"TÜV" for gene scissors to make gene therapies safer
Researchers at the Medical Center - University of Freiburg have developed a method to comprehensively assess the precision of gene scissors for the first time / Testing is of great importance for the development and use of safe gene therapies
Gene therapies are already being used to treat congenital diseases and in cancer therapy. A much larger number of similar therapies are currently under development. Whether and how precisely the gene scissors used in this process cut exclusively at the desired location in the genome has so far been insufficiently investigated. Researchers at the Medical Center - University of Freiburg have now developed a new evaluation method that for the first time makes it possible to identify the location and extent of faulty cuts and potentially dangerous restructuring in the genome. The researchers found numerous unwanted genetic rearrangements in all the gene scissors tested. The study was published in the renowned journal Cell Stem Cell on February 23, 2021.
"The method we developed is something like a TÜV for gene scissors. The CAST-Seq method enables a risk assessment of gene scissors before clinical application in patients," says Prof. Dr. Toni Cathomen, Director of the Institute for Transfusion and Gene Therapy at the Medical Center - University of Freiburg.
Making gene therapies safer before use
Gene scissors such as CRISPR/Cas often cut not only at the desired location in the genome, but also at other sites. This is known as off-target effects. Cathomen and colleagues have now established the CAST-Seq method to identify and quantify such unwanted changes to chromosomes. They used it to investigate CRISPR/Cas and TALEN class gene scissors in blood stem cells, among others. "We detected off-target effects in all the gene scissors we examined. In addition, we were able to prove for the first time that entire sections of genetic material are rearranged." Such chromosomal rearrangements within the genetic material can restrict the functionality of the cells or trigger malfunctions. In the worst case, this can even lead to tumor-like cells.
The investigated gene scissors were in the preclinical test phase. With the help of CAST-Seq, it has now been possible to decide which CRISPR/Cas gene scissors are suitable for therapeutic use in patients. The researchers assume that the developers of gene scissors in particular - but also the regulatory authorities - will be very interested in this novel test procedure. CAST-Seq makes it possible to identify safe gene scissors at an early stage of development and to carry out a genetic risk analysis before initiating a clinical trial.
"Our results show that we must continue our efforts to make gene therapies even safer. At the same time, they do not contradict the great progress and therapeutic developments that we and many other researchers have made in recent years," says Cathomen.
Original title of the study: Quantitative evaluation of chromosomal rearrangements in gene-edited human stem cells by CAST-Seq
DOI: 10.1016/j.stem.2021.02.002
Link to the study:https://authors.elsevier.com/a/1cdm-6tu0CeSPF
Contact:
Prof. Dr. Toni Cathomen
Director
Institute for Transfusion and Gene Therapy
Uniklinik Freiburg
Phone: 0761 270-34801
toni.cathomen@uniklinik-freiburg.de
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