Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease

Abstract

CLN5 neuronal ceroid lipofuscinosis (NCL, Batten disease) is a rare, inherited fatal neurodegenerative disorder caused by mutations in the CLN5 gene. The disease is characterised by progressive neuronal loss, blindness, and premature death. There is no cure. This study evaluated the efficacy of intracerebroventricular (ICV) delivery of an adeno-associated viral vector encoding ovine CLN5 (scAAV9/oCLN5) in a naturally occurring sheep model of CLN5 disease. CLN5 affected (CLN5−/−) sheep received low, moderate, or high doses of scAAV9/oCLN5 at three disease stages. The treatment delayed disease progression, extended survival and slowed stereotypical brain atrophy in most animals. Of note, one high dose treated animal only developed mild disease symptomology and survived to 60.1 months of age, triple the natural life expectancy of an untreated CLN5−/− sheep. Eyesight was not preserved at any administration age or dosage. Histopathologic examination revealed that greater transduction efficiency was achieved through higher ICV doses, and this resulted in greater amelioration of disease pathology. Together with other pre-clinical data from CLN5−/− sheep, the safety and efficacy data from these investigational new drug (IND)-enabling studies supported the initiation of the first in-human CLN5 gene therapy clinical study using the ICV delivery route for the treatment of CLN5 NCL.Clinical Trial Registration:https://clinicaltrials.gov/, identifier NCT05228145

Efficacy of dual intracerebroventricular and intravitreal CLN5 gene therapy in sheep prompts the first clinical trial to treat CLN5 Batten disease

“…Previous studies have shown that delivery of CLN5 gene therapy to the CLN5 −/− sheep brain via ICV administration alone is sufficient to halt or slow disease onset and progression, intracranial volume loss, and ameliorate disease pathology ( Mitchell et al, 2018 ; Mitchell et al, 2023a ). The results of this study indicate a dose-dependent transduction efficiency and correlated improved efficacy with the high ICV dose in the early and advanced symptomatic sheep as compared with the moderate dose evaluated in the pre-symptomatic animals.…”

“…Immunohistochemical analyses of CNS tissues demonstrated far fewer CLN5-positive cells in the pre-symptomatic treated cohort, reflecting their lesser ICV dose. Previous attempts at a moderate dose ICV delivery (2.4 × 10 11 vg) in 9-month-old CLN5 −/− sheep with advanced disease symptoms resulted in only one animal responding favorably ( Mitchell et al, 2023a ). In the current study, however, a higher dose was administered to symptomatic sheep, and all three of the early symptomatic treated sheep and two of the three advanced symptomatic treated sheep were clinically stable at 24 months of age.…”

“…The first of two IND-enabling studies in CLN5 −/− sheep demonstrated the long-term safety and efficacy of ICV scAAV9/oCLN5 gene therapy when delivered at pre-symptomatic, early symptomatic, and more advanced symptomatic disease stages ( Mitchell et al, 2023a ). Here, the second study demonstrated proof-of-concept for the dual ICV/IVT delivery route.…”

“…Development of neurological CLN5 disease was delayed; however, although vision failure was delayed compared with untreated CLN5 sheep, the treated sheep still ultimately went blind. Furthermore, disease progression and brain atrophy were attenuated in sheep with early-stage or even advanced-stage disease treated with ICV delivery of recombinant self-complementary AAV9 vectors expressing codon-optimized ovine CLN5 (scAAV9/oCLN5) ( Mitchell et al, 2018 ) ( Mitchell et al, 2023a , manuscript co-submitted). In a separate study, intravitreal (IVT) administration of the same gene therapy vector ameliorated retinal function and structure in the treated eyes while the untreated eyes showed stereotypical loss of function and disease-associated pathology ( Murray et al, 2021 ).…”

“…Therefore, the effect of combined ICV and IVT scAAV9/oCLN5 administration was assessed at three previously identified disease stages–pre-symptomatic (3 months of age), early symptomatic (6 months of age), and advanced symptomatic (9 months of age) ( Mitchell et al, 2023b ). All sheep received the same IVT dose and pre-symptomatic sheep received the previously efficacious ICV dose ( Mitchell et al, 2023a ). Higher ICV doses were delivered to early and advanced symptomatic sheep in an effort to maximize efficacy.…”