Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy

Mansi Tiwari; Ahlima Roumane; Nadine Sommer; Weiping  Han; Mirela Delibegovic; Justin Rochford; George David McIlroy

doi:10.1038/s41434-024-00471-z

Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy

Mansi Tiwari, Ahlima Roumane, Nadine Sommer, Weiping Han, Mirela Delibegovic, Justin Rochford, George David McIlroy^* (Corresponding Author)

^*Corresponding author for this work

Agency for Science, Technology and Research (A*STAR)

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

1 Citation (Scopus)

Abstract

Lipodystrophy is a rare disorder which can be life-threatening. Here individuals fail to develop or maintain appropriate adipose tissue stores. This typically causes severe metabolic complications, including hepatic steatosis and lipoatrophic diabetes. There is no cure for lipodystrophy, and treatment options remain very limited. Here we evaluate whether tissue-selective adeno-associated virus (AAV) vectors can provide a targeted form of gene therapy for lipodystrophy, using a preclinical lipodystrophic mouse model of Bscl2 deficiency. We designed AAV vectors containing the mini/aP2 or thyroxine-binding globulin promoter to selectively target adipose or liver respectively. The AAV-aP2 vectors also contained the liver-specific microRNA-122 target sequence, restricting hepatic transgene expression. Systemic delivery of AAV-aP2 vectors overexpressing human BSCL2 restored adipose tissue development and metabolic health in lipodystrophic mice without detectable expression in the liver. High doses (1 × 1012 GCs) of liver-selective vectors led to off target expression and adipose tissue development, whilst low doses (1 × 1010 GCs) expressed selectively and robustly in the liver but did not improve metabolic health. This reveals that adipose tissue-selective, but not liver directed, AAV-mediated gene therapy is sufficient to substantially recover metabolic health in generalised lipodystrophy. This provides an exciting potential new avenue for an effective, targeted, and thereby safer therapeutic intervention.

Original language	English
Pages (from-to)	445–454
Number of pages	10
Journal	Gene Therapy
Volume	31
Early online date	28 Jul 2024
DOIs	https://doi.org/10.1038/s41434-024-00471-z
Publication status	Published - Sept 2024

Bibliographical note

Open access via the Springer Agreement
The authors would like to thank the staff at the University of Aberdeen’s Microscopy and Histology Core Facility and the Medical Research Facility for support with animal breeding and maintenance. The manuscript figure was created with BioRender.com.

Data Availability Statement

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

UN SDGs

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

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Cite this

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title = "Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy",

abstract = "Lipodystrophy is a rare disorder which can be life-threatening. Here individuals fail to develop or maintain appropriate adipose tissue stores. This typically causes severe metabolic complications, including hepatic steatosis and lipoatrophic diabetes. There is no cure for lipodystrophy, and treatment options remain very limited. Here we evaluate whether tissue-selective adeno-associated virus (AAV) vectors can provide a targeted form of gene therapy for lipodystrophy, using a preclinical lipodystrophic mouse model of Bscl2 deficiency. We designed AAV vectors containing the mini/aP2 or thyroxine-binding globulin promoter to selectively target adipose or liver respectively. The AAV-aP2 vectors also contained the liver-specific microRNA-122 target sequence, restricting hepatic transgene expression. Systemic delivery of AAV-aP2 vectors overexpressing human BSCL2 restored adipose tissue development and metabolic health in lipodystrophic mice without detectable expression in the liver. High doses (1 × 1012 GCs) of liver-selective vectors led to off target expression and adipose tissue development, whilst low doses (1 × 1010 GCs) expressed selectively and robustly in the liver but did not improve metabolic health. This reveals that adipose tissue-selective, but not liver directed, AAV-mediated gene therapy is sufficient to substantially recover metabolic health in generalised lipodystrophy. This provides an exciting potential new avenue for an effective, targeted, and thereby safer therapeutic intervention.",

author = "Mansi Tiwari and Ahlima Roumane and Nadine Sommer and Weiping Han and Mirela Delibegovic and Justin Rochford and McIlroy, {George David}",

note = "Open access via the Springer Agreement The authors would like to thank the staff at the University of Aberdeen{\textquoteright}s Microscopy and Histology Core Facility and the Medical Research Facility for support with animal breeding and maintenance. The manuscript figure was created with BioRender.com.",

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doi = "10.1038/s41434-024-00471-z",

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AU - Delibegovic, Mirela

AU - Rochford, Justin

AU - McIlroy, George David

N1 - Open access via the Springer Agreement The authors would like to thank the staff at the University of Aberdeen’s Microscopy and Histology Core Facility and the Medical Research Facility for support with animal breeding and maintenance. The manuscript figure was created with BioRender.com.

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N2 - Lipodystrophy is a rare disorder which can be life-threatening. Here individuals fail to develop or maintain appropriate adipose tissue stores. This typically causes severe metabolic complications, including hepatic steatosis and lipoatrophic diabetes. There is no cure for lipodystrophy, and treatment options remain very limited. Here we evaluate whether tissue-selective adeno-associated virus (AAV) vectors can provide a targeted form of gene therapy for lipodystrophy, using a preclinical lipodystrophic mouse model of Bscl2 deficiency. We designed AAV vectors containing the mini/aP2 or thyroxine-binding globulin promoter to selectively target adipose or liver respectively. The AAV-aP2 vectors also contained the liver-specific microRNA-122 target sequence, restricting hepatic transgene expression. Systemic delivery of AAV-aP2 vectors overexpressing human BSCL2 restored adipose tissue development and metabolic health in lipodystrophic mice without detectable expression in the liver. High doses (1 × 1012 GCs) of liver-selective vectors led to off target expression and adipose tissue development, whilst low doses (1 × 1010 GCs) expressed selectively and robustly in the liver but did not improve metabolic health. This reveals that adipose tissue-selective, but not liver directed, AAV-mediated gene therapy is sufficient to substantially recover metabolic health in generalised lipodystrophy. This provides an exciting potential new avenue for an effective, targeted, and thereby safer therapeutic intervention.

AB - Lipodystrophy is a rare disorder which can be life-threatening. Here individuals fail to develop or maintain appropriate adipose tissue stores. This typically causes severe metabolic complications, including hepatic steatosis and lipoatrophic diabetes. There is no cure for lipodystrophy, and treatment options remain very limited. Here we evaluate whether tissue-selective adeno-associated virus (AAV) vectors can provide a targeted form of gene therapy for lipodystrophy, using a preclinical lipodystrophic mouse model of Bscl2 deficiency. We designed AAV vectors containing the mini/aP2 or thyroxine-binding globulin promoter to selectively target adipose or liver respectively. The AAV-aP2 vectors also contained the liver-specific microRNA-122 target sequence, restricting hepatic transgene expression. Systemic delivery of AAV-aP2 vectors overexpressing human BSCL2 restored adipose tissue development and metabolic health in lipodystrophic mice without detectable expression in the liver. High doses (1 × 1012 GCs) of liver-selective vectors led to off target expression and adipose tissue development, whilst low doses (1 × 1010 GCs) expressed selectively and robustly in the liver but did not improve metabolic health. This reveals that adipose tissue-selective, but not liver directed, AAV-mediated gene therapy is sufficient to substantially recover metabolic health in generalised lipodystrophy. This provides an exciting potential new avenue for an effective, targeted, and thereby safer therapeutic intervention.

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Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy

Abstract

Bibliographical note

Data Availability Statement

UN SDGs

Access to Document

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Microscopy and Histology

Cite this

Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy

Abstract

Bibliographical note

Data Availability Statement

UN SDGs

Access to Document

Other files and links

Fingerprint

Equipment

Microscopy and Histology

Cite this