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  • Review Article
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Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges

Nature Reviews Genetics volume 12, pages 341–355 (2011)Cite this article

Subjects

A Corrigendum to this article was published on 24 May 2011

This article has been updated

Key Points

  • Inherited diseases still represent a substantial burden to modern societies. The identification of causative gene defects for several of these diseases facilitated the development of gene-based therapeutic strategies. Over the past few years, clinical translation of bench research resulted in the first examples of therapeutic success for the field of gene transfer.

  • Adeno-associated virus (AAV) vectors are among the most suitable tools for in vivo gene delivery given their superior efficiency of transduction of several tissues, including liver, muscle and nervous tissue. Preclinical studies with these vectors have shown stable transgene expression and long-term correction of disease phenotype with little to no toxicity in small and large animal models of disease.

  • In humans, some of the most promising results were obtained when AAV was used to transfer therapeutic genes to the retina for the treatment of congenital blindness caused by retinal pigment epithelium-specific protein 65kDa (RPE65) deficiency, to the liver to correct the bleeding phenotype of haemophilia B, and to focal areas of the brain to ameliorate the course of Parkinson's disease, an acquired neurodegenerative disease.

  • The clinical experience with AAV vectors also highlighted a number of issues, some of which are not predicted by animal studies. Among them, vector or transgene immunogenicity remains the major obstacle to long-term therapeutic transgene expression. Target-tissue- and disease-specific hurdles will also need to be addressed to expand the scope of success with the AAV gene transfer platform.

  • The eye represents an ideal target tissue for gene transfer as widespread organ transduction can be achieved at low vector doses, and because presentation of a foreign antigen in this compartment is usually not associated with inflammatory responses. Experience with RPE65 deficiency is paving the way for the development of a whole new class of gene therapeutics targeting the retina.

  • The liver is also one of the most attractive targets for gene transfer owing to its unique biosynthetic capabilities and its ability to favour antigen-specific tolerance upon gene transfer. Some exciting results have recently been obtained in the clinic with haemophilia B; overcoming the limit of capsid-driven immune responses promises even greater success.

  • Gene transfer to the central nervous system has also given promising results. Efficient global gene transfer — achieved with novel delivery techniques and/or novel serotypes — will be the key to successfully treating some neurodegenerative diseases, such as lysosomal storage disorders.

  • Efficient delivery techniques are under development to target large areas of muscle using AAV vectors. Hopefully this will help us to reach the levels of transgene expression needed for therapeutic efficacy in some diseases.

  • The identification of the hurdles for clinical translation of AAV gene transfer, along with the development of solutions to overcome these problems, will enable us to provide improved therapeutic options for a range of inherited diseases by fully exploiting the potential of in vivo gene transfer.

Abstract

In vivo gene replacement for the treatment of inherited disease is one of the most compelling concepts in modern medicine. Adeno-associated virus (AAV) vectors have been extensively used for this purpose and have shown therapeutic efficacy in a range of animal models. Successful translation to the clinic was initially slow, but long-term expression of donated genes at therapeutic levels has now been achieved in patients with inherited retinal disorders and haemophilia B. Recent exciting results have raised hopes for the treatment of many other diseases. As we discuss here, the prospects and challenges for AAV gene therapy are to a large extent dependent on the target tissue and the specific disease.

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Figure 1: AAV gene therapy for the retinal degenerative disorder Leber's congenital amaurosis.
Figure 2: Obstacles posed by the human immune response in a trial of AAV delivery to liver.
Figure 3: Hypothesis explaining the loss of factor IX expression and transient increase in serum liver enzymes observed in the AAV2 trial for haemophilia B.

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Change history

  • 24 May 2011

    In the above article, information on clinical trials using adeno-associated virus (AAV) vectors for the treatment of Leber's congenital amaurosis was omitted from table 1. This table has now been corrected online. The authors apologize for this omission.

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Acknowledgements

The authors would like to acknowledge the support of the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, the Howard Hughes Medical Institute, and the US National Institutes of Health (HL64190 and HL078810). The authors are also grateful to collaborators and colleagues who provided access to unpublished data.

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Authors and Affiliations

  1. Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, 5th Floor CTRB, Philadelphia, 19104, Pennsylvania, USA

    Federico Mingozzi & Katherine A. High

  2. Howard Hughes Medical Institute, The Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, 5th Floor CTRB, Philadelphia, 19104, Pennsylvania, USA

    Katherine A. High

  3. University of Pennsylvania School of Medicine, 3600 Market Street, Suite 240, Philadelphia, 19104-2646, Pennsylvania, USA

    Katherine A. High

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Correspondence to Katherine A. High.

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Competing interests

Federico Mingozzi consulted for companies developing adeno-associated virus (AAV) vector therapeutics. He also consulted for companies that are not involved in AAV gene transfer. Federico Mingozzi is an inventor of a patent licensed to Amsterdam Molecular Therapeutics.

Katherine A. High is a member of the Scientific Advisory Board of Bluebird Bio, Cambridge, Massachusetts, USA. She is also a consultant for: Genzyme, Cambridge, Massachusetts, USA; Tacere Therapeutics, San Jose, California, USA; Forrest Research Laboratories, New York, USA; and Shire PLC.

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Glossary

Tropism

Term used in virology to define the affinity of a virus for a particular host tissue. The tropism is mostly determined by the expression of specific molecules at the surface of a tissue to which the virus binds.

Immunoprivileged

Term used to refer to tissues or organs (such as the eye or the brain) where immune responses are less pronounced than in other tissues or body compartments.

Duchenne muscular dystrophy

An X-linked inherited disorder caused by mutations in the dystrophin gene associated with rapidly worsening muscle weakness, which leads to death in early adulthood.

Batten's disease

A family of fatal neurodegenerative disorders caused by enzyme deficiencies associated with the pathological accumulation of substrates leading to neuronal cell toxicity.

Haemarthrosis

The narrow definition of haemarthrosis is blood within the joint space. This occurs commonly in the bleeding disorder haemophilia and is associated with inflammation, increased chance of recurrent bleeding and gradual loss of joint function.

Lysosomal storage disorders

A family of inherited disorders associated with loss of function of lysosomal enzymes with consequent pathological accumulation of substrates. The symptoms include neurodegeneration, liver disease and bone abnormalities.

Serotype

In virology the term refers to the reactivity of a virus to certain antiviral antibodies. In vectorology, the term identifies different viral vector capsids, which might be isolated in nature or genetically engineered.

Stereotactic injection

A delivery method used in neurosurgery to locate points within the brain using a three-dimensional coordinates system.

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Mingozzi, F., High, K. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet 12, 341–355 (2011). https://doi.org/10.1038/nrg2988

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