Updated: First-in-Man: CRISPR, the Genome Editing Technology is Nearing Human Trials: Human T cells will soon be Modified using the CRISPR Technique in a Clinical Trial to attack Cancer Cells
Curator: Aviva Lev-Ari, PhD, RN
UPDATED on 12/18/2016
NATURE | NEWS
CRISPR gene-editing tested in a person for the first time
The move by Chinese scientists could spark a biomedical duel between China and the United States.
A Chinese group has become the first to inject a person with cells that contain genes edited using the revolutionary CRISPR–Cas9 technique.
On 28 October, a team led by oncologist Lu You at Sichuan University in Chengdu delivered the modified cells into a patient with aggressive lung cancer as part of a clinical trial at the West China Hospital, also in Chengdu.
April 29, 2015
Statement on NIH funding of research using gene-editing technologies in human embryos
Genomic editing is an area of research seeking to modify genes of living organisms to improve our understanding of gene function and advance potential therapeutic applications to correct genetic abnormalities. Researchers in China have recently described their experiments in a nonviable human embryo to modify the gene responsible for a potentially fatal blood disorder using a gene-editing technology called CRISPR/Cas9.
Genomic editing is already widely studied in a variety of organisms. For example, CRISPR/Cas9 has greatly shortened the time it takes to produce knockout mouse models of disease, enabling researchers to study more easily the underlying genetic causes of those diseases. This technology is also being used to develop the next generation of antimicrobials, which can specifically target harmful strains of bacteria and viruses. In the first clinical application of genomic editing, a related genome editing technique (using a zinc finger nuclease) was used to create HIV-1 resistance in human immune cells, bringing HIV viral load down to undetectable levels in at least one individual. All of these examples of research using genomic editing technologies can and are being funded by NIH.
However, NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed. Advances in technology have given us an elegant new way of carrying out genome editing, but the strong arguments against engaging in this activity remain. These include the serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent, and a current lack of compelling medical applications justifying the use of CRISPR/Cas9 in embryos.
Practically, there are multiple existing legislative and regulatory prohibitions against this kind of work. The Dickey-Wicker amendment prohibits the use of appropriated funds for the creation of human embryos for research purposes or for research in which human embryos are destroyed (H.R. 2880, Sec. 128). Furthermore, the NIH Guidelines state that the Recombinant DNA Advisory Committee,“…will not at present entertain proposals for germ line alteration”. It is also important to note the role of the U.S. Food and Drug Administration (FDA) in this arena, which applies not only to federally funded research, but to any research in the U.S. The Public Health Service Act and the Federal Food, Drug, and Cosmetic Act give the FDA the authority to regulate cell and gene therapy products as biological products and/or drugs, which would include oversight of human germline modification. During development, biological products may be used in humans only if an investigational new drug application is in effect (21 CFR Part 312).
NIH will continue to support a wide range of innovations in biomedical research, but will do so in a fashion that reflects well-established scientific and ethical principles.
Francis S. Collins, M.D., Ph.D.
Director, National Institutes of Health
Emerging Biotechnologies and the Role of the NIH RAC
Next week, we mark the 40th anniversary of the first publication of the NIH Guidelines governing experiments using recombinant DNA. On June 23rd, 1976, former NIH Director Dr. Donald Frederickson announced that all NIH funded and conducted research involving recombinant DNA would be expected to follow the NIH Guidelines, noting both the great potential benefits that could arise from this new technology and the lack of certainty about the risks.
We have come a long way in 40 years, and the use of recombinant DNA is ubiquitous in research, medicine, and many other aspects of our daily lives. Recently, the NIH announcedrevisions to the NIH Guidelines that included amending the criteria and process for how human gene transfer protocols would be selected for review by the Recombinant DNA Advisory committee (RAC), limiting in depth review and public discussion only for exceptional cases.
Just such an exceptional case comes before the RAC during their meeting this week. During the June 21-22 meeting, the RAC will review a protocol involving the first-in-human use of gene editing via CRISPR/Cas9 technology. This T cell immunotherapy protocol involves the use of CRISPR/Cas9 to edit two genes in T cells also modified to express T cell receptors targeting myeloma, melanoma, and sarcoma tumor cells. Consideration of this study underlines the purpose of changing the RAC process: to better use the collective breadth of experience of the RAC members in reviewing gene transfer trials and novel technologies that pose unknown risks, exactly as described by Dr. Frederickson four decades ago.
Researchers in the field of gene transfer are excited by the potential of utilizing CRISPR/Cas9 to repair or delete mutations that are involved in numerous human diseases in less time and at a lower cost than earlier gene editing systems. While the application of new gene editing technologies in this field has great potential to improve human health, it is not without concerns. In a previous statement, NIH Director, Dr. Francis Collins, reiterated NIH’s commitment to support innovations in biomedical research in a fashion that reflects well-established scientific and ethical principles. Having a body such as the RAC available to publicly discuss the scientific, safety, and ethical implications of such cutting-edge experiments helps to ensure we are living up to that commitment.
As the application of biotechnology innovations moves closer to the clinical realm, we are confident that the changes we have made to the NIH Guidelines will enable the RAC to devote its full resources to where they are most needed. And as science continues to evolve, we will strive for parallel evolution in our policies to make oversight of research commensurate with the risks involved.
I encourage you to either attend the upcoming RAC meeting in person, or through the NIH Videocast to learn more about the exciting advances being made in the field of gene transfer. Information about the RAC meeting, including an agenda and the meeting location can be found on the OSP website.
On 21 June, an advisory committee at the US National Institutes of Health (NIH), NIH’s Recombinant DNA Research Advisory Committee (RAC), which reviewed the proposal. CRISPR, approved a proposal to use CRISPR–Cas9 to help augment cancer therapies that rely on enlisting a patient’s T cells, a type of immune cell.
the main challenge will be overcoming CRISPR’s propensity for ‘off-target’ edits. These are instances in which the system cuts or mutates unintended parts of the genome. And despite precautions, the immune system could still attack the edited cells.
Potential Conflict of Interest
During the RAC meeting, one of the committee’s greatest concerns was a potential conflict of interest. Among other financial involvements,
- Immunologist Carl June at the University of Pennsylvania, who is a science adviser on the project, says that it could begin by the end of the year. June has ties to the pharmaceutical company Novartis, holds patents on T-cell technologies, and could stand to benefit from the success of this trial. June declined to give details on the exact nature of his conflicts of interest, but says that his university is taking steps to manage it, such as preventing him from being involved in selecting patients. Several RAC reviewers suggested that the University of Pennsylvania not be allowed to recruit patients at all and to leave it to other institutions: this language did not make it into their final approval.
- However, the RAC members say they are being extra careful with this study. “Penn has a very extensive conflict and has a history,” says Laurie Zoloth, a bioethicist at Northwestern University in Evanston, Illinois. Looming over the discussion is the name Jesse Gelsinger, who died at age 18 while participating in an early gene-therapy trial conducted by researchers at the University of Pennsylvania in 1999.
- A subsequent investigation found numerous problems with the study, including unreported animal data on the therapy’s ill effects and the fact that the investigators had a financial stake in the study’s outcome. The incident is generally considered to have set gene therapy back by decades. “Any first use in humans we have to be extraordinarily careful,” Zoloth says. So a lot is riding on this trial.
- Mildred Cho, a bioethicist at Stanford University in California and an RAC member, says that safety work in animals for a new therapy will take researchers only so far. “Often we have to take the leap of faith.”
The Investigative Process
“Cell therapies [for cancer] are so promising but the majority of people who get these therapies have a disease that relapses,” says study leader Edward Stadtmauer, a physician at the University of Pennsylvania in Philadelphia. Gene editing could improve such treatments and eliminate some of their vulnerabilities to cancer and the body’s immune system, he says.
This first trial is small and designed to test whether CRISPR is safe for use in people, rather than whether it effectively treats cancer or not. It will be funded by a US$250-million immunotherapy foundation formed in April by former Facebook president Sean Parker. The trial itself does not yet have a budget. The University of Pennsylvania will manufacture the edited cells, and will recruit and treat patients alongside centres in California and Texas.
The researchers will remove T cells from 18 patients with several types of cancers and perform three CRISPR edits on them. One edit will insert a gene for a protein engineered to detect cancer cells and instruct the T cells to target them, and a second edit removes a natural T-cell protein that could interfere with this process. The third is defensive: it will remove the gene for a protein that identifies the T cells as immune cells and prevent the cancer cells from disabling them. The researchers will then infuse the edited cells back into the patient.
- Leukaemia success heralds wave of gene-editing therapies
- CRISPR, the disruptor
- Gene-editing method tackles HIV in first clinical test
Other related articles published on this Open Access Online Scientific Journal include the follwoing:
Lab Management: About The Doudna Lab, RNA Biology at UC Berkeley, HHMI
Gene Editing: The Role of Oligonucleotide Chips
Search “CRISPR” @PharmaceuticalIntelligence.com