New era in gene therapy: end of the beginning

Despite recent progress in effective biologic drugs, such as monoclonal antibodies, there are still a number of diseases for which no known effective therapy exists, such as inherited genetic disorders. Although gene therapy is believed to be emerging as a potential strategy to address the unmet medical needs in various diseases, its limitations have blocked its success for long time. The first approved human gene therapy protocol was started on 14 September 1990 for adenosine deaminase deficiency. Over 20 years since commencement of the first trial, numerous adenosine deaminase deficiency patients have been treated by gene therapy.

Gene therapy trial objectives are generally to evaluate: i) the in vivo efficacy of the gene transfer method; ii) the safety of the gene transfer method; and iii) the possible therapeutic efficacy. Although there are still many unresolved issues in the clinical application of gene therapy, several gene therapy drugs have now entered to the market. In 2012, the European Commission approved the marketing authorization for alipogene tiparvovec (Glybera®), which introduced the lipoprotein lipase gene using an adeno-associated virus vector to treat lipoprotein lipase deficiency [1-4]. In addition, VEGF gene therapy using plasmid DNA was approved as a drug to treat peripheral artery disease in Russia in 2011 [5]. Furthermore, mipomersen sodium (KYNAMRO®), an oligonucleotide inhibitor of apolipoprotein B-100 synthesis, was approved by the US FDA in 2013, to reduce low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia [6].

Further modification of gene therapy technology including: i) further innovations in gene transfer methods; ii) well-defined disease targets; iii) cell-specific targeting strategies; and iv) effective and safe delivery systems would increase the targeted disease. Various techniques have been developed to increase the transfection efficiency without causing damage in tissues and cultured cells. Those include the improvement of the structure of vectors and the development of devices. Indeed, gene therapy seems to be a puzzle. It is necessary to answer the right therapeutic gene, the right gene delivery vector, the right gene expression amount and period, and other questions to treat the right target disease. We are still a long way from answering these enigmas. Further development of vectors and devices are likely to lead to improvement of transfection efficiency and development of gene therapy. This issue focuses on the future potential of gene therapy to treat various diseases, as gene therapy is now becoming a real therapeutic option.