CRISPR editing can produce ‘life-altering’ changes in patient health, Nobel laureate says
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The CRISPR/Cas9 gene-editing system already is producing results that may fundamentally transform the treatment of certain diseases, according to one of the recipients of the 2020 Nobel Prize in Chemistry.
One of the best examples is for the treatment of sickle cell disease, according to Jennifer A. Doudna, PhD, Li Ka Shing chancellor’s chair in biomedical and health sciences at University of California, Berkeley.
The earliest laboratory application of CRISPR showed how it was possible to correct the mutation that causes sickle cell disease by using genetically altered cells from the patient, Doudna said. More recently, it was shown that CRISPR could both correct the mutation in vivo or elevate the presence of fetal hemoglobin that suppresses the effects of sickle cell disease among adults.
“This is not a theoretical possibility, but an actual application that’s happening now,” Doudna said in her keynote address during the virtual AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
Several dozen patients with sickle cell disease and other blood disorders — including beta-thalassemia — have been successfully treated using CRISPR gene editing, Doudna added.
“This application illustrates one of the most powerful uses of CRISPR — namely to alter somatic cells in an individual to make a life-altering change to their health outcomes,” she said. “We will see increasing opportunities to use CRISPR in this fashion.”
Doudna — who discovered the CRISPR/Cas9 system with her colleague Emmanuelle Charpentier, PhD — called it a “truly programmable type of tool” that allows scientists to make targeted changes to the DNA of cells.
The system uses an RNA guide to detect a DNA sequence within a cell. When the Cas9 protein and its guide RNA find a DNA sequence match, it triggers local unwinding of the DNA duplex that cuts each strand. During subsequent DNA repair, gene editing occurs and small changes in the DNA can be introduced.
“Anything with DNA can theoretically be altered using CRISPR,” Doudna said. “This is a technology that has exciting implications for clinical use, particularly for cancer therapeutics.”
One of the barriers to using CRISPR to treat diseases like solid tumors is delivery of the genome-editing proteins into cells, Doudna said. Research is underway to examine how more compact genome editors can be used with even greater DNA editing precision, she added.
Many researchers already have successfully produced gene and cell therapies using ex vivo gene editing; however, Doudna said she anticipated “new therapeutic approaches” that will simplify how CRISPR is used to treat diseases.
"The long-term goal of this work is to make this process efficient enough that this type of [gene] editing can be done within the patient without requiring ex vivo editing,” she said.
CRISPR already is being applied to enhance the efficacy of chimeric antigen receptor T-cell therapies. Researchers are using the gene-editing system to create targeted knockouts within CAR T cells so they simultaneously express a T-cell receptor that helps CAR T cells avoid fratricide and introduces a template that encodes an anti-CD19 CAR for antitumor activity, Doudna said.
"This is an approach for creating the types of engineered T cells that will become increasingly useful for different types of cancer therapies,” Doudna said. “We hope to increase the efficiency and availability of these types of cells.”
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Doudna JA. Keynote address. Presented at: 2021 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (virtual meeting); Oct. 7-10, 2021.
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