Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Will a Biomedical Duel Between China and the United States Improve Gene-Editing Outcomes

A high-stakes clinical trial kicked off on October 29 in Chengdu, China, as You Lu, M.D., and colleagues began testing the gene-editing technology CRISPR, or clustered regularly interspaced short palindromic repeats, to knock out a gene encoding the programmed death protein 1 (PD-1) in patients with non-small-cell lung cancer (NSCLC). Treatment in these patients, including chemotherapy, radiation therapy, and other approaches, had failed. The trial will be the first time CRISPR gene-editing technology has been used in humans.

Dr. Lu and his team from Sichuan University’s West China Hospital in Chengdu announced their plan for a CRISPR clinical trial in July 2016 shortly after the University of Pennsylvania’s (Penn) application for human CRISPR trials received approval by the Recombinant DNA Advisory Committee (RAC), an independent review panel for the National Institutes of Health (NIH). The U.S. trial still requires the approval of the medical centers where it would be conducted and the U.S. Food and Drug Administration (FDA).

Dr. Lu’s trial approval took six months of discussion between the hospital’s internal review board and the scientists. The NIH’s approval of the Penn study “strengthened ours and our IRB’s confidence in this study,” Dr. Lu said, when the approval came through.  

The Penn trial, expected to begin in early 2017, will focus on treating cancer but still requires a go-ahead from the FDA and the university review board.

Some have cast the clinical trial as part of an unfolding competitive drama between China and the United States. Carl June, M.D., who specializes in immunotherapy at Penn, will act as a scientific advisor for the proposed U.S. CRISPR study. He said “I think this is going to trigger ‘Sputnik 2.0’, a biomedical duel on progress between China and the United States, which is important since competition usually improves the end product.”

As for Sichhuan University’s  Dr. Lu, he commented “I hope we are the first. And more importantly, I hope we can get positive data from the trial.

Previous CRISPR Experiments

Currently, China is ahead in the contest for recent gene-editing firsts, including CRISPR-edited monkeys in 2014 and CRISPR-edited human embryos in 2015.

Xingxu Huang, Ph.D., while a geneticist at the Model Animal Research Center of China’s Nanjing University in China, and his colleagues successfully engineered twin cynomolgus monkeys (Macaca fascicularis) with two targeted mutations using the CRISPR/Cas9 system. These scientists “monkeyed” with three genes in a cell line, disrupting each of the genes with 10–25% success. They subsequently targeted the three genes simultaneously in more than 180 single-celled monkey embryos. Ten pregnancies resulted from 83 embryos that were implanted, one of which led to the birth of a pair with mutations in two genes: Ppar-γ, which helps to regulate metabolism, and Rag1, which is involved in healthy immune function.

But a human embryo experiment failed, confirming some specific fears related to off-target effects about the technology. Puping Liang, Ph.D., and colleagues at Sun Yat-sen University in Guangzhou used CRISPR/Cas9 to cleave the endogenous β-globin gene (HBB), which is mutated in patients with the blood disorder β-thalassemia. They used nonviable tripronuclear (3PN) zygotes.

These investigators found that CRISPR/Cas9 could effectively cleave the endogenous HBB; however, homologous recombination-directed repair (HDR) efficiency of HBB was low, and the resulting edited embryos were mosaic.

Study coauthor Junjiu Huang told Nature News that he and his colleagues were surprised by the number of off-target effects they observed, including some in remote locations in the genome. “If you want to do it in normal embryos, you need to be close to 100%” on target,” Huang told Nature, adding: “That’s why we stopped. We still think it’s too immature.”  The authors wrote in their β-globin gene article that, “Taken together, our work highlights the pressing need to further improve the fidelity and specificity of the CRISPR/Cas9 platform, a prerequisite for any clinical applications of CRISPR/Cas9-mediated editing.”

China’s Commitment to CRISPR Research

But the Chinese government remains heavily committed to CRISPR research. Last year, the National Natural Science Foundation of China, a prominent government-backed institution that funds research, awarded more than 23 million yuan ($3.5 million) to at least 42 CRISPR projects, more than double the previous year and only one of several government institutions providing CRISPR funding in China. 

Most of China’s funding for CRISPR research comes from the government; very few private companies are putting money into gene modification work, according to Lai Liangxue, Ph.D., deputy director of the Southern China Institute of Stem Cell Biology and Regenerative Medicine. “Whether it’s animal or plant, our country has special funds for this aspect of work.”

CRISPR Research and Investment in the United States

In contrast to China, private investment in the United States is enormous, with companies having raised hundreds of millions in U.S. dollars in venture capital and other funds in under three years.

“I would rank the United States and China as first and second CRISPR/Cas9 research countries, respectively, at this time. Both countries have much strength in this area,” said Paul Knoepfler, Ph.D., an associate professor of cell biology and human anatomy at the University of California’s UC Davis School of Medicine. Recently, Dr. Knoepfler published a book titled GMO Sapiens: The Life-Changing Science of Designer Babies, which discusses the application of gene-modifying technology on humans.

High-profile U.S. papers have laid the groundwork for an enormous patent estate residing for the most part with two major research institutions—the University of California, Berkeley and MIT/Broad Institute and Harvard.

Editas Medicine in Cambridge, Massachusetts, with its intellectual property from the Broad and Harvard, filed its IPO in February raising $94 million, but does not intend to enter clinical trials until 2017. Intellia Therapeutics, whose IPO raised $108 in its May 2016 public debut, got its IP from the University of California, Berkeley, through company biochemist Jennifer Doudna, Ph.D., and her colleagues, who first described the therapeutic potential of CRISPR/Cas9 in a 2012 paper in Science.

Potential Effects of the CRISPR Patent Dispute

The highly contentious patent dispute between the University of California, Berkeley and the Broad Institute has raised the stakes on the Chinese trial outcome. A positive result validating the technology as a therapeutic tool would affirm the enormous investments in companies aiming to use CRISPR/Cas9 for gene therapy that have licensed the technology from these institutions.

Should the Chinese become committed to commercialization of the technology through companies, part of the challenge for Chinese companies will be obtaining licenses to use CRISPR commercially once patents are awarded internationally. “Without obtaining licenses from these parties, commercial applications in China or elsewhere will be hampered,” noted Jin-Soo Kim, Ph.D., a professor with the Center for Genome Engineering at Seoul National University.

As attorneys defending rival CRISPR/Cas9 gene-editing patents faced off on December 6, 2016, at the U.S. Patent & Trademark Office (USPTO) in Alexandria, VA, the public hearing attracted a large turnout, prompting one attendee to describe it as a “spectator sport” for patent lawyers and investors. New York Law School associate professor Jacob S. Sherkow, who has been following the case, said after the debriefing hearing that there is no required deadline by which the judges must make a decision. “It is my hope that we will see a big substantive decision probably in February.”

If either or both parties appeal the decision, CRISPR could spend a long time in court holding up access and commercial development around the world, including in China.

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