Adeno-associated virus (AAV)-based therapies have shown some of the greatest potential, with low immunogenicity and toxicity, persistent gene expression, and favorable tropism patterns 20. Recently, gene therapy has shown promise for treating a variety of genetic disorders, including the NCLs.
Various small molecule treatments have shown some efficacy in animal models of CLN8 disease 17- 19, yet none have been adopted in the clinic, resulting in an unmet need to halt or reverse disease progression. Phenotypic severity varies from milder forms, such as the “Northern Epilepsy” caused by missense mutations in the Finnish population 12, to more severe forms caused by different sets of mutations, including null alleles 15, 16. Visual deficits or blindness can develop throughout the disease course 7- 12, or not at all 12- 14. Mutations in CLN8 can lead to an aggressive form of variant late infantile NCL in human patients that typically presents in childhood with myoclonus, tonic-clonic seizures, and progressive motor decline and dementia. In the absence of CLN8, lysosomal enzymes are depleted, leading to classic NCL CNS pathology including ASM accumulation, glial activation, and neurodegeneration throughout the CNS 6.
Recently, CLN8, a transmembrane endoplasmic reticulum (ER) protein, was shown to regulate the ER to Golgi trafficking of catabolic enzymes destined for the lysosome 5. Some CLN genes encode soluble lysosomal enzymes and are thus linked directly to lysosomal activity (CLN1, CLN2, CLN10, CLN13), while others have more elusive function 1. All forms of NCL are progressive, most are fatal, and none yet have a cure 1.Īt the cellular level, NCLs are characterized by the lysosomal accumulation of autofluorescent storage material (ASM) consisting of lipid-based lipofuscin and other waste products 4.
Patients typically present with CNS-related symptoms including mental and motor deficits, blindness, and epilepsy in the first decade of life, with variable symptomatology, onset, and progression depending on the genetic subtype. The neuronal ceroid lipofuscinoses (NCLs, also known as Batten Disease) are a phenotypically similar group of rare lysosomal storage disorders caused by mutations in one of at least 13 identified ceroid-lipofuscinosis neuronal (CLN)-related genes 1, and are collectively the most prevalent neurodegenerative disease in children (incidence 2-4/100,000 births) 2, 3. These results demonstrate, by far, the most successful rescue reported in an animal model of CLN8 disease, and supports gene therapy as a promising therapeutic strategy for this disorder. A single neonatal injection was safe and well-tolerated, resulting in robust transgene expression throughout the brain and spinal cord from 4 to 24 months, reducing histopathological and behavioral hallmarks of the disease and completely restoring lifespan from 10 months in untreated animals to beyond 24 months of age in treated animals. Using a mouse model of CLN8 disease, we tested the safety and efficacy of an intracerebroventricularly (ICV)-delivered self-complementary AAV9 (scAAV9) gene therapy vector driving expression of human CLN8. There are currently no treatments that can cure the disease or substantially slow disease progression. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with many cases resulting in premature death early in life.
CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes.
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