For patients with primary hyperoxaluria type 1, a single injection could soon replace a lifetime of fear.
Imagine your body constantly producing microscopic crystals that shred your kidneys from within.
Primary hyperoxaluria type 1 is a rare, inherited metabolic disorder that primarily affects the kidneys. It accounts for approximately 80% of all primary hyperoxaluria cases, making it the most common and severe form 7 .
AGT enzyme is deficient, dysfunctional, or mistargeted in liver cells 3 .
With AGT non-functional, glyoxylate builds up in liver cells.
Excess glyoxylate is converted to oxalate, a metabolic end-product with no useful function.
The treatment landscape for PH1 has evolved dramatically—from managing symptoms to addressing the root cause.
| Therapy Type | Mechanism of Action | Administration | Key Limitation |
|---|---|---|---|
| Conservative Management (fluids, citrate salts) 7 | Dilutes urine oxalate concentration and reduces crystal formation | Oral, daily | Does not reduce oxalate production |
| Pyridoxine (B6) 4 7 | Cofactor for some AGT variants, may enhance residual enzyme activity | Oral, daily | Only effective in ~30% of patients 7 |
| RNAi Therapeutics (lumasiran) 2 | Silences HAO1 gene mRNA, reducing glycolate oxidase production | Subcutaneous injections, periodically | Requires lifelong, repeated dosing |
| Organ Transplantation 4 | Replaces defective liver (source of oxalate overproduction) and/or damaged kidneys | Major surgery | Lifelong immunosuppression; significant morbidity/mortality risk |
| Gene Editing (LNP-CRISPR) 1 6 | Disrupts HAO1 gene in hepatocytes, permanently reducing oxalate production | Single intravenous infusion | Currently investigational |
The latest frontier in PH1 treatment involves in vivo gene editing using CRISPR-based technologies. Unlike RNAi, which temporarily silences gene expression, gene editing aims to permanently disrupt the target gene, potentially offering a one-time cure.
A landmark 2025 study published in Molecular Therapy detailed the development and testing of an LNP (lipid nanoparticle)-encapsulated CRISPR-Cas9 system targeting the HAO1 gene 1 .
Researchers packaged Cas9 mRNA and a single-guide RNA (sgRNA) targeting the HAO1 gene into proprietary lipid nanoparticles (LNPs) 1 6 .
Using the same LNP-CRISPR technology, the team first generated a PH1 mouse model by targeting the Agxt gene 1 .
Researchers administered a single intravenous dose of LNP-CRISPR-HAO1 to PH1 mouse models 1 .
Treated animals were followed for 12 months to assess both durability of effect and long-term safety 1 .
| Reagent/Tool | Function | Key Feature in PH1 Experiment |
|---|---|---|
| Cas9 mRNA | Encodes the CRISPR-associated protein 9 enzyme that cuts DNA | Transient expression; reduces off-target risk compared to viral DNA delivery 1 |
| Single-Guide RNA (sgRNA) | Directs Cas9 to a specific sequence in the HAO1 gene | High on-target specificity; designed to minimize off-target effects 1 |
| Lipid Nanoparticles (LNPs) | Delivery vehicle encapsulating Cas9 mRNA and sgRNA | Protects cargo, targets hepatocytes, biodegradable 1 6 |
| HAO1-targeting sgRNA | Specific guide RNA sequence targeting the glycolate oxidase gene | Disruption reduces glyoxylate/oxalate production 1 6 |
| Proprietary Cas12HF System (YolTech) 6 | Alternative to Cas9 with high fidelity | Enhanced editing precision; avoids Cas9 patent complexities |
The promising preclinical data has rapidly translated into human clinical trials.
YolTech Therapeutics
In an ongoing investigator-initiated trial, seven PH1 patients receiving high doses showed nearly 70% reduction in 24-hour urinary oxalate levels, sustained through the 16-week primary observation period 6 .
Arbor Biotechnologies
The first patient was dosed in the phase 1/2 redePHine trial in July 2025. The open-label study plans to enroll up to 23 adult and pediatric patients with PH1, with primary completion expected in March 2029 .
The development of molecular therapies for PH1 represents a paradigm shift from symptom management to targeted treatment and potentially definitive cure.
How durable will the effect be in human patients? Will earlier intervention in pediatric patients prevent kidney damage entirely?
Can these technologies be adapted for other forms of primary hyperoxaluria or related genetic disorders?
For the first time in history, the prospect of a single-treatment, lifelong cure for PH1 appears as an achievable goal on the near horizon.
As these technologies mature, they promise to transform a once-devastating diagnosis into a treatable condition, offering hope to patients and families affected by this rare genetic disorder.