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Abstract

Abstract 

  • Gene therapy is defined as the treatment or cure of human diseases by transfer of nucleic acids (DNA or RNA) to affected cells and it covers a broad range of therapeutic applications from Mendelian disorders to complex diseases. Gene therapy strategies are based on: (a) gene addition, (b) gene reprogramming, (c) gene repair, and (d) gene supply and are performed by either ex vivo or in vivo approaches. Gene addition is employed for disorders due to loss-of-function mutations and is based on delivery of a corrected copy of the defective gene without removal of the endogenous mutated gene. Gene reprogramming is based on inhibition of the expression of the mutated gene by modification of messenger RNA (mRNA) and is applied to disorders of gain-of-function mutations. Gene repair aims at correction of mutant sequences at the genomic DNA loci but is limited by low efficiency. Gene supply is the addition of a gene which is not directly implicated in the pathogenesis of the disease but whose expression can prevent or arrest disease progression.

  • Vectors for gene therapy are derived from viruses or can be non-viral. Each vector has its own advantages and disadvantages. Viral vectors exploiting the natural property of viruses to transfer their genetic material into the nucleus of the infected cells can be integrating or non-integrating. They have been genetically engineered to retain the ability of the virus to infect the target cells, but to avoid viral replication and the expression of cytotoxic viral proteins. Viral vectors integrating into the host genome, such as retroviral and lentiviral vectors, result in efficient gene transfer into replicating cells and the expression of the transgene into the cell progeny. They are more frequently used for ex vivo gene transfer applications, mainly directed at gene transfer into hematopoietic stem cells. Non-integrating vectors, such as adenoviral and adeno-associated viral vectors, are mostly used for in vivo gene transfer into non-replicating cells, including neurons, retinal cells, hepatocytes, and muscle cells. Non-viral vectors have reduced toxicity and are simpler to produce but they lack an efficient and clinically relevant method for in vivo delivery.

  • Following the promising results of preclinical studies in multiple disease animal models, several human clinical trials have been performed. Immune responses against the vector or its transgene product, vector-related genotoxicity, and difficulties with clinical grade vector production have been important problems in the clinical arena. Overcoming these obstacles will allow successful applications of gene transfer to liver, lung, and muscle which are relevant for the correction of inherited disorders, including several inborn errors of metabolism and cystic fibrosis. Despite the lack of clearly sustained efficacy and the unexpected adverse outcomes observed in some trials, the recent successes obtained by multiple groups, especially in severe combined immunodeficiencies and in Leber congenital amaurosis, clearly support the continued development of gene replacement therapies.

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