Abstract
Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8– /– mice at P7–P10 or P120 with high or low dose led to clear age- and dose-dependent effects. A high dose of AAV9/MFSD8 at P7–P10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median life span, and extended normal body weight gain. In vivo safety studies in rodents concluded that intrathecal administration of AAV9/MFSD8 was safe and well tolerated. In summary, these results demonstrated that the AAV9/MFSD8 vector is both effective and safe in preclinical models.
Highlights
The variant late infantile neuronal ceroid lipofuscinosis type 7 disease is a lysosomal storage disease (LSD) caused by a mutation in the gene named major facilitator superfamily domain containing 8 (MFSD8)
To determine whether adenoassociated viral (AAV)-mediated expression of WT MFSD8 could rescue the function of the lysosomal system in fibroblasts from ceroid lipofuscinosis type 7 (CLN7) patient, we created a self-complementaryAAV2/MFSD8 vector, which is packaged with an expression cassette comprising a mutant AAV2 inverted terminal repeat (ITR) with the D element deleted (Δ ITR), the low expressing JeT promoter [30, 39], the human MFSD8 codon-optimized coding sequence, simian virus 40 polyadenylation (SV40pA) signal, and WT AAV2 ITR (Figure 1A)
Efficacy with associated viral vector type 9 (AAV9) has been demonstrated in multiple Batten diseases including CLN3, CLN6, and CLN8 using other routes of administration [48,49,50]
Summary
The variant late infantile neuronal ceroid lipofuscinosis type 7 (vLINCL7 or CLN7) disease is a lysosomal storage disease (LSD) caused by a mutation in the gene named major facilitator superfamily domain containing 8 (MFSD8). The genetic mutations in the MFSD8 gene resulting in CLN7 disease are well documented and the MFSD8 protein is a member of the major facilitator superfamily (MFS), the function, nature of metabolite(s) transported by MFSD8 protein [3], and disease mechanisms of this progressive neurodegenerative disease are unknown. Loss of vision from progressive degeneration of the retina and neuroinflammation in the cerebellar and cerebral cortical regions of human patients are key features of the disease. Defective lysosomal function and dysregulation of autophagy have been suggested as potential contributors to the neurodegenerative mechanism of CLN7 disease [5, 6]
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