisense oligonucleotides, do you foresee any complications with the mRNA Bobcat being used in combination with other agents?

It's probably too early to compare between the in-development programs and then our program, for example, but we're very positive about the potential for this Bobcat mRNA, and especially the ability to deliver full length dystrophin. In development, there are of course, always difficulties, but we believe that there are a lot of advantages in potentially bringing this mRNA full length dystrophin into patients.

Transcript was edited for clarity. Click here for more coverage of MDA 2024.