Safety and Efficacy of Gene Therapy for Danon Disease, Pt 2
In part two of this two-part series, Dr Greenberg delves into unexpected findings from a new study on gene therapy for Danon disease. He emphasizes the importance of early intervention, rigorous post-therapy surveillance to manage immune responses, and the successful delivery of therapeutic genes to the myocardium. He also discusses ongoing efforts to advance the therapy to larger clinical trials, aiming for regulatory approval and wider availability.
Additional Resource:
- Greenberg B, Taylor M, Adler E, et al. Phase 1 study of AAV9.LAMP2B gene therapy in Danon disease. N Engl J Med. Published online November 18, 2024. doi:10.1056/NEJMoa2412392
TRANSCRIPTION
Dr Barry Greenberg: I'm Barry Greenberg, I'm Distinguished Professor of Medicine at the University of California in San Diego.
Consultant360: Were there any unexpected findings during the study, either related to the therapy itself or the disease’s progression, that could inform clinical practice?
Dr Greenberg: I think we learned a lot from the study. One lesson we learned is the one that I just shared with you about not treating patients too late in the disease. This is a very unstable disease when patients start deteriorating. It leads to a rapidly progressive downhill course. That was one lesson. The second lesson was that that we looked at the surveillance of these patients after they received gene therapy.
What I learned personally was that particularly during the early period after gene therapy, you need to keep a very careful eye on these patients and test them consistently for evidence of activation of immune systems that are targeting either the vector that was used, that is, the virus that was used to carry the gene to the myocardium, to the gene itself, or to the protein that's being expressed. And if you see signs of activation of those immune mechanisms to treat aggressively early on. So that was another lesson that we learned.
And then finally the third lesson. This was the first time we had ever been able to demonstrate that we were able to get enough transduction of the delivery system that is the viral vector delivered to the myocardium successfully and we were able to show that in this study and we were able to show that the gene once it was delivered to the heart did indeed begin to reduce the deficient protein. This is what we were hoping for, but hoping for something and seeing it happen sometime don't coincide in clinical trials, but we saw exactly what we were hoping would occur.
C360: What do these results suggest about the potential for gene therapy to modify the course of Danon disease, and how might this influence future treatment protocols?
Dr Greenberg: So there are really two major take-home messages. One is for the patients with Danon then their families, the entire Danon community. This holds the promise of offering a therapy that would be effective in the patients with Danon disease. It would be the first drug therapy that has shown efficacy in treating these patients. Obviously, the results that we obtained need to be replicated in a larger number of patients. We need to continue following the patients, but we've already started doing that and hopefully will have definitive evidence over the next couple of years and that there would be a new therapy available.
The second piece of information is the importance of this study I believe to the gene therapy field in general. I've already mentioned that we've shown now that using the viral vector and the immunosuppression regimen that we employed that we were able to demonstrate delivery of adequate amounts of the gene to the myocardium. The gene was successfully delivered to the cardiac myocytes and once they were delivered within these cells, they set up shop and were able to produce protein that at least in the limited number of patients that we studied had beneficial effects on the structure of the heart.
I will point out that we not only saw that reduction in the left ventricular myocardial mass, that hallmark of Danon disease, but if you look at the ultra structure of the cardiac myocytes, and we did this by doing repeat endomyocardial biopsy and examined the tissue by electron microscopy, the ultra structure of the cells which had been very, very abnormal prior to treatment appeared much more like normal myocardium after treatment. Specifically, you saw less myofibrillar disarray and you saw a reduction in the number of the vacuoles that accumulated in the cell. These vacuoles contain these cellular debris that couldn't be broken down because of the deficient enzyme. There was now a much lower number of these vacuoles within the cells and they were smaller.
C360: What are the next steps in research or clinical trials to move closer to making gene therapy like RP-A501 more widely available to patients?
Dr Greenberg: The next step is moving on to a more definitive pivotal clinical trial which has now begun and patients have already been enrolled both here in the United States and there's another center in Germany that has enrolled a patient and there are two sites in addition to our site in San Diego. There are two sites on the east coast of the United States that are enrolling patients. The goal here is to enroll a larger number of patients than in the first study and to demonstrate the continued safety of this approach. Also, to provide additional evidence that we're getting expression of the protein in the heart.
And then finally, that there's a reduction in the left ventricular hypertrophy.
Now, we'll be looking at a lot of other factors. But those three things that I mentioned, the safety, the protein expression, and the reduction in myocardial mass. All of those are going to be looked at by regulatory agencies like the FDA and we're hoping that the results of this study will lead to regulatory approval in the United States and elsewhere and offer a therapy that would be effective for patients with that in disease. To me as an investigator and a clinician who takes care of these patients. It really is an unusually exciting opportunity to be involved in the development of a therapy like this and to get the kind of results that we got in this initial experience and I'm really looking forward to seeing additional patients and learning whether or not we actually have found a therapy that is going to be approvable by regulatory agents and offers this opportunity for these families and the patients.