Functional correction of CNS lesions in an MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes

Alessandro Fraldi, Kim Hemsley, Allison Crawley, Alessia Lombardi, Adeline Lau, Leanne Sutherland, Alberto Auricchio, Andrea Ballabio, John J. Hopwood

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Mucopolysaccharidosis type IIIA (MPS-IIIA or Sanfilippo syndrome) is a lysosomal storage disorder caused by the congenital deficiency of sulfamidase (SGSH) enzyme and consequent accumulation of partially degraded heparan sulfate (HS) in lysosomes. The central nervous system (CNS) is the predominant site of tissue damage in MPS-IIIA. Here we describe a gene therapy approach for MPS-IIIA in a mouse model using recombinant adeno-associated virus serotype 5 (AAV2/5) as a vehicle to deliver therapeutic genes to the CNS. SUMF1 (SUlfatase Modifying Factor 1) exhibits an enhancing effect on sulfatase activity when co-expressed with sulfatases. Consistent with these findings, we demonstrated that co-delivery of SUMF1 and SGSH (via an AAV2/5-CMV-SGSH-IRES-SUMF1 vector) resulted in a synergistic increase in SGSH activity, both in primary neural cells and in murine brain. A study aimed at testing the therapeutic efficacy of simultaneous brain administration of SUMF1 and SGSH was then performed by injecting the lateral ventricles of newborn MPS-IIIA/normal mice with either AAV2/5-CMV-SGSH-IRES-SUMF1 or AAV2/ 5-CMV-GFP vectors. Widespread GFP expression was observed within the GFP-injected brain, and a stable and significant increase of SGSH activity was detected in several brain regions following SGSH-IRES-SUMF1 administration. Treatment with AAV2/5-CMV-SGSH-IRES-SUMF1 vectors resulted in a visible reduction in lysosomal storage and inflammatory markers in transduced brain regions. Finally, the MPS-IIIA mice treated with therapeutic genes displayed an improvement in both motor and cognitive functions. Our results suggest that early treatment of CNS lesions by AAV-mediated intraventricular injection of both SGSH and SUMF1 genes may represent a feasible therapy for MPS-IIIA.

LanguageEnglish
Pages2693-2702
Number of pages10
JournalHuman Molecular Genetics
Volume16
Issue number22
DOIs
Publication statusPublished - 15 Nov 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Fraldi, Alessandro ; Hemsley, Kim ; Crawley, Allison ; Lombardi, Alessia ; Lau, Adeline ; Sutherland, Leanne ; Auricchio, Alberto ; Ballabio, Andrea ; Hopwood, John J. / Functional correction of CNS lesions in an MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes. In: Human Molecular Genetics. 2007 ; Vol. 16, No. 22. pp. 2693-2702.
@article{99a02aab692a4419b9b07e9d7c2fa54a,
title = "Functional correction of CNS lesions in an MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes",
abstract = "Mucopolysaccharidosis type IIIA (MPS-IIIA or Sanfilippo syndrome) is a lysosomal storage disorder caused by the congenital deficiency of sulfamidase (SGSH) enzyme and consequent accumulation of partially degraded heparan sulfate (HS) in lysosomes. The central nervous system (CNS) is the predominant site of tissue damage in MPS-IIIA. Here we describe a gene therapy approach for MPS-IIIA in a mouse model using recombinant adeno-associated virus serotype 5 (AAV2/5) as a vehicle to deliver therapeutic genes to the CNS. SUMF1 (SUlfatase Modifying Factor 1) exhibits an enhancing effect on sulfatase activity when co-expressed with sulfatases. Consistent with these findings, we demonstrated that co-delivery of SUMF1 and SGSH (via an AAV2/5-CMV-SGSH-IRES-SUMF1 vector) resulted in a synergistic increase in SGSH activity, both in primary neural cells and in murine brain. A study aimed at testing the therapeutic efficacy of simultaneous brain administration of SUMF1 and SGSH was then performed by injecting the lateral ventricles of newborn MPS-IIIA/normal mice with either AAV2/5-CMV-SGSH-IRES-SUMF1 or AAV2/ 5-CMV-GFP vectors. Widespread GFP expression was observed within the GFP-injected brain, and a stable and significant increase of SGSH activity was detected in several brain regions following SGSH-IRES-SUMF1 administration. Treatment with AAV2/5-CMV-SGSH-IRES-SUMF1 vectors resulted in a visible reduction in lysosomal storage and inflammatory markers in transduced brain regions. Finally, the MPS-IIIA mice treated with therapeutic genes displayed an improvement in both motor and cognitive functions. Our results suggest that early treatment of CNS lesions by AAV-mediated intraventricular injection of both SGSH and SUMF1 genes may represent a feasible therapy for MPS-IIIA.",
author = "Alessandro Fraldi and Kim Hemsley and Allison Crawley and Alessia Lombardi and Adeline Lau and Leanne Sutherland and Alberto Auricchio and Andrea Ballabio and Hopwood, {John J.}",
year = "2007",
month = "11",
day = "15",
doi = "10.1093/hmg/ddm223",
language = "English",
volume = "16",
pages = "2693--2702",
journal = "Human molecular genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "22",

}

Fraldi, A, Hemsley, K, Crawley, A, Lombardi, A, Lau, A, Sutherland, L, Auricchio, A, Ballabio, A & Hopwood, JJ 2007, 'Functional correction of CNS lesions in an MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes', Human Molecular Genetics, vol. 16, no. 22, pp. 2693-2702. https://doi.org/10.1093/hmg/ddm223

Functional correction of CNS lesions in an MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes. / Fraldi, Alessandro; Hemsley, Kim; Crawley, Allison; Lombardi, Alessia; Lau, Adeline; Sutherland, Leanne; Auricchio, Alberto; Ballabio, Andrea; Hopwood, John J.

In: Human Molecular Genetics, Vol. 16, No. 22, 15.11.2007, p. 2693-2702.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Functional correction of CNS lesions in an MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes

AU - Fraldi, Alessandro

AU - Hemsley, Kim

AU - Crawley, Allison

AU - Lombardi, Alessia

AU - Lau, Adeline

AU - Sutherland, Leanne

AU - Auricchio, Alberto

AU - Ballabio, Andrea

AU - Hopwood, John J.

PY - 2007/11/15

Y1 - 2007/11/15

N2 - Mucopolysaccharidosis type IIIA (MPS-IIIA or Sanfilippo syndrome) is a lysosomal storage disorder caused by the congenital deficiency of sulfamidase (SGSH) enzyme and consequent accumulation of partially degraded heparan sulfate (HS) in lysosomes. The central nervous system (CNS) is the predominant site of tissue damage in MPS-IIIA. Here we describe a gene therapy approach for MPS-IIIA in a mouse model using recombinant adeno-associated virus serotype 5 (AAV2/5) as a vehicle to deliver therapeutic genes to the CNS. SUMF1 (SUlfatase Modifying Factor 1) exhibits an enhancing effect on sulfatase activity when co-expressed with sulfatases. Consistent with these findings, we demonstrated that co-delivery of SUMF1 and SGSH (via an AAV2/5-CMV-SGSH-IRES-SUMF1 vector) resulted in a synergistic increase in SGSH activity, both in primary neural cells and in murine brain. A study aimed at testing the therapeutic efficacy of simultaneous brain administration of SUMF1 and SGSH was then performed by injecting the lateral ventricles of newborn MPS-IIIA/normal mice with either AAV2/5-CMV-SGSH-IRES-SUMF1 or AAV2/ 5-CMV-GFP vectors. Widespread GFP expression was observed within the GFP-injected brain, and a stable and significant increase of SGSH activity was detected in several brain regions following SGSH-IRES-SUMF1 administration. Treatment with AAV2/5-CMV-SGSH-IRES-SUMF1 vectors resulted in a visible reduction in lysosomal storage and inflammatory markers in transduced brain regions. Finally, the MPS-IIIA mice treated with therapeutic genes displayed an improvement in both motor and cognitive functions. Our results suggest that early treatment of CNS lesions by AAV-mediated intraventricular injection of both SGSH and SUMF1 genes may represent a feasible therapy for MPS-IIIA.

AB - Mucopolysaccharidosis type IIIA (MPS-IIIA or Sanfilippo syndrome) is a lysosomal storage disorder caused by the congenital deficiency of sulfamidase (SGSH) enzyme and consequent accumulation of partially degraded heparan sulfate (HS) in lysosomes. The central nervous system (CNS) is the predominant site of tissue damage in MPS-IIIA. Here we describe a gene therapy approach for MPS-IIIA in a mouse model using recombinant adeno-associated virus serotype 5 (AAV2/5) as a vehicle to deliver therapeutic genes to the CNS. SUMF1 (SUlfatase Modifying Factor 1) exhibits an enhancing effect on sulfatase activity when co-expressed with sulfatases. Consistent with these findings, we demonstrated that co-delivery of SUMF1 and SGSH (via an AAV2/5-CMV-SGSH-IRES-SUMF1 vector) resulted in a synergistic increase in SGSH activity, both in primary neural cells and in murine brain. A study aimed at testing the therapeutic efficacy of simultaneous brain administration of SUMF1 and SGSH was then performed by injecting the lateral ventricles of newborn MPS-IIIA/normal mice with either AAV2/5-CMV-SGSH-IRES-SUMF1 or AAV2/ 5-CMV-GFP vectors. Widespread GFP expression was observed within the GFP-injected brain, and a stable and significant increase of SGSH activity was detected in several brain regions following SGSH-IRES-SUMF1 administration. Treatment with AAV2/5-CMV-SGSH-IRES-SUMF1 vectors resulted in a visible reduction in lysosomal storage and inflammatory markers in transduced brain regions. Finally, the MPS-IIIA mice treated with therapeutic genes displayed an improvement in both motor and cognitive functions. Our results suggest that early treatment of CNS lesions by AAV-mediated intraventricular injection of both SGSH and SUMF1 genes may represent a feasible therapy for MPS-IIIA.

UR - http://www.scopus.com/inward/record.url?scp=35548941400&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddm223

DO - 10.1093/hmg/ddm223

M3 - Article

VL - 16

SP - 2693

EP - 2702

JO - Human molecular genetics

T2 - Human molecular genetics

JF - Human molecular genetics

SN - 0964-6906

IS - 22

ER -