John Murphy, PhD, on Using Gene Editing to Tackle Primary Hyperoxaluria Type 1

“What we are able to do—we hope, if this product works as intended—is to provide a once in a lifetime treatment that will really allow patients to have normalized oxalate and avoid all the complications of the disease.”

Primary hyperoxaluria type 1 (PH1) is a rare genetic disease, caused by a mutation in the AGXT gene, that can cause damage to the kidneys and the formation of kidney stones through the build up of oxalate produced by the liver. If left untreated, the disease can lead to kidney failure, and patients may require kidney transplant in their adolescence. Currently, standard of care treatment for PH1 includes Alnylam Pharmaceuticals’ lumasiran (marketed as Oxlumo), a small interfering RNA (siRNA) therapy. Lumasiran targets messenger RNA encoded by HAO1, the gene responsible for producing the glycolate oxidase enzyme, which is a precursor of oxalate; thus, it indirectly lowers levels of oxalate. The siRNA approach comes with several drawbacks, however, including the need for regular dosing every few months, accessibility issues, and tolerability issues for some patients. As such, there is an interest in the continued development of new treatments for PH1.

Arbor Biotechnologies is currently developing ABO-101, a lipid nanoparticle (LNP)-delivered Cas12i2-based gene editing approach to treating the disease. ABO-101 is intended to permanently inactivate the HAO1 gene in the cells of the liver via a one-time treatment. Preclinical data from mouse model and nonhuman primate (NHP) research regarding ABO-101 was recently presented by the company at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, MD. In an interview with CGTLive® at the conference, John Murphy, PhD, the chief scientific officer of Arbor Biotechnologies, spoke about the background behind ABO-101 and gave an overview of the promising data presented, which indicated potential for the approach to lower levels of oxalate in a safe manner.

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REFERENCES
1. DiTommaso T, Kuefner MS, Halwasia S, et al. Development of ABO-101, a novel gene editing therapy for primary hyperoxaluria type 1. Presented at: ASGCT Annual Meeting 2024, May 7-10; Baltimore, Maryland. Abstract #165