Treatment of Congenital Neurotransmitter Deficiencies by Intracerebral Ventricular Injection of an Adeno-Associated Virus Serotype 9 Vector
Ni‐Chung LeeYin‐Hsiu ChienMin-Hsiu HuWen-Shin LiuPin-Wen ChenWeihua WangKai‐Yuan TzenBarry J. ByrneWuh‐Liang Hwu
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Dopamine and serotonin are produced by distinct groups of neurons in the brain, and gene therapies other than direct injection have not been attempted to correct congenital deficiencies in such neurotransmitters. In this study, we performed gene therapy to treat knock-in mice with dopamine and serotonin deficiencies caused by a mutation in the aromatic L-amino acid decarboxylase (AADC) gene (Ddc(KI) mice). Intracerebral ventricular injection of neonatal mice with an adeno-associated virus (AAV) serotype 9 (AAV9) vector expressing the human AADC gene (AAV9-hAADC) resulted in widespread AADC expression in the brain. Without treatment, 4-week-old Ddc(KI) mice exhibited whole-brain homogenate dopamine and serotonin levels of 25% and 15% of normal, respectively. After gene therapy, the levels rose to 100% and 40% of normal, respectively. The gene therapy improved the growth rate and survival of Ddc(KI) mice and normalized their hindlimb clasping and cardiovascular dysfunctions. The behavioral abnormalities of the Ddc(KI) mice were partially corrected, and the treated Ddc(KI) mice were slightly more active than normal mice. No immune reactions resulted from the treatment. Therefore, a congenital neurotransmitter deficiency can be treated safely through inducing widespread expression of the deficient gene in neonatal mice.Keywords:
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Gene therapy is an experimental treatment being investigated to correct defective genes that are responsible for disease development. To treat cancer and genetic illnesses, researchers are looking into a variety of gene therapy techniques. Finding a proper vector to transfer DNA into tissues is one of the most difficult aspects of gene therapy. Some gene therapy vectors have issues with infecting both quiescent and dividing cells, provoking an immunological response, lack of indefinite expression, and reproducible high titre. The adenovirus, retrovirus, and recombinant modified adeno-associated virus are top contenders for gene therapy vectors (rAAV). The issues with gene therapy may be resolved by the adeno associated virus (AAV). Hemophilia is a condition which may be benefited by the gene therapy using AAV as vector. Aim of this review is to emphasize on the role of adeno associated virus receptors(AAVR) and co-receptors in tropism and transduction of adeno associated virus(AAV) in the gene therapy of hemophilia In Vitro as well as In Vivo.
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The purpose of this chapter is to provide an overview of recombinant adeno-associated virus (rAAV) vectors and the current "state of the art" of their potential utility in gene therapy of hematopoietic disorders. The authors briefly review AAV biology and genetics and suggest more general reviews about AAV. The basic requirements that need to be fulfilled for gene therapy as treatment of hematopoietic disorders are presented.
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Recombinant adeno-associated virus (rAAV) is one of the most promising delivery vectors for gene therapy, due to its nonpathogenic property, nonimmunogenecity to host, and broad cell and tissue tropisms. This article summarizes the biological characteristics of AAV; the procedures to prepare, purify, and characterize the rAAV for gene therapy applications; and some of the clinical trials utilizing rAAV as delivery vehicles. Also discussed are the current efforts to modify rAAV to change its tropism, the application of different promoters to accommodate specific transgene expression, and the strategy to expand its capacity.
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Abstract Hemophilia A and B are diseases caused by a single gene deficiency and are thus suitable for gene therapy. In recent clinical research, adeno-associated virus (AAV) was employed by several teams in the treatment of hemophilia A and B, and the outcomes were encouraging. In this review, we summarized the most recent research on the mechanism and application of AAV in the treatment of hemophilia, trying to analyze the advantages of AAV gene therapy and the main challenges in its clinical use. We also summarized the clinical trials involving hemophilia, especially those employing AAV gene therapy to treat hemophilia A and B, some of which have already been completed and some that are still ongoing. From the reports of the completed clinical trials, we tried to determine the correlations among AAV dose, AAV serotype, immune response, and gene expression time. Finally, taking into account the most recent studies investigating AAV capsid modification, transgene optimization, and AAV chaperones, we summarized the direction of basic research and clinical applications of AAV in the future.
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Recombinant adeno-associated virus(rAAV)has good safety and low immunogenicity,which may infect both di-vided and undivided cells and mediate the long-term and stable gene expression.As a gene delivery system,rAAV is paid more and more attentions in study on gene therapy.The application of rAAV in gene therapy is reviewed in this paper.
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Vectors used to carry foreign genes play an important role in gene therapy, among which, the adeno-associated virus (AAV) has many advantages, such as nonpathogenicity, low immunogenicity, stable and long-term expression and multiple-tissue-type infection, etc. These advantages have made AAV one of the most potential vectors in gene therapy, and widely used in many clinical researches, for example, Parkinson's disease. This paper introduces the biological characteristics of AAV and the latest research progress of AAV carrying neurotrophic factor, dopamine synthesis related enzymes and glutamic acid decarboxylase gene in the gene therapy of Parkinson's disease.
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Lysosomal storage disorders (LSDs) are a group of single-gene inherited metabolic diseases caused by defects in lysosomal enzymes or function-related proteins. Enzyme replacement therapy is the main treatment method in clinical practice, but it has a poor effect in patients with neurological symptoms. With the rapid development of multi-omics, sequencing technology, and bioengineering, gene therapy has been applied in patients with LSDs. As one of the vectors of gene therapy, adeno-associated virus (AAV) has good prospects in the treatment of genetic and metabolic diseases. More and more studies have shown that AAV-mediated gene therapy is effective in LSDs. This article reviews the application of AAV-mediated gene therapy in LSDs.溶酶体贮积症（lysosomal storage disorders，LSDs）是一组由溶酶体酶或功能相关蛋白缺陷所致的单基因遗传代谢性疾病。临床治疗以酶替代疗法为主，但该疗法对有神经系统症状的LSDs患者疗效较差。随着多组学、测序技术和生物工程学的快速发展，基因治疗已在LSDs患者中开展。腺相关病毒（adeno-associated virus，AAV）作为基因治疗的载体之一，在治疗遗传代谢性等疾病中具有较好的前景。越来越多的研究表明，AAV介导的基因治疗在LSDs中有效。该文就其在LSDs中的应用作一综述。.
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