Arbor Biotechnologies’ CRISPR-Based Gene Editing Therapy ABO-101 Cleared for US Trial in Primary Hyperoxaluria Type 1
Arbor noted it has designed redePHine, a phase 1/2 clinical trial (NCT identifier pending) that will evaluate ABO-101 in adults and children with PH1.
Arbor Biotechnologies’ ABO-101, a lipid nanoparticle (LNP)-delivered CRISPR-based gene editing therapy, has received clearance from the FDA for an investigational new drug (IND) application, enabling a phase 1/2 study in primary hyperoxaluria type 1 (PH1).1
In light of the IND clearance, Arbor noted it has designed redePHine, a phase 1/2 clinical trial (NCT identifier pending) that will evaluate ABO-101 in adults and children with PH1. ABO-101 consists of mRNA expressing a novel Type V CRISPR Cas12i2 nuclease and a guide RNA directed at the human HAO1 gene, both of which are delivered via an LNP licensed from Acuitas Therapeutics. It is intended to inactivate HAO1 in order to decrease build up of oxalate, buildup of which is caused by enzyme deficiencies in patients with PH1.
“We are thrilled to advance ABO-101 to the clinic as we believe it has the potential to be a first-in-class treatment for PH1, a rare disease with a high unmet need, and reinforces the promise of our precisely tailored gene editing approach,” Dan Ory, MD, the chief medical officer of Arbor Biotechnologies, said in a statement.1 “ABO-101 is supported by a strong suite of preclinical data demonstrating specific and durable in vivo editing of HAO1 and corresponding, therapeutically relevant reductions in urinary oxalate in PH1 disease models.”
Currently, standard of care treatment for PH1 includes Alnylam Pharmaceuticals’ lumasiran (marketed as Oxlumo), a small interfering RNA (siRNA) therapy that targets messenger RNA encoded by HAO1.2 Although, the siRNA approach comes with several drawbacks, including the need for regular dosing every few months, accessibility issues, and tolerability issues for some patients; thus, a continued need for new therapeutic options exists for patients with PH1.
“The FDA approval of the ABO-101 IND marks a significant milestone for the hyperoxaluria community,” Kim Hollander, the executive director of the Oxalosis and Hyperoxaluria Foundation (OHF), said in a statement.1 “At OHF, we are committed to partnering with industry leaders to advance care, research, and patient-focused drug development for hyperoxaluria. Arbor’s innovative CRISPR-based approach represents a groundbreaking opportunity in genomic medicine, with the potential to transform the lives of patients with PH1.”
Notably, preclinical data from mouse model and nonhuman primate (NHP) research regarding ABO-101 were presented by Arbor at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, MD.2 The data indicated potential for the approach to lower levels of oxalate in a safe manner.
At the conference, CGTLive® interviewed John Murphy, PhD, the chief scientific officer of Arbor Biotechnologies, to learn more the data presented. Murphy also spoke about how ABO-101 functions and discussed the rationale behind Arbor’s approach to treating PH1.
“In patients with PH1, they have a deficit in [the AGT enzyme]...” Murphy told CGTLive. "Oxalate is insoluble, so it forms basically kidney stones. That's kind of the root cause of the disease, so we're trying to block that process. The way we're blocking it is by inhibiting an enzyme that converts glycolate, which is a dietary metabolite to glyoxylate, which is the intermediate. We're doing that through gene editing, so we're making edits in the DNA that will that will block that pathway and lead to basically an increase in glycolate, which is harmless and gets excreted through the urine. There are actually people who don't have this enzyme that we're trying to target... So we think the pharmacology is very safe for this.”
