Addition’s gene therapy for Fabry yields positive preclinical results
Data suggest non-viral approach could reduce need for frequent infusions
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A single dose of an RNA-based gene therapy for Fabry disease produced long-lasting levels of the missing key enzyme and reduced the toxic buildup of fatty molecules linked to the disease, according to new preclinical data from Addition Therapeutics.
The findings were presented in a poster at the recent American Society of Gene & Cell Therapy (ASGCT) annual meeting in Boston. Titled “Preclinical proof of concept of treatment for Fabry disease via precise RNA-mediated insertion of a GLA transgene,” the poster adds to a growing body of evidence supporting the company’s proprietary PRINT technology as a potential treatment for Fabry and other severe conditions.
“The proof-of-concept data [we’ve presented] at ASGCT demonstrate our PRINT technology’s potential to create medicines that hold transformative potential for patients suffering with a spectrum of severe, lifelong non-genetic and genetic diseases,” Ron Park, MD, president and CEO of Addition, said in a company press release.
Understanding the current Fabry treatment paradigm
Fabry disease is caused by mutations that result in a lack of alpha-galactosidase A, an enzyme that normally breaks down globotriaosylceramide (Gb3) and other fatty molecules inside cells. Without enough alpha-Gal A, these fatty molecules build up to toxic levels and damage tissues and organs. Current treatment usually requires regular infusions to replace the missing enzyme.
“The current treatment paradigm for most lifelong diseases involves perpetual repeat-dose therapies, which lead to peaks and troughs in therapeutic serum levels that adversely impact safety and efficacy, in addition to being extremely difficult to take for an entire lifetime,” Park said.
Addition’s technology PRINT stands for Precise, RNA-Mediated, Insertion of Transgenes. A transgene is a healthy copy of a gene added to cells to replace a mutated one. This therapy uses RNA, a molecule that carries instructions for proteins — including enzymes — inside cells, rather than viral vectors, which are modified viruses often used in gene therapy.
PRINT is delivered with lipid nanoparticles, very small fat-coated particles that carry RNA into cells. According to the company, this may be safer and easier to manufacture than traditional viral gene therapies. In nonhuman primates, PRINT enabled stable, durable production of therapeutic proteins.
In addition to Fabry, the company also presented preclinical studies in several diseases, including a rare type of obesity, human immunodeficiency virus infection, and eye disease, providing proof of concept that the technology may work before human testing begins.
In a mouse model of Fabry disease, researchers tested a single dose of a PRINTed gene therapy carrying a healthy copy of GLA genetic instructions. After gene therapy, mice produced functional alpha-Gal A enzyme at levels higher than normal in the blood. They also showed lower levels of lyso-Gb3, a biomarker of Fabry disease, in the liver, kidneys, and heart.
Addition believes its PRINT technology could provide a longer-lasting alternative with fewer doses. If future studies in humans confirm these findings, the technology could eventually offer multi-year benefits while avoiding some challenges associated with viral gene therapies.
