Journal Article

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

Mingozzi, Federico, High, Katherine A.

2011

Overview

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. Recent clinical and preclinical studies have described exciting results using recombinant adeno-associated virus (AAV) vectors for therapeutic gene transfer in genetic disease. This Review explores the potential for using this form of therapy in the context of different tissues and diseases. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/326/596/2561 / Adeno-associated virus / Agriculture / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Care and treatment / Clinical Trials as Topic / Dependovirus - genetics / Dependoviruses / Disease / Dogs / Gene Function / Gene therapy / Gene Transfer Techniques / Genetic aspects / Genetic Diseases, Inborn - therapy / Genetic disorders / Genetic Therapy - methods / Genetic transformation / Genetic Vectors / Genomes / Health aspects / Hemophilia / Hemophilia B - genetics / Hemophilia B - therapy / Human Genetics / Humans / Male / Methods / Mice / Mutagenesis / Rats / Retinal Diseases - genetics / Retinal Diseases - therapy / review-article / Risk factors / Toxicity / Vectors (Biology) / Viruses