Therapeutic Genome Editing Shows Promise, but Numerous Challenges Remain

By Will Boggs MD

February 13, 2020

NEW YORK (Reuters Health) - Current technology has allowed for the identification of genetic mutations associated with various diseases, but there is a growing separation between diagnostics and treatments, according to a new report.

"Genome editing, and CRISPR technology in particular, increasingly enables precise changes to be introduced into cells, with extraordinary potential to transform healthcare," said Professor Jennifer A. Doudna of the University of California, Berkeley.

"In the coming decade, CRISPR-based therapies could become the standard of care for common and rare genetic diseases and may also accelerate the pace of immunotherapies to treat cancer," she told Reuters Health by email.

"At least 5,000 genetic disorders stem from known mutations of a single gene in the human genome," she added. "Together, these monogenic diseases, such as cystic fibrosis, Huntington's chorea, Duchenne muscular dystrophy, and sickle cell anemia, affect at least 250 million individuals. As genome editing enters the clinic, attention will be focused on safety, efficacy, and the balance between regulation and speed of application."

In a review in Nature, Doudna discusses the therapeutic opportunities of genome editing and describes what it will take to apply therapeutic genome editing in the real world.

She focuses on CRISPR technology for therapeutic applications in humans. CRISPR-based tools can perform genome editing, base editing, and gene regulation.

For any of these methods to be useful clinically, the enzymes used in CRISPR, associated guide RNAs, and any DNA repair templates must reach and enter cells that are in need of genetic repair. Viral vectors, nanoparticles, and electroporation of protein-RNA complexes are currently used to enable functioning genome-editing complexes to reach cells in target organs.

The clinical utility of genome editing depends on both accuracy (the ratio of on- versus off-target genetic changes) and precision (the fraction of on-target edits that produce the desired genetic outcome). Other important factors include the immunogenicity of bacterially derived editing proteins, the potential for pre-existing antibodies against CRISPR components to cause inflammation, and the unknown long-term safety and stability of genome-editing outcomes.

The clinical potential of therapeutic genome editing has been evaluated in sickle cell disease and other inherited blood disorders, muscular dystrophy, and a few other monogenetic disorders, but extreme pricing of such therapeutics could stymie progress.

Germline editing can also introduce genetic changes that are heritable if the edited cells are used to initiate a pregnancy. This raises a range of ethical and policy questions that have yet to be fully addressed.

Currently, a host of organizations agree that it is inappropriate to perform germline genome editing that culminates in human pregnancy, but that in vitro germline genome editing on human embryos and gametes should be allowed with appropriate oversight and consent from donors to facilitate research on the possible future clinical applications of gene editing.

They also agree that future clinical applications of human germline genome editing should not proceed absent a compelling medical rationale, an evidence base that supports its clinical use, an ethical justification, and a transparent public process involving all stakeholders.

How to move the technology forward while ensuring responsible use is the subject of ongoing international commissions whose objective is to draft detailed requirements for any potential future clinical use.

"CRISPR genome editing has the potential to address the unmet medical needs of millions of people worldwide, but we must ensure that ultimately, CRISPR-based personalized therapies are safe, effective, fairly priced, and widely accessible," Doudna said.

"It is vital that we continue to fund and support basic science," she said. "CRISPR technology was the outcome of a fundamental research project and now underpins the development of a new generation of advanced therapeutics that can improve the health and wellness of millions."

Professor Doudna is the co-founder of several biotech companies and is an inventor on patents for CRISPR-related technologies.

SOURCE: Nature, online February 12, 2020.