Role of Gene Transfer Therapy in SMA

John Brandsema, MD: A couple of years after the original foray into targeted treatment, we then had onasemnogene abeparvovec approved for our patients, which I am going to refer to now as “gene transfer” because it is very hard to say that very long name repetitively. The concept behind gene transfer is that you give back an SMN1 functional gene to the motor neurons you are targeting, but perhaps other tissues also, through a single intravenous [IV] dose of medication. This, again, was developed through a parallel development program where we are still actively learning about these patients. There have been data updates now in all of the programs; we have learned about presymptomatic dosing, dosing in symptomatic infants, and dosing in people with milder forms of SMA [spinal muscular atrophy] and how they have been doing in long-term follow-up. How has the introduction of gene transfer evolved the thinking from 2019 or 2020 in your clinic [Children’s Hospital Colorado], now that you have 2 options, especially for the youngest patients?

Julie Parsons, MD: It has been life altering as well. It is a sexy option because it is a single IV infusion, but also the safety issues are real with the gene transfer. I think we are learning more about this. There have been fewer patients who have been treated. I am not certain of the numbers right now, frankly; I think it might be about 1200 patients, perhaps a little bit more globally. It is definitely a smaller number of patients who have been treated. I think what we are experiencing as a community is that the younger the patient is—maybe from birth to 6 months—it seems a little easier with less complicated delivery than it does when treating patients who are from 6 months to 2 years of age. As you know, onasemnogene is indicated for children under the age of 2. We are able to treat them from the newborn period up to 2 years of age. The treatment itself is relatively easy because it is an IV with a gene transfer product; it is given once. However, there are implications in terms of some immune issues with patients. To be able to be treated, patients cannot have an elevation of AAV9 titers—adeno-associated virus [serotype 9] capsid—which is utilized to transport that gene transfer product. If a baby has elevated AAV9 titers, they are not able to have the product infused. We must think about that piece of it.

Then, we know in the first trial that was done, the START trial, babies had marked elevation in transaminases as they were treated as the liver was hit and there was a decrease in their platelets, or thrombocytopenia. Babies are pretreated with steroids on a schedule, and then if their laboratory and safety values have stabilized or are normal, those steroids are tapered off. They do have steroid treatment, which is something families need to know about. I think the issue of monitoring, babies with SMA, as I said, [have veins that are hard to find]. There is a lot of laboratory monitoring. There is a lot of looking at platelet counts and liver function studies to be able to see whether this is safe. There have been a couple of other issues that have come up, with some microangiopathy as well, in patients who have been treated. I think we are seeing this along other disorders, neuromuscular disorders, being treated with gene transfer therapy, there is a potential for severe liver injuries, liver failure, thrombocytopenia hitting the bone marrow, as well as microvasculature. This, to me, is also evolving, but for parents to be able to say, “You just get a single IV for your little baby and they are fixed,” is very attractive. For the newborns, that has emerged as something parents are pretty happy about, as opposed to having spinal taps.

John Brandsema, MD: I think, going back to our earlier conversation, in the basic science model, not every motor neuron gets transduced when you give gene replacement. You do not tend to see totally asymptomatic people after gene therapy treatment. It is very important to still have that follow-up because we will need to support all of these different aspects of care that we keep emphasizing. The efficacy data from the original START trial, going into the STRIVE trial, looking again at the infantile onset patients, has been quite promising. There has been a significant improvement; however, there is a separation when you look at even the presymptomatic patients in the…. 

Julie Parsons, MD: The SPRINT trial?

John Brandsema, MD: The SPRINT trial is the one I am trying to think of. When you look at the SPRINT trial, 2 copies versus 3 copies of SMN2, there is still a difference in the development of those patients, even if they are treated during the same period early on, in terms of their response to treatment. It is also interesting that, around the world, it is not always by age. There have been approvals in other countries that go up to a much higher weight than what was originally studied in the index trials here. As we start to understand better some of these very rare but real complications we can see, such as the hemolytic uremic syndrome or sustained liver inflammation that can happen in some patients, the thought is that there may be a point at which intravenous dosing is not the preferred option, and we may give our patients intrathecal dosing to try to limit the amount of viral vector being delivered directly to the targeted motor neurons that need it the most. 

The challenge there, in the STRONG study that was being developed, is that there was some preclinical concern for dorsal root ganglia toxicity in some of the animal models. Right now, as of the time of this taping, that trial is on hold by the FDA while this gets sorted out. That leads to a challenge in the United States in terms of anybody older than 2 years of age having access to the gene transfer treatment. There is hope that we can understand how to either safely dose at a higher rate or figure out the safety aspects of this intrathecal delivery over time, so that we can give more people access to that treatment option. Is that something your older patients are still asking about?

Julie Parsons, MD: Absolutely. They love that idea.

John Brandsema, MD: Thank you to the audience for watching this NeurologyLive® Peers & Perspectives®. If you enjoyed this content, please subscribe to our e-newsletters to receive upcoming programs and other great content right in your inbox. Thanks for watching and have a great day.

Transcript Edited for Clarity