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Targeted Therapeutic Genome Engineering: Opportunities and Bottlenecks in Medical Translation

This post is an excerpt from Targeted Nanosystems for Therapeutic Applications: New Concepts, Dynamic Properties, Efficiency, and Toxicity‘.

Genome and epigenome editing is rapidly being adopted into all fields of biomedical research; it has revolutionized our approach to treatments and models for diseases and conditions that have an underlying genetic basis. Treatments where we can reprogram a diseased cell to transition to a healthy phenotype or where we can initiate a regulatory process resulting in the apoptosis of diseased cells are an exciting near-reality and represent a new era in medicine.

Despite huge advances in genomic sciences, drug development, and medicines, it is estimated that there is only an effective treatment for less than 5% of rare diseases. Additionally, over 3,000 human genes have been associated with single-gene diseases in humans. The treatment of diseases with gene therapies has been investigated in clinics since the 1990s, but the field and potential of gene therapies skyrocketed in the early 2000s with the discovery and application of site-specific endonucleases such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and then Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9) for a timeline of gene therapies.

While it may seem logical to use gene therapies to treat genetic diseases, instead of small-molecule traditional therapies, there are advantages and disadvantages to both sides. Currently, there are few small-molecule traditional drugs aimed at the reactivation of endogenous tumor suppressor genes, approved by the United States Food and Drug Administration. These drugs have demonstrated promise for the treatment of cancers; however, they are hindered by potential toxicity, a lack of target specificity, and the development of drug resistance. Spinal muscular atrophies are a neuromuscular disorder with typical onset in childhood, with no small-molecule cure. Current clinical management involves aggressive treatments of respiratory infections, ventilator support, and invasive interventions for skeletal deformities such as scoliosis. However, new research has identified gene replacement therapy of the SMN1 gene, or SMN2 gene upregulation or modification as attractive potential cures for this devastating disease. Therefore, in each of the examples, gene therapies may overcome current clinical treatment issues, but safe and efficient delivery of said therapies, in addition to efficiency and off-target concerns associated with the therapy design itself, remain major barriers to clinical translation.

Editors: Kazuo Sakurai and Marc A. Ilies
Publication Date (Web): March 20, 2019
Copyright © 2019 American Chemical Society
Read a free sample chapter: Targeted Therapeutic Genome Engineering: Opportunities and Bottlenecks in Medical Translation

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