A primer to gene therapy: Progress, prospects, and problems

Journal of Inherited Metabolic Disease, vol. 44, pp. 54–71

Abstract

Genetic therapies based on gene addition have witnessed a variety of clinical successes and the first therapeutic products have been approved for clinical use. Moreover, innovative gene editing techniques are starting to offer new opportunities in which the mutations that underlie genetic diseases can be directly corrected in afflicted somatic cells. The toolboxes underpinning these DNA modifying technologies are expanding with great pace. Concerning the ongoing efforts for their implementation, viral vector-based gene delivery systems have acquired center-stage, providing new hopes for patients with inherited and acquired disorders. Specifically, the application of genetic therapies using viral vectors for the treatment of inborn metabolic disorders is growing and clinical applications are starting to appear. While the field has matured from the technology perspective and has yielded efficacious products, it is the perception of many stakeholders that from the regulatory side further developments are urgently needed. In this review, we summarize the features of state-of-the-art viral vector systems and the corresponding gene-centered therapies they seek to deliver. Moreover, a brief summary is also given on emerging gene editing approaches built on CRISPR-Cas9 nucleases and, more recently, nickases, including base editors and prime editors. Finally, we will point at some regulatory aspects that may deserve further attention for translating these technological developments into actual advanced therapy medicinal products (ATMPs).

Authors 3

1. Hidde A. Zittersteijn corresponding Aachen Department of Cell and Chemical Biology Leiden University Medical Center Leiden the Netherlands Department of Cell and Chemical Biology

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology Leiden University Medical Center Leiden The Netherlands

   Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands

2. Manuel A.F.V. Gonçalves Aachen Department of Cell and Chemical Biology Leiden University Medical Center Leiden the Netherlands Department of Cell and Chemical Biology

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology Leiden University Medical Center Leiden The Netherlands

   Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands

3. Rob C. Hoeben Aachen Department of Cell and Chemical Biology Leiden University Medical Center Leiden the Netherlands Department of Cell and Chemical Biology

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology Leiden University Medical Center Leiden The Netherlands

   Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands