Adeno-associated viral vector serotype 9–based gene therapy for Niemann-Pick disease type A

Samaranch, Lluı́s; Pérez-Cañamás, Azucena; Soto-Huelin, Beatriz; Sudhakar, Vivek; Jurado‐Arjona, Jerónimo; Hadaczek, Piotr; Ávila, Jesús; Bringas, John; Casas, Josefina; Chen, Haifeng; He, Xingxing; Schuchman, Edward H.; Cheng, Seng H.; Forsayeth, John; Bankiewicz, Krystof S.; Ledesma, María Dolores

doi:10.1126/scitranslmed.aat3738

Cited by 38 publications

(30 citation statements)

References 51 publications

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“…The development of enzyme replacement therapy with ASM (in clinical trial, [92]) and gene therapies could be helpful for the treatment of type B patients. Recently, Samaranch et al published a successful study of the treatment of animal models of Niemann-Pick disease type A by adeno-associated viral vector serotype 9-based gene therapy [93].…”

Section: Niemann-pick Disease Type a And Bmentioning

confidence: 99%

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

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Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

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Section: Niemann-pick Disease Type a And Bmentioning

confidence: 99%

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

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“…eye, 13 cardiac muscles 14 ), treatment of hemophilia, 15 neurodegenerative diseases 16 and cystic fibrosis. 17 Unfortunately, therapies in clinical studies have faced serious setbacks through side effects such as serious liver injuries.…”

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confidence: 99%

Materials promoting viral gene delivery

Kaygisiz

Synatschke

2020

Biomater. Sci.

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“…Intracisterna magna (ICM) injection is reported to induce a broad distribution. 29 The distribution is considered to be better than that after intracerebroventricle (ICV) or lumbar puncture injection. [30][31][32] To achieve further distribution than ICV injection alone, 21 we combined ICM and ICV injection.…”

Section: Discussionmentioning

confidence: 99%

Gene Therapy in a Mouse Model of Niemann–Pick Disease Type C1

et al. 2021

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Niemann-Pick disease type C1 (NPC1) is a fatal congenital neurodegenerative disorder caused by mutations in the NPC1 gene, which is involved in cholesterol transport in lysosomes. Broad clinical manifestations of NPC1 include liver failure, pulmonary disorder, neurological deficits, and psychiatric symptoms. The main cause of death in NPC1 patients involves central nervous system (CNS) dysfunction; there is no essential treatment. We generated a tyrosine-mutant adeno-associated virus (AAV) 9/3 vector that expresses human NPC1 under a cytomegalovirus (CMV) promoter (AAV-CMV-hNPC1) and injected it into the left lateral ventricle (5 lL) and cisterna magna (10 lL) of Npc1 homo-knockout (Npc1 -/-) mice. Each mouse received total 1.35 • 10 11 vector genome on days 4 or 5 of life. AAV-treated Npc1 -/mice (n = 11) had an average survival of >28 weeks, while all saline-treated Npc1 -/mice (n = 11) and untreated Npc1 -/mice (n = 6) died within 16 weeks. Saline-treated and untreated Npc1 -/mice lost body weight from 7 weeks until death. However, the average body weight of AAV-treated Npc1 -/mice increased until 15 weeks. AAV-treated Npc1 -/mice also showed a significant improvement in the rotarod test performance. A pathological analysis at 11 weeks showed that cerebellar Purkinje cells were preserved in AAV-treated Npc1 -/mice. In contrast, untreated Npc1 -/mice showed an almost total loss of cerebellar Purkinje cells. Combined injection into both the lateral ventricle and cisterna magna achieved broader delivery of the vector to the CNS, leading to better outcomes than noted in previous reports, with injection into the lateral ventricles or veins alone. In AAV-treated Npc1 -/mice, vector genome DNA was detected widely in the CNS and liver. Human NPC1 RNA was detected in the brain, liver, lung, and heart. Accumulated unesterified cholesterol in the liver was reduced in the AAV-treated Npc1 -/mice. Our results suggest the feasibility of gene therapy for patients with NPC1.

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Adeno-associated viral vector serotype 9–based gene therapy for Niemann-Pick disease type A

Cited by 38 publications

References 51 publications

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Materials promoting viral gene delivery

Gene Therapy in a Mouse Model of Niemann–Pick Disease Type C1

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