Liver-directed AAV gene therapy corrects alkaptonuria metabolically in mouse model
A preprint from Cold Spring Harbor Laboratory reports that AAV-mediated delivery of the HGD gene to the liver normalised homogentisic acid accumulation in Hgd-deficient mice, pointing to a potential curative approach for this rare metabolic disorder.
Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by loss-of-function variants in the HGD gene, which encodes homogentisate 1,2-dioxygenase (HGD). Deficiency of this enzyme leads to accumulation of homogentisic acid (HGA), causing progressive damage to connective tissue, joints, and other organs — a process known as ochronosis. The current standard pharmacological intervention, nitisinone (NTBC), reduces HGA levels but does not correct the underlying genetic defect and is associated with hypertyrosinaemia as an adverse metabolic consequence.
A preprint posted to bioRxiv reports that Hgd-deficient mice treated with liver-directed adeno-associated virus (AAV)-mediated delivery of the HGD gene achieved metabolic correction, with normalisation of HGA accumulation. The approach is described as potentially curative in contrast to nitisinone, which is purely suppressive.
The work is a preprint and has not yet undergone peer review. Findings in Hgd-deficient mice may not translate directly to the human disease, and further preclinical and clinical evaluation would be required before any conclusions about therapeutic application could be drawn. AKU is an ultra-rare condition and this remains early-stage experimental work.
Plain-language version
For patients, families, and general readers. Educational only — not medical advice.
Alkaptonuria (sometimes called AKU) is a rare inherited condition caused by a fault in a gene called HGD. The fault means the body cannot properly break down a substance called homogentisic acid, which builds up and over time can damage joints and other parts of the body.
There is a medicine called nitisinone that can lower levels of this substance, but it does not fix the underlying genetic problem and can cause other side effects.
Researchers have been testing a different approach in mice: using a harmless virus to deliver a working copy of the HGD gene directly to the liver. In mice with the same gene fault as people with AKU, this approach corrected the metabolic problem. This research is at an early, laboratory stage in mice and has not yet been tested in people.
This is an educational summary, not medical advice. If anything here raises questions for you, please speak with your GP or a clinical professional.
Sources
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Primary sourcePreprint bioRxiv (Cold Spring Harbor Laboratory) · 2026-06-02Liver-directed AAV gene therapy metabolically corrects AKU in Hgd deficient mice