Q&A: ‘An exciting breakthrough’: Gene transfer therapy promising in Danon disease
Key takeaways:
- Danon cardiomyopathy is a rare but severe genetic disease that drastically reduces life expectancy.
- A novel gene therapy may be the first treatment to prolong survival aside from heart transplantation.
Danon disease is a rare but serious cardiomyopathy that drastically reduces life expectancy.
Male patients infrequently live past age 20 years and female patients infrequently live past age 50 years. Therapies for cardiovascular disease other than heart transplantation don’t improve outcomes.
But, as evidenced by a presentation at the American Heart Association Scientific Sessions and a paper simultaneously published in The New England Journal of Medicine in November, a treatment other than heart transplantation or a defibrillator may be on the horizon.
The results of a phase 1 study of a gene transfer therapy (RP-A501, Rocket Pharmaceuticals) were encouraging, as all seven patients who received the therapy when they were between the ages of 15 and 20 years were alive at follow-up ranging from 24 to 54 months after treatment; all serious adverse events from the therapy were resolved by 5 months; the treatment achieved its goal of expressing a missing protein in the heart, the lack of which leads to a defect in autophagy (or clearing debris within cells) that is the hallmark of Danon cardiomyopathy. All patients experienced improvements in cardiac structure, cardiac function and quality of life.
Healio spoke with Barry H. Greenberg, MD, FHFSA, distinguished professor of medicine and director of the Advanced Heart Failure Treatment Program at the University of California San Diego School of Medicine, cardiologist at UC San Diego Health, and a member of the Healio | Cardiology Today Editorial Board, about the mechanisms of Danon cardiomyopathy, the obstacles patients with it face, the function and promise of RP-A501, the key findings of the phase 1 study and what the future might hold for this population.
Healio: How is Danon different from other kinds of cardiomyopathies? What are the challenges these patients face?
Greenberg: Danon is a rare genetic cardiomyopathy caused by a mutation in a sex-linked gene. The gene mutation leads to a defect in a process called autophagy, which is responsible for clearance of debris within cells. What that ends up doing is allowing a collection of broken-down particles within cells to accumulate and leads to the formation of vacuoles within these cells. The cells subsequently enlarge and become dysfunctional, predisposing them to premature death. In the heart, that’s a major problem since cardiomyocytes divide very slowly and loss of cells adversely affects the heart’s ability to serve as a pump. In male Danon patients, the predominant phenotype is the development of hypertrophic cardiomyopathy and their hearts get enormously enlarged. As the disease progresses, substantial fibrosis forms within the heart. Ultimately, this leads to development of heart failure, cardiac arrhythmias and premature death. In the male patient, survival is markedly truncated, with most male patients dying around the age of 17 to 19 years.
The only existing therapies are placement of an intracardiac defibrillator, and cardiac transplant. Neither of these are optimal. The defibrillators may not sense all of the arrhythmias these patients are experiencing, nor be able to treat them adequately because of the structure of the heart. Cardiac transplantation, although lifesaving, has associated problems that end up reducing overall survival, and there’s considerable morbidity associated with cardiac transplant.
Female patients have a form of Danon disease also; however, it’s more variable and tends to be less severe. The onset is later in life and the typical cardiac phenotype varies from hypertrophic cardiomyopathy to dilated cardiomyopathy. Female patients can also have cardiac arrhythmias. Survival is affected, but female patients die 2 to 3 decades later than male patients with this disease.
Danon disease has other clinical manifestations throughout the body: skeletal muscle weakness, mild cognitive impairment and also some visual issues. These are somewhat variable, even in the male patients with Danon. But by and large, the cardiac phenotype is the major issue with these young males, and is the cause of premature death in the Danon population.
Danon is relatively rare. It’s estimated that in the U.S. and Europe, there are somewhere around 15,000 to 30,000 cases of Danon. But that’s really an estimate rather than an accurate depiction of how common Danon is. The reason is that it may go unrecognized or be attributed to other causes of cardiac hypertrophy. It’s becoming increasingly easy to make the diagnosis now, with greater availability and physician attention to the use of genetic testing in patients who have hypertrophic cardiomyopathy. Genetic testing along with evidence of the hallmark cardiac phenotype gives you a definitive diagnosis.
Healio: How does RP-A501 work and what kind of difference might it be able to make for these patients?
Greenberg: This is an exciting breakthrough, both for patients with Danon disease and for the field of gene transfer therapy. The way the therapy works, based on earlier studies done initially in cell cultures and then transferred to animal models, is that it employs a drug that’s made up of a normal copy of the mutated gene. That gene is called LAMP2B. It plays a key role in maintaining autophagy in cells within the heart, and its absence leads to impaired autophagy. A normal copy is inserted into an AAV viral backbone, from which the viral genes have been stripped out. And then you put in a promoter, and some other elements that help facilitate the expression of the gene. The viral backbone, which is called the capsid, is important because it enables delivery of the virus to tissues throughout the body. The virus which has been used for this study and has been used for the majority of gene transfer therapies are viruses in the adeno-associated virus family. We call them AAV viruses. There are multiple serotypes, slightly different forms of the AAV virus, going from AAV1 to AAV9, among others. Those viral delivery vectors can be tweaked a little bit so that there are some changes made that may make them a little more effective as delivery vehicles. In this study, we used the AAV9 vector and we used the capsid from the AAV9 virus, in which we inserted the gene for LAMP2B along with the other elements that I mentioned. The reason we selected AAV9 is that it shows very strong tropism for cardiac tissue, which means it is taken up relatively avidly within cardiac myocytes.
The study was planned to look at the safety and also to get a preliminary indication of whether this therapy would have efficacy in treating Danon disease.
Healio: What were the key findings of this study?
Greenberg: This was a phase 1 study that involved seven young male patients with Danon. Two were in the pediatric age range, younger than 15 years, and five were in the range of 19 to 21 years. They were treated with doses of the therapy for Danon disease. All of them had substantial evidence of cardiac hypertrophy and mild-to-moderate symptoms that limited their activity. All of them were NYHA class II at the time of entry into this study. There was one patient who was more symptomatic, and in retrospect was entering the more rapidly progressing stage of the disease. His left ventricular ejection fraction had recently dropped considerably and it continued to decline even after treatment. Fortunately, he underwent a successful cardiac transplantation and is doing well with his new heart. The data involving the efficacy portion that I’ll discuss involved the six other patients.
As far as safety, there are anticipated challenges with using a viral vector for delivery of gene therapy. There is also a risk for expression of proteins that previously had been deficient, which the body may treat as foreign.
As an example, in Danon disease, the male patients usually have no measurable protein for LAMP2B. If you deliver a gene that now sets up shop within this cell nucleus and it starts producing this protein, the body’s immune system may recognize this as being a foreign protein. Both to tamp down the body’s immune system and to try to enhance the delivery of the viral vector to the heart, and also the maintenance of or the expression of the gene within the heart, we administer immunosuppressant therapy to these young males. We start this therapy about 2 weeks before they come in for treatment and then continue it for about 3 months. We start tapering back on the doses of immunosuppressant drugs beginning about 1 month to 6 weeks after initiating therapy.
There still are issues related to the use of gene therapy. We have learned about the safety. There are a number of minor side effects that come on that are easily treatable, but there are some important ones. Probably the most important is a condition called thrombotic microangiopathy, or TMA. This is seen within a few days after gene therapy is administered It is caused by the activation of the patient’s innate immune system which recognizes the viral capsid as being a foreign protein. This leads to activation of the complement system, and if that’s severe and left untreated, can result in propensity for bleeding, because you reduce the number of platelets, and also thrombosis within small vessels: the most susceptible organ appears to be the kidney, and effects on renal function can occur with TMA. We looked very carefully and learned from this study about how to do surveillance and treatment. We did, however, have one patient who developed this severe complication.
The other severe complications were related to the immune therapy. And it turns out that the patients with Danon disease, because the gene mutation leads to abnormalities not only in cardiac muscle but in skeletal muscle, already have baseline abnormalities in their skeletal muscle. Three of the patients developed a skeletal myopathy that was probably steroid-related. So based on this, we now try to spare steroids as much as possible. We are very cognizant of this steroid effect and we assess muscle strength closely, looking for early signs that skeletal myopathy may be developing.
Those were the major side effects. Overall, the therapy was well tolerated. All serious side effects had resolved by 5 months. The patients are all doing well now. Remarkably, given what we know from the natural history of the disease, up to 5 years later, they are continuing to function well. All are improved in their NYHA class from class II to class I. Several of them are working full time. Several of them who had been living at home have moved out on their own.
I can tell you from a very personal experience that this is the most gratifying aspect of the study for me, having worked with several of these families, knowing the boys and their parents and seeing how well they’re doing.
As far as efficacy data is concerned, we were able to demonstrate that we got an adequate number of viral particles taken up in the heart. Even more important, we were able to demonstrate that the gene set up shop within the nucleus of the cardiomyocytes and was producing proteins. We documented this by doing endomyocardial biopsies and taking pieces of myocardium out at various intervals of time after treatment. We found evidence of robust expression of the LAMP2B protein within the hearts of these patients, and evidence that gene expression was maintained over a period of up to 3 years. We don’t have data beyond that at this point. The appearance of protein within the heart was associated with favorable effects on measures of cardiac hypertrophy, a hallmark of the disease. In this study, we showed that all patients had a reduction in the amount of hypertrophy as measured by echocardiography, so that at 1 year, there was already a reduction in left ventricular mass.
This was associated with a reduction in biomarkers of cardiac stress. For this, we looked at natriuretic peptide levels. It was also associated with a reduction in myocardial injury. Here, we looked at high-sensitivity troponin levels. Both of these biomarkers were substantially reduced in the patients.
We also looked at indicators of quality of life. NYHA class improved, as already mentioned. There were also improvements in the Kansas City Cardiomyopathy Questionnaire scores. Those changes need to be considered with the knowledge that we have no comparison group, since all of these patients were treated, and that these are subjective measures. However, they all go in the right direction, and they are consistent with the other parameters we looked at.
All in all, there were very favorable signals for efficacy in this patient population. To me, the highlights are fourfold:
No. 1, we can deliver this therapy, get it to the heart and get the gene to set up shop and produce the protein that is deficient using a therapy that is relatively safe and well tolerated.
No. 2, gene therapy using RP-A501 was associated with improvements in cardiac structure that are the hallmark of Danon disease.
No. 3, the improvements in cardiac structure were associated with functional changes and quality of life that were favorable.
No. 4, my own personal experience is that these boys, contrary to what was seen in the natural history studies of untreated patients, are alive and doing well.
Healio: Now that the study has been completed and the paper is out there, what are the next steps?
Greenberg: We have treated patients with Danon disease in a phase 2 study, which will be a pivotal clinical trial. The primary endpoints in this trial are expression of the protein in the heart, which is critically important, and reduction in left ventricular mass. There are a number of secondary endpoints including assessment of biomarkers and quality of life. And of course there will be continued observations about safety.
It is great to see what we have learned being made available to other investigators in the field who can now benefit from this, and eventually bring benefit to patients who have genetic causes of cardiomyopathy.
References:
- Greenberg B, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2412392.
- Rossano J, et al. FS.05. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2024; Chicago.
For more information:
Barry H. Greenberg, MD, FHFSA, can be reached at bgreenberg@ucsd.edu.
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