A novel gene insertion therapy may be able to cure infants of a rare genetic liver disease.
Ornithine transcarbamylase (OTC) deficiency is a rare, X-linked genetic condition caused by variants in the gene encoding the OTC enzyme. Newborns with this condition are unable to break down proteins completely, leading to a build-up of ammonia in their blood causing a metabolic crisis, which if not controlled can cause permanent brain damage. Currently, the only cure for OTC is a liver transplant. Preliminary findings of a novel in vivo gene insertion therapy targeting the OTC gene has achieved a complete clinical response in the first infant with neonatal OTC deficiency to receive the treatment.
'To our knowledge, this is the very first infant to have ever received an in vivo, liver-directed, gene insertion investigational product...' said Dr Gabriel Cohn, chief medical officer of the Philadelphia-based biotechnology company iECURE, who developed the therapy. 'While still early days and follow up is limited to the first six months post exposure, the elimination of this baby's need for the current standard of care observed after a few months of receiving [the therapy] may represent a historic milestone…'
The therapy, called ECUR-506, involves the delivery of two adeno-associated virus vectors – one that cuts the patient's DNA and one that inserts a functional OTC gene. The cut at a specific site serves as the insertion site for the OTC gene, which the scientists believe provides a potential path to permanent expression of a functional gene.
Unlike most other genome editing therapies currently in development, which use the CRISPR/Cas9 approach to cut DNA, the scientists used a genome editing approach called ARCUS, which uses the naturally occurring genome-editing enzyme, I-CreI, found in a species of unicellular green algae.
The patient, a six-month-old boy, was diagnosed with OTC following a metabolic crisis at one week old. A further crisis was reported at 3.5 months old. After the stabilisation of his condition, which included taking an ammonia-reducing drug and the administration of a strict diet, the patient received a single infusion of the therapy.
One month after receiving the therapy, the patient exhibited a severe elevation of liver enzymes in the blood, which resolved within a month of taking immunosuppressants.
The amino acid glutamine, which is used to build proteins, is reduced in OTC patients and thus used as a marker for monitoring the levels of ammonia in a patient. Three months after treatment, due to the observation of a reduction in glutamine, the patient's ammonia-reducing medication was reduced and he returned to a normal diet.
Furthermore, six months after treatment, his ammonia and glutamine levels returned to normal and the patient has not experienced any metabolic crises since the administration of the therapy.
Dr Julien Baruteau from University College London and principal investigator in the study said: 'While this is very early data, I am hopeful that this baby will continue along this encouraging trajectory and that other babies who enrol in this study will have similar experiences. This novel gene therapy technology may herald new avenues to treat babies with severe liver genetic diseases.'
However, it is not yet known whether the insertion of the functional OTC gene has resulted in permanent expression into the infant's genome, which will affect the therapy's long-term success.
Complete study data on the first patient will be presented at a medical conference in March, and the company intends to trial this therapy on another three male infants in the first half of 2025.
This is not the first time that gene therapy has been explored as a way to treat OTC deficiency. iECURE's founder, Professor James Wilson, attempted to use adenoviruses to insert a healthy copy of the OTC gene into livers of patients with OTC deficiency 25 years ago. However, the study was terminated due to the death of 18-year old Jesse Gelsinger who suffered a lethal immune reaction to the treatment (BioNews 28 and 295).
Sources and References
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iECURE reports complete clinical response in first infant dosed with its in vivo genome editing candidate ECUR-506 in an ongoing Phase 1/2 clinical trial in ornithine transcarbamylase (OTC) deficiency
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First-of-its-kind infant DNA edit leads to apparent cure in disease that set back field 25 years ago
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Gene therapy pioneer Jim Wilson comments on iECURE's announcement of complete clinical response for ECUR-506
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