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CHICAGO -- Gene therapy for Danon disease, a rare inherited cause of hypertrophic cardiomyopathy, appeared to improve or stabilize the structure and function of the heart over a period of 24 to 54 months without major safety concerns in the first seven patients treated.

Phase I and interim long-term follow-up study data showed that the six patients with normal left ventricular ejection fraction (LVEF ≥40%) at baseline had no evidence of heart failure progression with preservation of ejection fraction and reduction or stabilization of left ventricular (LV) mass index, cardiac troponin I, and N-terminal pro-B-type natriuretic peptide.

The seventh patient, who already had LV systolic dysfunction at baseline, had progressive heart failure and underwent transplantation 5 months after the single-dose infusion.

All survived with resolution of the mostly mild to moderate side effects after a few months without sequelae, reported Joseph Rossano, MD, of Children's Hospital of Philadelphia, at the American Heart Association (AHA) annual meeting.

Notably, "the adult patients are presently 21 to 24 years of age, which is beyond the age at which male patients with Danon disease typically undergo heart transplantation or die of heart failure," Rossano's group wrote in a paper simultaneously published in the .

"There really is no treatment at all ... so seeing any sort of response is really a big improvement," commented Evan Kransdorf, MD, PhD, director of cardiomyopathy genetics research at the Smidt Heart Institute in Los Angeles, who was not involved in the trial. "This would certainly be a breakthrough for the patients and their families."

With Danon disease, which is thought to account for about 5% of pediatric forms of hypertrophic cardiomyopathy, symptoms usually develop in males during their late teens and females during their late 20s. Progression to end-stage disease, usually end-stage cardiomyopathy, typically occurs 5 to 10 years later, although it is somewhat more variable for women than men.

Danon disease is a rare X-linked lysosomal glycogen storage disease caused by genetic mutations in the LAMP2 gene. It typically manifests as cardiomyopathy, skeletal myopathy, and intellectual disability.

The treatment in the trial, RP-A501, involves a single dose of the recombinant adeno-associated virus serotype 9 (AAV9) vector carrying the full-length LAMP2B transgene. The dose used was "considered unlikely to address the skeletal myopathy component of Danon disease," the researchers noted. It was given with a transient immunomodulatory regimen of prednisone, tacrolimus or sirolimus, and rituximab (Rituxan).

The trial phased in younger patients, with enrollment of those ages 15 years and older in the first two cohorts, and then shifting down to those ages 8 years and older. The age range was 11 to 21 years.

Given the variable presentation among females, only males were included. Confirmed or likely pathogenic LAMP2 variant and cardiac involvement documented on echocardiography, MRI, or ECG were required.

The treatment successfully led to LAMP2 protein expression on immunohistochemistry in all six evaluable patients at 12 months, which was maintained in five at 24 to 36 months. No patients had any staining for this protein at baseline.

The researchers predicted that dilution of the effect of the transduced genetic changes would be unlikely over time, "[b]ecause cardiomyocytes are a nondividing cell population in children and adults," they wrote. However, ongoing follow-up will track durability of the genetic correction.

The median reduction in LV mass index from baseline was 23% (range 7-48) from a hypertrophic 438 g at baseline. LV mass index fell from 98 g/m² at baseline by 10% or more at 12 months in five patients. Septal-wall thickness decreased by 8%, and posterior-wall thickness decreased by 24%.

Cardiac troponin I level decreased by a median 84% from a starting point well above the upper limit of normal (0.86 ng/mL). Four of the six patients had their level drop by at least 80%.

Natriuretic peptide levels were variably elevated in all patients at baseline but dropped by a median 57% over 24 to 54 months after treatment.

All of these measures typically increase over time in Danon disease, the researchers noted.

"Doing any type of gene study for the heart is not easy because there's very commonly inflammatory responses that lead to myocarditis and arrhythmias," Kransdorf said. "Even in this study they saw some adverse reactions, but overall the fact that therapy had a net clinical benefit and delayed development of end-stage disease is very exciting."

All the patients had New York Heart Association class II symptoms at baseline, but these improved after treatment. Quality of life improved by a clinically significant degree, with at least 5-point gains in Kansas City Cardiomyopathy scores on the 100-point scale.

"Most of the patients -- many of whom in the absence of this therapy would have probably had end-stage heart failure or died -- reported full participation in school, work, and leisure-related activities after RP-A501 treatment," the researchers noted.

In terms of safety, most adverse events were mild or moderate and deemed not related to RP-A501. Most common were vomiting (19 events), headache (18 events), myopathy (13 events), and increase in alanine aminotransferase level (12 events). "One patient had complement-mediated thrombotic microangiopathy (grade 4) with thrombocytopenia and acute kidney injury," the researchers wrote. "Three patients had glucocorticoid-related exacerbation (grade 3) of Danon disease-related skeletal myopathy."

Limitations included the open-label design and small sample size.

A pivotal phase II study is now underway in 12 males ages 8 and older with Danon disease.

The findings are part of a revolution in precision cardiovascular diseases treatment, said session study discussant Eric Adler, MD, of the University of California San Diego, who was a sub-investigator in the trial. He noted that some 87 gene therapies are in the pipeline for cardiovascular diseases using similar screen strategies from the discovery stage to phase III development.

What's going to be needed for trials going forward are finding the so-called Goldilocks patients who aren't too sick to derive biological benefit or too well to show a benefit during trial and developing a consensus around appropriate surrogate endpoints, Adler noted.

"If we all think of ourselves as ultimately code, if we can rewrite this code, can we change our outcomes in our patients that unfortunately have a genetic root cause of their disease? And now we can do that as illustrated here with loss-of-function diseases," he said. "I think we're on the precipice of something really amazing."

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