AAV gene transfer halts disease progression in clinicallly affected sheep with CLN5 Batten disease

Abstract

The lysosomal storage diseases, the neuronal ceroid lipofuscinoses (NCLs; Batten disease) are the most common degenerative brain diseases in childhood. At least 13 different causal genes have been implicated (designated CLN1-8, 10-14). Despite this genetic diversity, the NCLs are defined by similar pathological and clinical features, namely the near-ubiquitous accumulation of lysosome-derived storage bodies, progressive neuronal loss and retinal degeneration, seizures and psychomotor decline culminating in premature death. Currently there are no effective treatments however encouraging translational studies in animal models, including sheep, have resulted in several gene therapy and enzyme replacement clinical trials now underway. Sheep with naturally occurring CLN5 disease are ideal candidates for testing gene therapies. Their gyrencephalic brains are similar in physical organisation to human brains and in size to non-human primates thus they provide good surrogates for estimating the dose requirements and vector distribution for humans. Additionally CLN5 affected (CLN5-/-) sheep share the main neuropathological features of the human disease. We have previously shown that the single intracranial administration of an AAV9 vector encoding ovine CLN5 into 3 month old pre-symptomatic CLN5-/- sheep provided protection against stereotypical disease, the only clinical sign being a much delayed-onset loss of vision. Whilst therapeutic intervention at the earliest possible time is desirable, the diagnosis of NCL in humans normally follows clinical presentation and can be prolonged. Here, in a more clinically relevant setting, 7 month old CLN5-/-sheep with established disease symptoms and overt neurodegenerative changes received similar corrective gene therapy. Monthly clinical assessments and maze tests showed that the treatment halted any further decline in motor, neurological or behavioural capability over the next 14 months. Although treated sheep lost their vision, they remain healthy in the field at 21 months of age. In contrast, untreated CLN5-/- sheep developed advanced disease symptoms, with manifest seizure activity, and did not survive beyond 21 months. Longitudinal computed tomography (CT) scans indicated little further post-injection brain atrophy in the treated sheep. Monitoring of these sheep continues, to determine if there are any signs of late-onset disease and to see if another dose of gene therapy may be warranted. Together, these data in both pre- and post-symptomatic sheep provide a strong rationale for clinical translation to CLN5 affected human patients