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Though human genome editing research that would create inheritable changes in offspring is the subject of somewhat ominous discussions, IRBs are much more likely to see research proposals involving genetically modified somatic cells.
A recently published report1 by the National Academy of Sciences explains that “somatic cells are all those present in the tissues of the body except for sperm and egg cells and their precursors. This means that the effects of genome editing of somatic cells are limited to treated individuals and are not inherited by their offspring. The idea of making genetic changes to somatic cells — referred to as ‘gene therapy’ — is not new, and genome editing for somatic applications would be similar. Gene therapy has been governed by ethical norms and subject to regulatory oversight for some time, and this experience offers guidance for establishing similar norms and oversight mechanisms for genome editing of somatic cells.”
Most basic research on human cells uses somatic cells such as those of the skin, liver, lungs, and heart. By contrast, “germline research” involves reproductive cells that could alter the human genome in a way that would affect descendants. Though the field holds great promise, it raises sufficient ethical and moral questions that intentionally creating or modifying an embryo to include heritable genetic modification is banned in the U.S.
On the other hand, somatic gene editing trials are in process, with one HIV clinical trial targeting the receptors that enable the virus to infect cells.2 Likewise, another targeted trial is aimed at correcting sickle cell mutations.3 Both of these trials involve somatic cell editing cells ex vivo, with therapy beginning as the cells are returned to the body.
“For persistent benefit, the therapeutic modification should be made in long-term repopulating cells, such as hematopoietic stem cells,” a researcher notes.4 “As other stem cell approaches are mastered, including induced pluripotent stem cells from patients, genome editing can be applied to them as well. Prospects for in vivo genome editing are less rosy due to the challenges of delivering the materials effectively to the target tissues, but there is active research in this area.”
With somatic gene cell editing already underway in some trials, IRBs should prepare to deal with protocols involving noninheritable genetic changes, says Bernard Lo, PhD, president of the Greenwall Foundation in New York City and director emeritus of the medical ethics program at the University of California, San Francisco.
“Somatic cell gene editing is highly innovative and, thus, presents many unknowns to participants in clinical trials,” he says. “IRBs will need to be vigilant to assure subjects are adequately protected. One particular issue is getting adequate scientific expertise to understand the science and potential risks.”
This is done by consultation with a Recombinant DNA Advisory Committee (RAC) to assess the protocol’s risks and benefits. Among the techniques currently being used that may require some consultation is gene editing that recognizes DNA sequences via CRISPR (clustered regularly interspaced short palindromic repeats).
“Although the RAC gives an in-depth review of the study, this is done earlier in the process, before the details of how adverse effects will be identified and monitored are set,” Lo says. “Thus, IRBs will need to look closely at these parts of the protocol, and will require members who are experts in both CRISPR science and in the disease being studied. Also, IRBs should reach out to patients affected by the disease and disease advocacy groups to assure they have expertise on how to explain new, complicated concepts to participants.”
IRB Advisor asked Lo to further clarify this situation, particularly the aspect of the RAC not being involved through trial completion.
“The in-depth scientific and ethical review by the RAC can be very helpful to IRBs, who should read the RAC minutes carefully,” he says. “However, because the RAC does not review the final protocol, the IRB will need to assure that all the scientific and ethical concerns raised by the RAC are adequately addressed in the final protocol and that any issues raised since the RAC review are addressed.”
Thus, an IRB without such expertise on the current board may need to form an ad hoc panel of scientific experts to pursue evaluation of somatic gene cell research.
Informed consent to somatic cell research participants should address the possibility of “therapeutic misconception,” Lo says. This effect may be compounded by enthusiastic press coverage of novel therapies.
“Somatic cell gene editing will be used to try to treat serious illnesses for which current treatments are inadequate,” he says. “Potential clinical trial participants will bring great hopes to the trial. The scientific rationale seems compelling: correct the gene that is responsible for the pathophysiology of the illness. IRBs and investigators will need to assure that patients do not have serious misunderstandings that would compromise their informed consent.”
Lo recommends encouraging questions by research participants, identifying and correcting misunderstandings, and perhaps testing comprehension of the key issues. In addition, the protocol must have robust adverse event reporting, looking for problems like editing at unintended sites, finding uncontrolled growth of modified cells, or unexpected immunological reactions, Lo advises.
“These concerns, and others, will need to be addressed by the IRB,” he says. “As with all highly innovative studies, there will need to be a good deal of back-and-forth to assure that the researchers understand the IRB concerns and that the IRB understands how the researchers have changed the protocol in response to these concerns.”
Another challenge is protecting privacy, as there may be considerable press interest in obtaining materials and clinical information IRBs or researchers share with colleagues, he notes. IRBs should be wary of conflicts of interest, with red flags triggered if institutions or investigators have financial stake in the intervention tested.
Regarding the research participants, issues of compensation and access will likely arise, including whether there are barriers to low-income patients. And while current somatic cell gene therapy is accepted for critical medical conditions, at what point could the risk be sufficiently low to treat less serious conditions, Lo asks. That raises the specter of nonmedical use, “enhancements” that could be possible with such gene research. Public input and debate are essential as the social and moral considerations go beyond the current risk/benefit equation, he emphasizes.
Financial Disclosure: Author Melinda Young, Medical Writer Gary Evans, Editor Jill Drachenberg, Editor Dana Spector, Physician Editor Lindsay McNair, MD, MPH, MSBioethics, and Nurse Planner Kay Ball, RN, PhD, report no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.