Aspects of Gene Therapy Products Using Current Genome-Editing Technology in Japan

Abstract

The development of genome-editing technology could lead to breakthrough gene therapy. Genome editing has made it possible to easily knock out or modify a target gene, while current gene therapy using a virus vector or plasmid hampering modification with respect to gene replacement therapies. Clinical development using these genome-editing tools is progressing rapidly. However, it is also becoming clear that there is a possibility of unintended gene sequence modification or deletion, or the insertion of undesired genes, or the selection of cells with abnormalities in the cancer suppressor gene p53; these unwanted actions are not possible with current gene therapy. The Science Board of the Pharmaceuticals and Medical Devices Agency of Japan has compiled a report on the expected aspects of such genomeediting technology and the risks associated with it. This article summarizes the history of that discussion and compares the key concepts with information provided by other regulatory authorities.

Identification of Novel Modalities Through Bibliometric Analysis for Timely Development of Regulatory Guidance: A Case Study of T Cell Immunity

“…Genome-editing of endogenous TCR is undertaken to overcome the harmful effects inherent to these molecules, such as GvHD (donor cells attacking recipient tissue). However, genome-editing is accompanied with safety concerns regarding off-target effects, as described in the PTC of the PMDA Science Board ( 100 ). Besides the structure-engineering of CAR, consideration as alternative sources of T cells, such as NK cells, unconventional T cells, or Tregs should also be regarded, as discussed below.…”

PMDA’s Vision for Horizon Scanning of Emerging Technologies Potentially Relevant to the Development of New Medical Products: The Regulatory Challenge

“…In the new method, the Science Board released a report on genome editing technologies on February 7, 2020 8,9 . The report contains the points to be considered when assessment of products involving genome editing is performed by PMDA, such as: The tools used for genome editing Genome editing tools: viral vectors, plasmids, mRNA, genome editing protein Necessity of qualification analysis and safety evaluation for each tool Analysis of genome modifications caused by gene disruption using double strand break followed by nonhomologous end joining or homology‐directed repair, including diversity of analysis methods, and limitations, such as detection sensitivity Evaluation of safety associated with genome editing: unintended modifications (off‐target), introduction of large deletions or insertion mutations in the on‐target, risk of introducing p53 mutations by homology‐directed repair, and chromosomal abnormalities Risk of germ cell alteration when applying in vivo genome editing Need for long‐term follow‐up, because genome editing introduces persistent modifications into genes …”

“…In the new method, the Science Board released a report on genome editing technologies on February 7, 2020. 8,9 The report contains the points to be considered when assessment of products involving genome editing is performed by PMDA, such as: The Science Board started the discussion on the basis of what is similar to, or not similar to, gene therapy vectors that are already in use. As shown in Table 1, the report on genome editing elaborated in the new method follows that dealing with tumorigenicity in induced pluripotent stem cells.…”

Current trends and risks associated with the use of therapies based on genome editing

“…Точное редактирование генома с последующим восстановлением двухцепочечного разрыва посредством ГР оказалось довольно эффективным и для ряда линий опухолевых клеток [9]. Напротив, редактирование геномов нетрансформированных клеток труднее осуществить из-за возникающего с большой долей вероятности апоптоза в ответ на повреждение ДНК и/или более вероятного осуществления репарации ДНК по принципу НСК [10,11]. В настоящее время разработано несколько перспективных подходов к повышению эффективности редактирования генома клеток посредством ГР, основанных на увеличении концентрации матрицы репарационной ДНК, доставке ингибиторов НСК и оптимизации методов трансфекции ДНК матрицы [12][13][14].…”