OPINION
DOCTORS Lounge
In other words, we could now target, and edit, a single gene.
That is not gene therapy as previously understood: that involved adding genes to certain cells. Gene editing involves changing specific genes inside the cells. Pre-CRISPR, a 2009 stem cell trial targeting the CCR5 gene, which is critical for HIV replication, was done in a man with both HIV and AML. But that was very labor-intensive gene editing. The CRISPR-CAS9 technique is even now being promoted in sales of less than $ 200“ do it yourself” gene lab kits.
What do we do with that information? What should we do with that information?
In China, there are already about 20 clinical trials in the works or underway. The first clinical reports of a very small Phase-1 trial came in October 2016, when doctors led by Lu-You at the Sichuan University inserted CRISPR-modified cells into a patient with metastatic non-small cell lung cancer. The immune cells had been edited outside the body to disable the production of PD-1, which slows the immune response to cancer( when that protein is disabled, the immune system fights off the cancer cells more effectively). The edited cells were cultured and then injected back into the patient.
In the US, an NIH Advisory Committee on June 21 approved Dr. Edward Stadtmauer’ s Phase-1 trial( funded by former Facebook exec Sean Parker’ s $ 250 million immunotherapy foundation). The trialists plan to remove T cells from 18 people with various cancers and use three separate gene edits, then infuse them back. One edit detects and targets the cancer cells; the second removes a T cell protein that would block the targeting process; the third prevents the cancer cells from identifying and disabling the immune cells that fight them off. The research team will now have to pass its own institutional review boards.
Other means of gene editing include the TALENS method and the zinc-finger nuclease( my fave scientific name in ages). Both are being pursued now as well. Sangamo Technologies, a biotech company, is recruiting patients for an inside-the human-body gene editing study for patients with Hemophilia B, Hurler Syndrome( lysosomal storage disease with average lifespan under 10 years) and Hunter Syndrome( another storage disease whose severe form is usually lethal by age 15). A new, functional gene will be inserted into the gene for albumin, a protein in liver cells, said to be a“ safe harbor” for this type of therapy. The zinc-finger nuclease method involves“ tinier”( if one can imagine smallness on that scale) delivery systems into the targeted cell, and requires only one“ anchor” to attach, both considered advantages over the CRISPR method.
The risk of CRISPR is cited as when the delivered“ missile” makes only a partial match, but enough to latch on to its target, and therefore target the wrong process. Previous immune-therapy agents have had multiple dangerous side effects, but none has used this particular method. It’ s stepping into the unknown, which is a familiar feeling for cancer patients and doctors.
Patients with Sickle Cell and Huntington’ s Chorea could have their lives changed forever, if these single-gene diseases could be targeted and eliminated inside them. Women with the BRCA gene have already contacted gene researchers and asked to be notified of actual trials.
The“ eugenic” scenario of germline editing – changing the reproductive cells – has been a hot topic in scientific circles since the invention of CRISPR. Are we going to make designer children, or designer warriors, or designer football players? Are we going to target non-lethal but life-changing genetic disorders like Down Syndrome? Germline editing affects not only the patients involved, but their descendants, and their descendants, so on. Because of this, the National Academy of Sciences and the National Academy of Medicine in February released a joint position statement recommending a ban on germline research in the USA. Much more study will have to be done, they said, and many ethical concerns raised and discussed, and scientific and moral consensus must first be reached.
In contrast, gene-editing therapy for somatic cells was felt to offer great promise, at currently unknown risk, and they recommended proceeding with utmost caution and all due process. Gene editing holds out the promise of curing heretofore incurable inherited diseases.
That’ s why I support it.“ What God has joined together, let no man put asunder” is something vital for marriages, but not genes.
Dr. Barry practices Internal Medicine with Norton Community Medical Associates-Barret. She is a clinical associate professor at the University of Louisville School of Medicine, Department of Medicine.
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