First AAV gene therapy trial for type 1 diabetes to begin this year

The first-ever clinical trial of an adeno-associated virus (AAV) gene therapy for type 1 diabetes will begin this year, aiming to promote insulin production in muscles. The PROGRESS study will enrol adults with type 1 diabetes to receive a one-time intramuscular injection of KRIYA-839 and will follow them for one year for both safety and efficacy endpoints.

KRIYA-839 is designed to promote endogenous expression of glucokinase (GCK) and insulin in the quadriceps muscles. The therapy uses the non-pathologic AAV vector to deliver two genes, for GCK and insulin, into muscle, where the genes then remain in the nuclei of the cells to produce genetic material for the life of the patient. It does not integrate with the host genome and is not gene editing or changing genetic make-up.

Pre-clinical data demonstrated efficacy and safety of both gene products in normalising blood glucose levels in mouse and dog models of type 1 diabetes without immune suppression for up to four years. Advantages of AAV gene therapy include durable clinical benefit, single administration, no need for chronic immunosuppression, and broad patient eligibility.

In this approach, the two genes within the AAV are delivered into the thigh muscle, where the cells are not actively dividing. The muscle then secretes insulin, which activates glucose transporter type 4 to bring glucose into the cells. GCK is activated at higher glucose levels to move glucose out of the bloodstream, while remaining inactive when blood glucose levels are low.

Treatment administration would require a short course of immune modulation around the response to the virus capsid. Delivery would probably require several intramuscular injections, likely in both legs, over about 30-60 minutes during one outpatient clinic visit. After that, it takes two to three months to get to a steady state.

The planned 52-week phase 1 dose escalation study will enrol patients with type 1 diabetes who have A1c levels above 7% while using automated insulin delivery systems. That requirement is intended to ensure that insulin dosing can be precisely quantified and de-escalated as needed. If successful, people who use multiple daily injections would also be eligible.

Unlike current transplants of either cadaver or stem-cell derived islets that require immune suppression and are therefore limited to those with severe hypoglycaemia or recurrent diabetic ketoacidosis, this therapy could potentially be for broader use in type 1 diabetes. A conference speaker said he would not use the word cure just yet, but added that if the approach were able to achieve more than 70% of time in tight range, 70-140 mg/dL, possibly in combination with technology, then it could represent a functional cure.