CNS Gene Therapy for CLN2 Disease Using Parallel Multiple Routes of Administration

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Abstract. In partnership with the Crystal laboratory, Weill Cornell, LEXEO is developing an adeno-associ- ated virus (AAV)-based gene therapy to treat the central nervous system (CNS) manifestations of CLN2 (Batten) disease, a fatal, childhood autosomal recessive neurodegenerative lysosomal storage disorder caused by mutations in the CLN2 gene, coding for a lysosomal enzyme, tripeptidyl peptidase 1 (TPP-I). The loss of TPP-I activity leads to accumulation of storage material in lysosomes and resultant neuronal cell death with progressive neurodegeneration. Genotype/phenotype comparisons suggest that the severe phenotype should be ameliorated with increase of CNS TPP-I levels to 5 to 10% of normal. This possibly can be achieved using an AAV vector efficient in transferring genes to the CNS, mediating persistent ex- pression of TPP-I, a secreted protein capable of cross-correcting neighboring cells via uptake by the man- nose-6-phosphate receptor. However, since the CNS manifestations of CLN2 disease are throughout the brain, it is essential that the therapy mediates wide distribution in the CNS. Based on efficacy studies in CLN2-/- mice, and CNS biodistribution and safety studies in nonhuman primates, the Crystal laboratory carried out a phase 1 clinical trial with the AAV serotype rh.10 expressing the normal human CLN2 coding sequence (AAVrh.10hCLN2, LEX08) to treat children with CLN2 disease. CNS intraparenchymal (IP) LEX08 therapy met the 1° endpoint of significantly slowing the clinical progression of neurologic decline, with 42.4 - 47.5% % reduction in the quantitative assessment of the rate of decline of motor + language function compared to 2 different untreated natural history control cohorts. However, while IP administration of LEX08 significantly slowed the progression of the disease, it did not completely halt progression, sug- gesting that the IP route may not be sufficient to distribute the vector and/or the vector TPP-I product throughout the CNS. The focus of the phase I STTR is to assess whether parallel administration via multi- ple routes of delivery of LEX08 to the CNS will achieve broader distribution of TPP-I, resulting in an effec- tive therapy that more completely halts progression of the disease. Aim 1. To assess the hypothesis that by using 3 parallel routes of administration, intraparenchymal + intracisternal + intracerebroventricular, the vector-derived TPP-I product will be distributed throughout the CNS of nonhuman primates with resulting TPP-I enzyme activity greater than two standard deviations above background in >2 fold of the % CNS by the intraparenchymal route alone. The proposed studies in nonhuman primates will include assessment at 8 wk of CNS biodistribution of LEX08 DNA, mRNA and TPP-I enzyme activity throughout the CNS. As- suming the multi-route strategy provides significantly broader distribution than that of the IP route alone, LEXEO will apply for a phase II STTR for a pre-IND meeting with the FDA, GMP production of LEX08, for- mal toxicology studies, and revision of the current IND.