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Rescue of lysosomal acid lipase deficiency in mice by AAV liver gene transfer

ABSTRACT: Rescue of lysosomal acid lipase deficiency in mice by AAV liver gene transfer

PROVIDER: PRJNA1062373 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27464865_1.fastq.gz	Fastqsanger.gz
	SRR27464865_2.fastq.gz	Fastqsanger.gz
	SRR27464866_1.fastq.gz	Fastqsanger.gz
	SRR27464866_2.fastq.gz	Fastqsanger.gz
	SRR27464867_1.fastq.gz	Fastqsanger.gz

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Rescue of lysosomal acid lipase deficiency in mice by AAV liver gene transfer

Project description:Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder caused by mutation in LIPA gene, which results in fat accumulation in liver and spleen leading to multi-organ failure. The severe form of LAL-D (infantile-onset; ≤5% residual LAL activity), if left untreated, results in premature death within the first year of life due to failure to thrive and hepatic insufficiency. Enzyme replacement therapy is the only available supportive treatment consisting in weekly systemic injection of recombinant LAL. Here, we characterize a novel LAL-D mouse model and develop a curative gene therapy treatment based on the in vivo administration of recombinant AAV8 (rAAV8) vector encoding for human LIPA transgene under the control of hepatocyte-specific promoter. We define the minimal AAV dose required to rescue disease lethality and to produce and secrete sufficient LAL to correct cholesterol and triglycerides accumulation in liver, spleen, blood cells and plasma. Finally, using liver transcriptomic and biochemical analysis, we also show the impairment of mitochondria associated with LAL-D and its recovery by gene therapy. Overall, our in vivo gene therapy strategy achieves stable long-term LAL expression to correct disease phenotype in LAL-D mouse model and opens a new therapeutic option for LAL-D patients.

2024-06-01 | GSE252742 | GEO

Gene profile of Myeloid derived Suppressive Cells from the Bone Marrow of Lysosomal Acid Lipase Knock-out Mice

Project description:Expression profile of MDSC isolated from Bone marrow of lysosomal acid Lipase mice compared to the WT counterpart four samples

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Gene profile of Myeloid derived Suppressive Cells from the Bone Marrow of Lysosomal Acid Lipase Knock-out Mice

Project description:Expression profile of MDSC isolated from Bone marrow of lysosomal acid Lipase mice compared to the WT counterpart

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Triple vectors expand AAV transfer capacity in the retina

Project description:Maddalena et al. showed that the limited DNA transfer capacity (~4.7kb) of adeno associated viral (AAV) vectors can be expanded up to 14kb with triple AAV vectors for the efficient expression of the therapeutic CDH23 (10.1kb) and ALMS1 (12.5kb) genes.

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ANGPTL4 suppress clear cell renal cell carcinoma via inhibition lysosomal acid lipase

Project description:Renal cell carcinoma (RCC), the most common form of kidney cancer, is a heterogeneous disease with clear cell RCC (ccRCC) being the most prevalent and aggressive subtype. While most ccRCC tumors have elevated expression of angiopoietin-like 4 (ANGPTL4), in our study we identified a significant subset of patients whose cancers show no increase in ANGPTL4 expression. These patients have a worse prognosis compared to the patients with high expression of ANGPTL4. These ANGPTL4-low cancers are characterized by the increased frequency of wild-type Von Hippel-Lindau (wt VHL), a gene that is commonly mutated in ccRCC, and an enrichment for genes associated with lipid metabolism. Using RCC tumor models with wild type VHL, we demonstrate that ANGPTL4 behaves as a tumor suppressor. The loss of ANGPTL4 in ccRCC cell lines results in increased tumor growth and colony formation in a lysosomal acid lipase (LAL)-dependent manner, a phenotype rescued by the expression of N-terminus ANGPTL4. At the mechanistic level, the loss of ANGPTL4 increases lysosomal acid lipase activity in ccRCC cells. This data suggests that ANGPTL4 enacts its tumor-suppressive effects in ccRCC by regulating LAL activity. Importantly, the identified patient cohort with low ANGPTL4 expression may exhibit increased reliance on lipid metabolism, which can be a point of target for future therapy.

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Project description:Pompe disease is a neuromuscular disorder caused by mutations in the gene encoding for the lysosomal enzyme acid α-glucosidase (GAA). GAA converts lysosomal glycogen to glucose, and its deficiency leads to pathologic glycogen accumulation. Enzyme replacement therapy (ERT) is the only available treatment for Pompe disease at the moment with several shortcomings. We have shown that liver expression of secGAA has better therapeutic efficacy than non-engineered GAA after long-term treatment of four months old Gaa-/- mice with low vector doses. Based on those results, we have treated severely affected nine months old Gaa-/- mice with the AAV-secGAA vector and followed the animals for nine months thereafter. At the end of the study, AAV-treated Gaa-/- mice showed complete rescue of the Pompe phenotype. Transcriptomic profiling of skeletal muscle highlighted mitochondrial bioenergetics defects, supported by electron microscopy, western blotting and biochemical findings, which were partially corrected after AAV treatment. Together, these results provide insight into the reversibility of advanced Pompe disease in the Gaa-/- mouse model via liver gene transfer of secGAA.

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2022-05-21 | GSE203250 | GEO

Gene expression profile of brain tissue from wildtype and GRN knock-out mice treated with an AAV driving expression of PTV-Progranulin in the liver

Project description:PGRN is involved in lysosomal function and is expressed in the brain. Grn knock-out (KO) mice develop several pathologies including lysosomal lipi accumulation, gliosis and neurodegeneration. Here we seek to determine if we can rescue Grn KO pathologies with a peripherally delivered AAV, that targets the liver, and drives expression of full length PGRN fused to a mouse TfR binding scFv (AAV(L):bPGRN. The PGRN fusion protein expressed by this AAV (8D3:PGRN), is brain penetrant. To study this, Grn KO mice were given a single IV injection of either saline or AAV(L):bPGRN at 4 months of age. After 8 months when the mice were 12 months of age, brain samples were collected and bulk RNA sequencing was performed to assess correction of transcriptional changes. Grn wild type (WT) mice treated with saline were also included as a control.

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