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Encouraging results from achromatopsia gene therapy trials

Achromatopsia is a disorder that affects one in every 30,000 people and is characterized by the partial or total absence of colour vision due to lack of function of cones, one type of retinal cells. Achromatopsia patients have other visual problems such as extreme sensitivity to light (photophobia), uncontrollable and involuntary eye movements (nystagmus) and decreased visual acuity.

Achromatopsia is a genetic disease following a recessive pattern of inheritance. Five achromatopsia genes have been identified (GNAT2, PDE6C, PDE6H, CNGA3, and CNGB3), of these, the most frequently mutated is CNGB3, followed by CNGA3. As of today there is no approved treatment for achromatopsia but recent studies from two biotechnology companies, Meira GTx and AGTC, and research teams from the universities of Tübingen and Munich open very promising scenarios for effective gene therapies.

Therapies are based on a modified virus that provides patients with normal copies of the gene to rescue its missing function. This type of therapy, known as gene addition therapy, is administered only once by subretinal injection.

Meira GTx is conducting two phase 1/2 clinical studies for CNGB3 and CNGA3. Regarding CNGB3, 11 adults and 12 children have been recruited for the gene therapy trial, and patients are currently under follow-up. On the other hand, for the CNGA3 trial, only paediatric patients, aged 3 to 15 years old, are now being enrolled.

The American company AGTC announced in March that it had completed the recruitment of adult patients in its Clarity phase 1/2 clinical studies to evaluate CNGB3 and CNGA3 gene therapies, and the recruitment of paediatric patients is still ongoing.

Although no data has still been published, AGTC reports that the two gene therapies have been well tolerated by all patients, with no substantial adverse effects, and they have also shown the first signs of efficacy in light sensitivity tests.

Finally, researchers from the University Hospital of Tübingen and the Ludwig-Maximilians University of Munich have recently published in the journal JAMA Ophthalmology the results of a phase 1/2 clinical trial promoted by STZ eyetrial of another gene therapy for CNGA3. In this study, 9 adult patients participated (3 in each dose group), between ages 25 and 59. The therapy was administered to the worst affected eye and after 12 months of follow up no substantial tolerability problems were detected in the patients and all of them showed some degree of improvement, both in visual acuity and in contrast sensitivity.

The studies from Meira GTx, AGTC, and STZ eyetrial, are paving the way to have, in the short or medium term, the first approved gene therapies for achromatopsia.

To participate in all gene therapy studies, it is mandatory that patients have an accurate genetic diagnosis. In the case of achromatopsia, this must conclusively indicate that they have biallelic mutations in one of the achromatopsia genes, be it CNGB3 or CNGA3.

Image credit: Stylianos Michalakis. A simulation of an image in the eyes of a person with complete colorblindness (achromatopsia). Source: University Hospital of Tübingen press release.

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