AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann–Pick type C1 disease

Hughes, Michael P.; Smith, Dave; Morris, Lauren; Fletcher, Claire; Colaço, Alexandria; Huebecker, Mylene; Tordo, Julie; Palomar, Nuria; Massaro, Giulia; Henckaerts, Els; Waddington, Simon N.; Platt, Frances M.; Rahim, Afidah Abdul

doi:10.1093/hmg/ddy212

Cited by 55 publications

(44 citation statements)

References 46 publications

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“…The standard approach to gene therapy of the brain is the use of adeno-associated virus (AAV), and certain AAV serotypes, such as AAV9, cross the BBB following IV administration 8 . The use of ssAAV, which has twice the cloning capacity of scAAV 9 , and the development of mini-promoters, allows for the insertion of a large therapeutic gene such as the 3.9 kb NPC1 open reading frame into the AAV genome 22,23,24 . The NPC1 gene with a 227 nucleotide elongation factor-1α (EF1α) promoter was delivered to NPC1 −/− mouse brain with AAV9 following IV administration of high injection doses (ID), 1-2 × 10 14 vg/kg of the virus 22 .…”

Section: Discussionmentioning

confidence: 99%

Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes

Jiang

Lee

Pardridge

2020

Sci Rep

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Niemann-Pick C1 (NPC1) is a lysosomal cholesterol storage disorder, that severely affects the brain, and is caused by mutations in the NPC1 gene, which encodes an intracellular membrane transporter of non-esterified cholesterol. Therapeutic options for NPC1 are few, and classical enzyme replacement therapy with the recombinant protein is not possible as the NPC1 gene product is an insoluble membrane protein, which increases the need for development of gene therapy for NPC1. While viral based gene therapy is under development, it is important to investigate alternative approaches to brain gene therapy without viral vectors. The present work develops a plasmid DNA approach to gene therapy of NPC1 using Trojan horse liposomes (THLs), wherein the plasmid DNA is encapsulated in 100 nm pegylated liposomes, which are targeted to organs with a monoclonal antibody against the mouse transferrin receptor. THLs were encapsulated with a 8.0 kb plasmid DNA encoding the 3.9 kb human NPC1 open reading frame, under the influence of a 1.5 kb platelet derived growth factor B (PDGFB) promoter. THLs were administered weekly beginning at 6-7 weeks in the NPC1 −/− null mouse, and delivery of the plasmid DNA, and NPC1 mRNA expression in brain, spleen, and liver were confirmed by quantitative PCR. THL treatment reduced tissue inclusion bodies in brain, and peripheral organs, but did not prolong lifespan in these mice. The work suggests that early treatment after birth may be required to reverse this disease model with NPC1 gene replacement therapy. Niemann-Pick C1 (NPC1) disease is an inherited lysosomal storage disorder caused by mutations in the gene encoding the NPC1 protein, which is a 200 kDa intracellular membrane transporter of non-esterified cholesterol. Cell cholesterol accumulation leads to intracellular inclusion bodies, which cause neurodegeneration, and hepatosplenomegaly 1. The diseases causes early mortality in most cases, and is associated with dementia, seizures, ataxia, and decreased audition 1. There is no approved therapy for NPC1. New treatments may be tested in the NPC1 null mouse (NPC1 −/−) such as the NPC1 m1N mouse 2,3 , and the systemic administration of large doses of hydroxypropyl beta cyclodextrin (HPβCD) to NPC1 −/− mice prolongs lifespan 4. HPβCD does not cross the blood-brain barrier (BBB) 5 , and HPβCD administration to NPC1 patients uses intrathecal administration via injections into the lumbar cerebrospinal fluid (CSF) 6. However, intrathecal drug delivery to brain only allows for drug exposure at the CSF surface of the brain 7 , and intrathecal HPβCD has not been approved. NPC1 gene therapy with adeno-associated virus (AAV) serotypes, e.g. AAV9, is possible, particularly with selfcomplementary AAV (scAAV), as these serotypes cross the BBB 8. However, the maximal size of the expression cassette that can be inserted in the scAAV is < 2.3 kb 9 , and the size of the NPC1 open reading frame alone is 3.9 kb. Single stranded AAV (ssAAV) traverses the BBB less efficiently 9,10 , but this viral genome will acce...

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Section: Discussionmentioning

confidence: 99%

Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes

Jiang

Lee

Pardridge

2020

Sci Rep

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“…--SRT (Platt et al, 1997) (Sango et al, 1995) + + AAV (Sargeant et al, 2011;Cachon-Gonzalez et al, 2014), BMT (Norflus et al, 1998;Wada et al, 2000), CM (Pelled et al, 2003), Diet (Denny et al, 2010), HSP (Kirkegaard et al, 2016), MIP-1 (Wu and Proia, 2004), SRT (Jeyakumar et al, 1999) HexB ( Npc1 (−/−) (Morris et al, 1977) + -AAV (Chandler et al, 2017b;Xie et al, 2017;Hughes et al, 2018), AI (Alvarez et al, 2008), AO (Fu et al, 2013), CM (Erickson et al, 2000;Repa et al, 2007;Abi-Mosleh et al, 2009;Liu et al, 2010;Taylor et al, 2012;Hovakimyan et al, 2013;Nusca et al, 2014;Tanaka et al, 2014;Soga et al, 2015;Demais et al, 2016), Diet (Jelinek et al, 2015;Soga et al, 2015), HSP (Chung et al, 2016;Kirkegaard et al, 2016), NS (Griffin et al, 2004;Liao et al, 2009), Transplant (Veyron et al, 1996) Npc1 (Otterbach and Stoffel, 1995) + +…”

Section: Metachromatic Leukodystrophymentioning

confidence: 99%

“…The I1061T mutant, which harbors the most common human NPC1 mutation, was generated to specifically study the effects of proteostatic modulation on disease progression. Various preclinical trials including GT, ERT, and transplant in these models have shown different but promising levels of success in prolonging mutant lifespan, reducing Purkinje cell atrophy and the storage phenotype (Veyron et al, 1996;Soga et al, 2015;Chandler et al, 2017b;Xie et al, 2017;Hughes et al, 2018).…”

Section: Metachromatic Leukodystrophy (Mld Omim #250100)mentioning

confidence: 99%

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

Favret

Weinstock

Feltri

et al. 2020

Front. Mol. Biosci.

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There are over 50 lysosomal hydrolase deficiencies, many of which cause neurodegeneration, cognitive decline and death. In recent years, a number of broad innovative therapies have been proposed and investigated for lysosomal storage diseases (LSDs), such as enzyme replacement, substrate reduction, pharmacologic chaperones, stem cell transplantation, and various forms of gene therapy. Murine models that accurately reflect the phenotypes observed in human LSDs are critical for the development, assessment and implementation of novel translational therapies. The goal of this review is to summarize the neurodegenerative murine LSD models available that recapitulate human disease, and the pre-clinical studies previously conducted. We also describe some limitations and difficulties in working with mouse models of neurodegenerative LSDs.

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“…Therefore, the use of in vivo disease models allows investigators to observe and analyze symptomatic manifestation of NDDs alongside with the therapeutic outcomes of their experimental treatment. This also aids in getting a comprehensive insight into the complex interconnection between etiological and symptomatic changes during the progression of NDDs, such as neuronal ceroid lipofuscinosis (NCL or Batten disease) [35], spinal muscular atrophy [101], or Niemann-Pick disease [102], whose development is typically associated with genetic perturbations in multiple genes. Therefore, in contrast to in vitro models, a mouse model of NDD would allow recapitulating onset and progression of the counterpart human disease of a given degree of severity.…”

Section: In Vitro Vs In Vivo Modelsmentioning

confidence: 99%

Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches

Mijanović

Branković

Borovjagin

et al. 2020

Viruses

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Neurodegenerative diseases (NDDs) are most commonly found in adults and remain essentially incurable. Gene therapy using AAV vectors is a rapidly-growing field of experimental medicine that holds promise for the treatment of NDDs. To date, effective delivery of a therapeutic gene into target cells via AAV has been a major obstacle in the field. Ideally, transgenes should be delivered into the target cells specifically and efficiently, while promiscuous or off-target gene delivery should be minimized to avoid toxicity. In the pursuit of an ideal vehicle for NDD gene therapy, a broad variety of vector systems have been explored. Here we specifically outline the advantages of adeno-associated virus (AAV)-based vector systems for NDD therapy application. In contrast to many reviews on NDDs that can be found in the literature, this review is rather focused on AAV vector selection and their testing in experimental and preclinical NDD models. Preclinical and in vitro data reveal the strong potential of AAV for NDD-related diagnostics and therapeutic strategies.

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AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann–Pick type C1 disease

Cited by 55 publications

References 46 publications

Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes

Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches

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