Primary hyperoxaluria type 1 (PH1) is a rare, inherited genetic disorder characterized by the overproduction of oxalate in the liver due to mutations in the AGXT gene, which encodes the enzyme alanine-glyoxylate aminotransferase (AGT). This deficiency leads to an accumulation of oxalate crystals, primarily in the kidneys and urinary tract, resulting in kidney stones, nephrocalcinosis, and potentially kidney failure. If kidney function declines significantly, oxalate can deposit in other organs and tissues, causing systemic oxalosis and affecting the heart, bones, and eyes. Symptoms include recurrent kidney stones, pain, hematuria, and urinary tract infections, with severe cases progressing to kidney failure and systemic complications. Diagnosis involves urine and blood tests, as well as genetic testing, to confirm the presence of the AGXT gene mutation. PH1 is the most common and severe form of primary hyperoxaluria, leading to significant morbidity and mortality if left untreated.

Treatment of primary hyperoxaluria type 1 (PH1) relies on traditional supportive care, which includes high fluid intake, crystallization inhibitors, and pyridoxine (Vitamin B6). These methods remain relevant in managing the disease. In cases of advanced PH1, particularly end-stage renal disease, transplantation, either combined liver-kidney or kidney-only, is a critical intervention. Transplantation remains a vital option for those with severe disease.

PH1 treatment has undergone a major shift with the 2020 FDA approval of Oxlumo (lumasiran), the first medication specifically for this rare genetic disorder. Developed by Alnylam Pharmaceuticals, lumasiran utilizes groundbreaking RNA interference (RNAi) technology to target and silence the HAO1 gene, effectively reducing oxalate production at its source. This RNAi therapeutic, delivered via subcutaneous injection, introduces small interfering RNA (siRNA) molecules that specifically bind to the messenger RNA (mRNA) of the hydroxyacid oxidase 1 (HAO1) gene. The HAO1 gene encodes glycolate oxidase (GO), a key enzyme in hepatic oxalate production. Upon binding, the siRNA triggers the cell's natural RNAi machinery, leading to the degradation of the HAO1 mRNA. Consequently, glycolate oxidase enzyme production is reduced, directly diminishing oxalate synthesis in the liver. This reduction in hepatic oxalate translates to lower urinary oxalate levels, mitigating the formation of kidney stones and slowing the progression of kidney damage. Utilizing Alnylam's ESC-GalNAc conjugate technology ensures efficient delivery of lumasiran to liver cells, enhancing potency and durability, ultimately providing a targeted approach to managing PH1.

The field of gene therapy has made remarkable strides, transforming the treatment landscape for rare diseases, including PH1. Once a distant prospect, one-time gene therapy treatments are now a tangible reality, driven by advancements in vector technology and targeted gene delivery. These developments are reflected in the increasing number of FDA approvals and ongoing clinical applications, signaling a paradigm shift in PH1 management.

Arbor Biotechnologies is pioneering a potential revolution in PH1 treatment with ABO-101, a groundbreaking, one-time intravenously administered gene editing therapy. By delivering a CRISPR Cas12i2 system via lipid nanoparticles, ABO-101 precisely targets and permanently disables the HAO1 gene within liver cells, effectively halting the overproduction of oxalate at its source. This innovative approach, now recognized with FDA orphan drug and rare pediatric disease designations, promises a durable, potentially curative solution for PH1, moving beyond chronic management to address the disease's genetic root. Arbor Biotechnologies has dosed the first patient at Mayo Clinic in the redePHine Phase 1/2 study for ABO-101.

The promise of one-time gene therapies and targeted RNAi treatments ushers in a new era where rare diseases, once considered intractable, may become manageable or even curable, offering the potential for improved quality of life and a future free from the burden of chronic illness.