The Development of Gene Therapy: From Monogenic Recessive Disorders to Complex Diseases Such as Cancer

Abstract

During the last 4 decades, gene therapy has moved from preclinical to clinical studies for many diseases ranging from monogenic recessive disorders such as hemophilia to more complex diseases such as cancer, cardiovascular disorders, and human immunodeficiency virus (HIV). To date, more than 1,340 gene therapy clinical trials have been completed, are ongoing, or have been approved in 28 countries, using more than 100 genes. Most of those clinical trials (66.5%) were aimed at the treatment of cancer. Early hype, failures, and tragic events have now largely been replaced by the necessary stepwise progress needed to realize clinical benefits. We now understand better the strengths and weaknesses of various gene transfer vectors; this facilitates the choice of appropriate vectors for individual diseases. Continuous advances in our understanding of tumor biology have allowed the development of elegant, more efficient, and less toxic treatment strategies. In this introductory chapter, we review the history of gene therapy since the early 1960s and present in detail two major recurring themes in gene therapy: (1) the development of vector and delivery systems and (2) the design of strategies to fight or cure particular diseases. The field of cancer gene therapy experienced an "awkward adolescence." Although this field has certainly not yet reached maturity, it still holds the potential of alleviating the suffering of many individuals with cancer.

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“…[1][2][3] However, clinical gene therapy is limited due to the lack of effi cient and safe gene vectors. [ 4 ] Cationic polymers are widely used as gene vectors due to unique features such as facile manufacturing, low cost, fl exibility, and ease of functionalization.…”

Sustained, localized transgene expression mediated from lentivirus‐loaded biodegradable polyester elastomers

“…However, a major barrier to clinically successful gene delivery is the lack of a safe and efficient mode of gene delivery. Nonviral vectors such as polyethyleneimine and lipofectamine, the most commonly studied polymer and lipid for nonviral gene delivery, not only elicit low levels of gene expression, but their clinical potential is limited due to their reported toxicity and lack of stable and sustained expression 34, 35. Lentiviral vectors are a unique type of retroviral vector that was developed to efficiently transduce both dividing and nondividing cells and allow for long‐term gene expression via stable integration of the cargo into host chromosome 6, 7.…”

“…Nonviral vectors such as polyethyleneimine and lipofectamine, the most commonly studied polymer and lipid for nonviral gene delivery, not only elicit low levels of gene expression, but their clinical potential is limited due to their reported toxicity and lack of stable and sustained expression. 34,35 Lentiviral vectors are a unique type of retroviral vector that was developed to efficiently transduce both dividing and nondividing cells and allow for long-term gene expression via stable integration of the cargo into host chromosome. 6,7 The fact that lentiviral vectors have low genotoxicity [8][9][10] and lack immunogenic viral proteins 11 makes lentiviral vectors one of the most promising gene-delivery vectors.…”

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“…Gene therapy has been studied as a means of addressing mostly single gene disorders for more than four decades, going through more than 1,000 clinical trials, ongoing or completed (32). The field has experienced many ups and downs but continues to develop and continues to hold great promise (33).…”