AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease

Marco A. Passini; Shannon L. Macauley; Michael R. Huff; Tatyana V. Taksir; Jie Bu; I. Huan Wu; Peter A. Piepenhagen; James C. Dodge; Lamya S. Shihabuddin; Catherine R. O'Riordan; Edward H. Schuchman; Gregory R. Stewart

doi:10.1016/j.ymthe.2005.01.011

AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease

Marco A. Passini
, Shannon L. Macauley
, Michael R. Huff
, Tatyana V. Taksir
, Jie Bu
, I. Huan Wu
, Peter A. Piepenhagen
, James C. Dodge
, Lamya S. Shihabuddin
, Catherine R. O'Riordan
, Edward H. Schuchman
, Gregory R. Stewart

Research output: Contribution to journal › Article › peer-review

86 Scopus citations

Abstract

Niemann-Pick A disease (NPA) is a fatal lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. The lack of functional ASM results in cellular accumulation of sphingomyelin and cholesterol within distended lysosomes throughout the brain. In this study, we investigated the potential of AAV-mediated expression of ASM to correct the brain pathology in an ASM knockout (ASMKO) mouse model of NPA. An AAV serotype 2 vector encoding human ASM (AAV2-hASM) was injected directly into the adult ASMKO hippocampus of one hemisphere. This resulted in expression of human ASM in all major cell layers of the ipsilateral hippocampus for at least 15 weeks postinjection. Transduced cells were also present in the entorhinal cortex, medial septum, and contralateral hippocampus in a pattern consistent with retrograde axonal transport of AAV2. There was a substantial reduction of distended lysosomes and an almost complete reversal of cholesterol accumulation in all areas of the brain that were targeted by AAV2-hASM. These findings show that the ASMKO brain is responsive to ASM replacement and that retrograde transport of AAV2 functions as a platform for widespread gene delivery and reversal of pathology in affected brain.

Original language	English
Pages (from-to)	754-762
Number of pages	9
Journal	Molecular Therapy
Volume	11
Issue number	5
DOIs	https://doi.org/10.1016/j.ymthe.2005.01.011
State	Published - May 2005

Bibliographical note

Funding Information:
We thank Nelson Yew (Genzyme), Denise Griffiths (Genzyme), Louise Janes (Genzyme), Trent Richardson (Genzyme), Leah Curtin (Genzyme), and Antoneta Radu (Children’s Hospital of Philadelphia) for assistance and Seng Cheng (Genzyme) and Richard Sidman (Harvard University) for critically reading the manuscript. We gratefully acknowledge NIH Grant R01 HD 28607 to E.H.S.

Funding

We thank Nelson Yew (Genzyme), Denise Griffiths (Genzyme), Louise Janes (Genzyme), Trent Richardson (Genzyme), Leah Curtin (Genzyme), and Antoneta Radu (Children’s Hospital of Philadelphia) for assistance and Seng Cheng (Genzyme) and Richard Sidman (Harvard University) for critically reading the manuscript. We gratefully acknowledge NIH Grant R01 HD 28607 to E.H.S.

Funders	Funder number
National Institutes of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health and Human Development	R01HD028607

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

AAV
ASMKO
Acid sphingomyelinase
Adeno-associated virus
Axonal transport
CNS
Cholesterol
Gene therapy
Lysosomal storage disease
Neurodegeneration

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

Access to Document

10.1016/j.ymthe.2005.01.011

Cite this

@article{49e27b9337ed495abca313ee0589d982,

title = "AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease",

abstract = "Niemann-Pick A disease (NPA) is a fatal lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. The lack of functional ASM results in cellular accumulation of sphingomyelin and cholesterol within distended lysosomes throughout the brain. In this study, we investigated the potential of AAV-mediated expression of ASM to correct the brain pathology in an ASM knockout (ASMKO) mouse model of NPA. An AAV serotype 2 vector encoding human ASM (AAV2-hASM) was injected directly into the adult ASMKO hippocampus of one hemisphere. This resulted in expression of human ASM in all major cell layers of the ipsilateral hippocampus for at least 15 weeks postinjection. Transduced cells were also present in the entorhinal cortex, medial septum, and contralateral hippocampus in a pattern consistent with retrograde axonal transport of AAV2. There was a substantial reduction of distended lysosomes and an almost complete reversal of cholesterol accumulation in all areas of the brain that were targeted by AAV2-hASM. These findings show that the ASMKO brain is responsive to ASM replacement and that retrograde transport of AAV2 functions as a platform for widespread gene delivery and reversal of pathology in affected brain.",

keywords = "AAV, ASMKO, Acid sphingomyelinase, Adeno-associated virus, Axonal transport, CNS, Cholesterol, Gene therapy, Lysosomal storage disease, Neurodegeneration",

author = "Passini, \{Marco A.\} and Macauley, \{Shannon L.\} and Huff, \{Michael R.\} and Taksir, \{Tatyana V.\} and Jie Bu and Wu, \{I. Huan\} and Piepenhagen, \{Peter A.\} and Dodge, \{James C.\} and Shihabuddin, \{Lamya S.\} and O'Riordan, \{Catherine R.\} and Schuchman, \{Edward H.\} and Stewart, \{Gregory R.\}",

note = "Funding Information: We thank Nelson Yew (Genzyme), Denise Griffiths (Genzyme), Louise Janes (Genzyme), Trent Richardson (Genzyme), Leah Curtin (Genzyme), and Antoneta Radu (Children{\textquoteright}s Hospital of Philadelphia) for assistance and Seng Cheng (Genzyme) and Richard Sidman (Harvard University) for critically reading the manuscript. We gratefully acknowledge NIH Grant R01 HD 28607 to E.H.S.",

year = "2005",

month = may,

doi = "10.1016/j.ymthe.2005.01.011",

language = "English",

volume = "11",

pages = "754--762",

number = "5",

}

TY - JOUR

T1 - AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease

AU - Passini, Marco A.

AU - Macauley, Shannon L.

AU - Huff, Michael R.

AU - Taksir, Tatyana V.

AU - Bu, Jie

AU - Wu, I. Huan

AU - Piepenhagen, Peter A.

AU - Dodge, James C.

AU - Shihabuddin, Lamya S.

AU - O'Riordan, Catherine R.

AU - Schuchman, Edward H.

AU - Stewart, Gregory R.

N1 - Funding Information: We thank Nelson Yew (Genzyme), Denise Griffiths (Genzyme), Louise Janes (Genzyme), Trent Richardson (Genzyme), Leah Curtin (Genzyme), and Antoneta Radu (Children’s Hospital of Philadelphia) for assistance and Seng Cheng (Genzyme) and Richard Sidman (Harvard University) for critically reading the manuscript. We gratefully acknowledge NIH Grant R01 HD 28607 to E.H.S.

PY - 2005/5

Y1 - 2005/5

N2 - Niemann-Pick A disease (NPA) is a fatal lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. The lack of functional ASM results in cellular accumulation of sphingomyelin and cholesterol within distended lysosomes throughout the brain. In this study, we investigated the potential of AAV-mediated expression of ASM to correct the brain pathology in an ASM knockout (ASMKO) mouse model of NPA. An AAV serotype 2 vector encoding human ASM (AAV2-hASM) was injected directly into the adult ASMKO hippocampus of one hemisphere. This resulted in expression of human ASM in all major cell layers of the ipsilateral hippocampus for at least 15 weeks postinjection. Transduced cells were also present in the entorhinal cortex, medial septum, and contralateral hippocampus in a pattern consistent with retrograde axonal transport of AAV2. There was a substantial reduction of distended lysosomes and an almost complete reversal of cholesterol accumulation in all areas of the brain that were targeted by AAV2-hASM. These findings show that the ASMKO brain is responsive to ASM replacement and that retrograde transport of AAV2 functions as a platform for widespread gene delivery and reversal of pathology in affected brain.

AB - Niemann-Pick A disease (NPA) is a fatal lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. The lack of functional ASM results in cellular accumulation of sphingomyelin and cholesterol within distended lysosomes throughout the brain. In this study, we investigated the potential of AAV-mediated expression of ASM to correct the brain pathology in an ASM knockout (ASMKO) mouse model of NPA. An AAV serotype 2 vector encoding human ASM (AAV2-hASM) was injected directly into the adult ASMKO hippocampus of one hemisphere. This resulted in expression of human ASM in all major cell layers of the ipsilateral hippocampus for at least 15 weeks postinjection. Transduced cells were also present in the entorhinal cortex, medial septum, and contralateral hippocampus in a pattern consistent with retrograde axonal transport of AAV2. There was a substantial reduction of distended lysosomes and an almost complete reversal of cholesterol accumulation in all areas of the brain that were targeted by AAV2-hASM. These findings show that the ASMKO brain is responsive to ASM replacement and that retrograde transport of AAV2 functions as a platform for widespread gene delivery and reversal of pathology in affected brain.

KW - AAV

KW - ASMKO

KW - Acid sphingomyelinase

KW - Adeno-associated virus

KW - Axonal transport

KW - CNS

KW - Cholesterol

KW - Gene therapy

KW - Lysosomal storage disease

KW - Neurodegeneration

UR - https://www.scopus.com/pages/publications/20244383300

UR - https://www.scopus.com/pages/publications/20244383300#tab=citedBy

U2 - 10.1016/j.ymthe.2005.01.011

DO - 10.1016/j.ymthe.2005.01.011

M3 - Article

C2 - 15851014

AN - SCOPUS:20244383300

SN - 1525-0016

VL - 11

SP - 754

EP - 762

JO - Molecular Therapy

JF - Molecular Therapy

IS - 5

ER -

AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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