Safety and Efficacy of Gene Therapy for Danon Disease, Pt 1
In part one of this two-part series, Barry Greenberg, MD, discusses the challenges and emerging insights in understanding and treating Danon disease. Dr Greenberg highlights the complexities of this rare monogenetic disorder, including its progressive nature, lack of effective medical therapies, and the profound cardiac hypertrophy characteristic of the condition. He also shares findings from a new study on gene therapy, which offers hope for improving patient outcomes.
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 a Distinguished Professor of Medicine at the University of California in San Diego.
Consultant360: What makes Danon disease such a challenging condition to study and treat, especially from a clinical perspective?
Dr Greenberg: Danon disease as you probably already know is a rare monogenetic disorder. And in male patients, it is a sex-linked disorder and the males get only one copy of the gene. And if that gene is defective, they have almost or absolutely no production of a protein LAMP2B that is vital for carrying out normal autophagy, which is the clearance of debris within a cell from that cell, so that these patients begin to develop the accumulation of this debris and critical cells in the body and the predominant phenotype is in the heart where these patients develop severe cardiac hypertrophy, probably the largest amount of cardiac hypertrophy in any condition, certainly that I've seen. And there's no known treatment for this. The disease is progressive, it becomes manifest early in life, generally about age 12 to 13, and the only therapies that are available are giving an ICD to try to prevent sudden cardiac death, but given the extent of hypertrophy and the amount of interstitial fibrosis and replacement tissue that takes place within the heart of these patients, it's not entirely certain whether or not the ICDs are going to be effective prevention.
And then the other main problem is progressive development of cardiac failure, so that as these patients get older their hearts become stiffer and then weaker and they die of progressive heart failure. The average age of mortality is somewhere around age 19 or 20 and cardiac transplant is the only other alternative. One would like not to transplant somebody that early in life because it does expose them to the problems with the transplant at heart and from the immunosuppression, but it's the only available treatment that does prolong life in these patients. There's no medical therapy that's going to change the natural history.
C360: What insights did this study provide about the progression of Danon disease that clinicians should consider when monitoring patients?
Dr Greenberg: We really had a glimmer of hope with this study. It is a small study and of the seven patients who were enrolled, there was data from six of the patients giving us some insight that gene therapy might be an effective means of treating patients with that in disease. And what the study showed was that over a period that extended up to 3 years in this patient population, there was not only evidence that we were able to get the gene to the tissue that we were targeting, which was the cardiac myocardium and in particular cardiac myocytes, perhaps even more important was that there was evidence that the gene was setting up shock there and making the deficient protein so that we were able to show expression of the gene in the myocardium that extended and was sustained up to 3 years after treatment.
What was really exciting is that if you looked at cardiac hypertrophy, and that's the hallmark pathophysiologically of this disease, this enormous hypertrophy that these patients develop, there was evidence of a reduction in cardiac hypertrophy so that if you looked at wall thickness there was actually a decrease in the wall thickness in these patients.
Accompanying that were also favorable trends in biomarkers that are associated with myocardial damage and worsening wall stress. In particular, there were reductions in high sensitivity troponin as a measure of injury to cardiac myocytes and in N-terminal pro BNP as a measure of wall stress on the myocardium. If you looked at these patients clinically, and remember we're enrolling patients, many of them were in their late 20s, which would be at a time when you would anticipate that they would be doing poorly clinically, and the rapid progressive nature of the disease would become apparent. All of the patients, or five of the six patients, were clinically stable and actually had reduction in the symptoms of heart failure.
Now I've alluded already to the fact that one patient did not do well. This was a patient whose left ventricular ejection fraction was dropping. It had dropped significantly from the normal range to a reduced range, and this occurred prior to treatment. We enrolled the patient regardless into the study. The patient continued to drop their ejection fraction and approximately 6 months after treatment underwent cardiac transplant. In looking at the transplant at heart, there was evidence of significant replacement of cardiac tissue with fibro-fatty tissue, and I think the lesson there was this was an individual who had already started down that progressive road to worsening cardiac function probably was not a good patient to include in the study.
But the other patients who were stable remained stable during that time and actually showed signs of clinical improvement.