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The low-dose cohort of RP-A501 conferred cardiac LAMP2B transgene expression.
A new study presented at the American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting evaluated the safety of RP-A501 in male patients with danon disease (DD).
An X-linked disease, DD has characteristics of cardiomyopathy, cognitive impairment, and skeletal myopathy. It is caused by a mutation of the lysosome-associated membrane protein (LAMP2), an essential protein for autophagy.
Investigators, led by Barry Greenberg, MD of the UC San Diego School of Medicine, found that in the first in-human trial, the low dose cohort of RP-A501 gene therapy for DD was well-tolerated and conferred cardiac LAMP2B gene expression.
The team initiated an open-label phase 1 study in 2019. A population of 12-24 participants would receive an IV infusion of RP-A501.
Greenberg and team evaluated two dose levels: 6.7 x 1013 GC/kg and 1.1 x 1014 GC/kg.
The investigators included 2 age groups, including ≥15 years and 8 – 14 years. The eligibility included a DD diagnosis with confirmed LAMP2 mutation, with at least 1 abnormal finding through ECG, echo, cardiac MRI, or electrophysiology.
The first cohort included 3 patients, ≥15 years old with a dose level of 6.7 x 1013 GC/kg.
The team found the treatment with RP-A501 increased cardiac LAMP2B expression by Western blot (WB) and immunohistochemistry (IHC).
Of the 3 patients in Cohort 1, 2 patients with closely monitored compliance with the treatment regimen had high levels of cardiac LAMP2B expression, with 68% and 92% versus normal control in IHC. Investigators also found the patients had up to 61% versus normal control by WB.
The team noted that NT-proBNP tended to improve, while CPK-MB improved or stabilized.
In all patients in cohort 1, there were visible improvement in autophagic vacuoles within myocardium.
Further, the team observed elevation of transaminases, CK, CK-MB, and Troponin 1, which returned to baseline within 2 months.
“This first in-human trial demonstrates that the low dose cohort of RP-A501 gene therapy for DD was generally well-tolerated and confers cardiac LAMP2B transgene expression,” investigators wrote.
The results from patients treated with a higher dose of RP-A501 gene therapy is pending.
The study, “Results from First-in-Human Clinical Trial of RP-A501 (AAV9:LAMP2B) Gene Therapy Treatment for Danon Disease,” was presented online at ASGCT.