Effective gene therapy in CLN5 Ovine Batten disease

Abstract

Lambs homozygous for a mutation causing CLN5 Batten disease (neuronal ceroid lipofuscinosis, NCL) injected with viral vectors containing the corrective gene showed no signs of disease development a year later, whereas uninjected affected animals declined considerably.

AAV9 and lentiviral derived vectors expressing green fluorescent protein showed widespread expression 30 days after direct injection into the lateral ventricles or parenchyma of sheep with no ill effects. Injection of vectors loaded with the corrective ovine CLN5 sequence into preclinical affected lambs at 2-4 months was followed by monitoring over the next 12 months. In all three tests performed monthly, neurological and eyesight tests, monitoring of their ability to join cohorts by navigating through a maze and estimates of cranial cavity volumes in vivo from CT scans, the injected sheep were indistinguishable from the unaffected controls. Over this time the non-injected affected controls declined markedly and developed obvious clinical symptoms, to the point of being unable to navigate the maze. Monitoring of the injected sheep continues. Similar injections into CLN6 affected sheep were not nearly as effective, only 1/6 showing a difference from non-injected affected controls.