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AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease
Xin Chen, … , Joseph R. Mazzulli, Steven J. Gray
Xin Chen, … , Joseph R. Mazzulli, Steven J. Gray
Published January 13, 2022
Citation Information: J Clin Invest. 2022;132(5):e146286. https://doi.org/10.1172/JCI146286.
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Research Article Neuroscience Article has an altmetric score of 8

AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease

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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.

Authors

Xin Chen, Thomas Dong, Yuhui Hu, Frances C. Shaffo, Nandkishore R. Belur, Joseph R. Mazzulli, Steven J. Gray

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Figure 1

AAV2/MFSD8 vector construct expressing human MFSD8 and its rescue of lysosomal function in primary fibroblasts from a CLN7 patient.

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AAV2/MFSD8 vector construct expressing human MFSD8 and its rescue of lys...
(A) Schematic diagram of AAV2/MFSD8 construct comprising a mutant AAV2 ITR with the D element deleted (ΔITR), the JeT promoter, the human MFSD8 codon-optimized coding sequence (hMFSD8opt), the synthetic polyadenylation SV40pA signal, and WT AAV2 ITR. (B) Lysosomal GCase activity (n = 4–5) was measured in fibroblasts from age-matched healthy control and a CLN7 patient. GCase activity was normalized to the cell volume. (C and D) Lysosomal and total GCase activity (n = 3–5) was measured following AAV2-mediated transduction of JeT-GAN (negative control), JeT-MFSD8 (therapeutic transgene at increasing doses), or UsP-MFSD8 (therapeutic transgene with stronger promotor). The fold differences in lysosomal (C) and total (D) GCase activity were normalized to the cell volume and to cohorts transfected with JeT-GAN. (E and F) MFSD8 mRNA and MFSD8 protein (n = 3–4) were assayed following AAV2-mediated transduction of CBh-GFP (negative control), JeT-MFSD8, or UsP-MFSD8. A ROUT test was used first to remove any outlier. All data in B–F are presented as mean ± SEM, with the scatter plot representing measurements from individual culture wells. Data sets that passed tests for normality or homogeneity of variance were analyzed using unpaired t test or 1-way ANOVA with α set at 0.05 and Dunnett’s correction for relevant pairwise comparisons. Data sets that did not pass tests for normality or homogeneity of variance were analyzed using the Kruskal-Wallis test with α set at 0.05 and Dunn’s correction for relevant pairwise comparisons. **P < 0.01; ****P < 0.0001, compared with control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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