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Covid-19 Vaccine: Gene Therapy Risks

The Death of Jesse Gelsinger, 20 Years Later

By Meir Rinde | June 4, 2019

CRISPR is a fundamentally new way to change genes. The basic technology consists of an enzyme that cuts DNA and a segment of guide RNA that tells the enzyme where to snip. The package may include other components, such as a new piece of DNA code to plug into the edited area. The cell’s natural repair mechanism completes the edit. Scientists can deliver CRISPR using AAVs, as Editas is doing, but that’s not the only option; CRISPR can be encapsulated in bubbles of fat, injected directly into cells, or sent through a hole created by an electric current, among other techniques. Editing is meant to occur when the enzyme comes in contact with the target DNA, and only then.

“The hope that we have now for CRISPR technology is that it literally is a way to program enzymes to go to exactly the place in the DNA where a change is desired, and nowhere else, and make a precise alteration,” Doudna said. “It’s a very different way of altering genomes that is controllable. The potential is clearly very, very exciting.”

But cell biology is complex, and learning how to avoid unintended consequences remains a work in progress. Last year, for example, two groups of researchers said they found a possible problem when they tested CRISPR on retinal cells and stem cells. The intended edits often didn’t work because they triggered a cell’s p53 gene, which responds to DNA damage by telling a cell to self-destruct. The gene plays an important role in keeping mutations from becoming cancerous, yet CRISPR worked better in cells with a dysfunctional p53 gene. In other words, CRISPR apparently subverted one of the body’s disease-fighting mechanisms, making healthy cells die and allowing potentially cancerous ones to remain.

No one has seen lab mice get cancer after CRISPR treatment, but it’s unclear if they have been observed long enough to allow tumors to develop. In the French SCID study, the children were diagnosed with leukemia years after their treatment. Potential long-term side effects are a concern with gene therapies because the treatments are basically permanent; they can’t be washed out of the body the way a conventional drug often can. The discovery of the p53 issue and the uncertainty about its importance are reminders that scientists simply don’t know everything that could happen when CRISPR is put into a human body.

Wilson said the question of whether a gene edit could inadvertently cause mutations elsewhere in the chromosome and cause cancer in a patient, much as SCID gene therapy caused leukemia, will not be resolved soon. “It’s definitely a theoretical concern, and it’s going to be a challenge to quantify what the risk is. That’s going to be a huge challenge,” he said.

That doesn’t mean clinical trials of CRISPR-based therapies shouldn’t happen, but it does affect the risk-benefit calculation, he said. Many patients with devastating diseases, such as muscular dystrophy, cystic fibrosis, and Huntington’s disease, as well as certain cancers and rare diseases for which few treatments are available, will accept the unknown chance they’ll experience some harm from an experimental therapy if it also might lessen their symptoms or extend their lives.

Trials that include such patients are ethically acceptable, whereas the possibility of serious side effects may make trials of less urgent therapies unacceptable. A clinical trial of a CRISPR-based treatment for color blindness, for example, might not be worth the risk.

“For [gene] editing you’re going to be focused for a while on diseases in which there is significant unmet need, not a lot of alternatives, and where the risk tolerance would be higher,” Wilson said.

“It’s going to be a long road before we get to the point where editing would be deemed safe enough for diseases other than those that have really significant morbidity and mortality,” he added.

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https://www.sciencehistory.org/distillations/the-death-of-jesse-gelsinger-20-years-later

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Covid-19 Vaccine: Gene Therapy Risks

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Biotech firms go to great lengths and spend hundreds of millions of dollars trying to make sure their products are effective and safe, but preclinical testing in animals and cell cultures goes only so far. Bosley said during her talk at the Science History Institute that the only way to see if a treatment really works is to put it into a person.

“The genetic context of a mouse or a rat has nothing to do with human genetic context. You just can’t know. You are taking a greater leap into the unknown with these kinds of experimental medicines,” she said.

“The FDA has learned lessons, the industry has learned lessons, and I think we are all seeking to be very careful in how we advance,” she said. Yet “the risk never goes away. That’s what it takes to make new medicines.”

https://www.sciencehistory.org/distillations/the-death-of-jesse-gelsinger-20-years-later

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Reminder

A lot of researchers have a financial stake in what they’re working on

sm.stanford.edu

Jesse's legacy - 2011 SPRING - Stanford Medicine Magazine

by Rosanne Spector

Eleven years after his son’s death, the heartbreak in Paul Gelsinger’s voice is clear. Jesse Gelsinger would have been 29 today. Instead his name is synonymous with the colossal failure of a clinical trial.

Jesse Gelsinger was born with a rare and sometimes fatal metabolic disorder, ornithine transcarbamylase deficiency syndrome, which causes ammonia to build up in the blood and can cause liver and nerve damage, lethargy and coma. Jesse’s case was not severe, and he was able to live a relatively normal life, controlling the disease through medication and diet. At 18, on Sept. 9, 1999, he entered a clinical trial run by the University of Pennsylvania aimed at developing gene therapy for infants born with the illness. His motive was pure altruism, as any treatment from the trial would most likely have had no impact on his life. Eight days later he was dead, apparently having suffered a massive immune response to the virus that was a component of the trial’s injections. Jesse Gelsinger became the first person ever publicly identified to have died in a clinical trial for gene therapy.

An investigation by the federal Food and Drug Administration found widespread problems. These included conflicts of interests, researcher misconduct and the failure to tell the young man and his family about the potential hazards of participation in the clinical trial.

If a young person’s death can ever be said to have meaning, Jesse’s did — it forever changed clinical research. His legacy is a warning to all researchers about the dangers of clinical trials with human subjects.

Gelsinger spoke about clinical trials and ethics with Paul Costello, the School of Medicine’s chief communications officer.

Costello: Eleven years after your son’s death, do you think that human subjects are any safer?

Gelsinger: The system hasn’t changed dramatically — not enough for me to be comfortable with it.

Costello: Why do you say that?

Gelsinger: I worked at this for seven, eight years, and I became really frustrated with the lack of change. The only changes that came about were at institutions where they got caught — institutions that were found to be lax in their ethical review and conduct in research. The University of Pennsylvania has a model program now, but it’s only because of what happened to Jesse there and the awareness it brought about. Unless this happens at many more institutions, and we have some concise guidelines for ethical conduct, I’m not really comfortable that things have changed enough.

Costello: What do you think are the most significant gaps that need to be addressed?

Gelsinger: For me, the primary one is conflict of interest related to financial matters. A lot of researchers have a financial stake in what they’re working on — they’re involved with companies that have a stake in the outcome of the research. And a lot of the medical institutions have ownership in these companies. The money puts blinders on people. Going after prestige is part of it too, but primarily it’s the money.

In my case, I came to see that these were not bad men who did this; these were very qualified scientists. It’s the companies pushing for these technologies. They want results, and they put pressure on these researchers, and so the researchers push the envelope further than they should.

Costello: I’m sure people have sought advice from you over the years about whether they should participate in clinical trials. What do you tell them?

Gelsinger: I try to steer away from giving advice, but if it’s somebody I know personally, then I just advise them: Be very careful. There are a lot of hidden things going on that you’re most likely not aware of. Try to get an advocate, somebody who’s got a lot of medical knowledge and can be there to ask the right questions and find the answers that you need.

Costello: What’s your message to those in government who oversee clinical trials?

Gelsinger: The whole system should be spending a whole lot more money on the ethical oversight of research, and they should be pushing for it all the time.

Costello: What has your experience with clinical trials taught you?

Gelsinger: I never will trust the system again. It was my first and only experience with clinical research, and you can be sure that I will not participate in a clinical trial, probably even if it would save my life.

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https://sm.stanford.edu/archive/stanmed/2011spring/article2.html

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Costello: You wouldn’t ever, ever participate in a clinical trial?

Gelsinger: The system’s not trustworthy yet. We need to get walls up to prevent financial conflicts of interest. Companies that want to do research shouldn’t be the sponsors, directly, of that research. They should not be able to have any communication with the researchers directly. There should be intermediaries that handle the money and the information. We should get this thing so it’s right and ethical. But I don’t see that happening. I think the laws that are in effect are there because of pressure from the financial interests that stand to benefit.

I’m a far less trusting person than I used to be, and that’s a shame. I want to trust people, and especially the medical profession, and it was just such a disappointing, disheartening experience. I still rely on doctors. I just had knee surgery this year, but I ask a lot of questions that have doctors raising their eyebrows at me.

Costello: What do you ask?

Gelsinger: Well, I get into, “So, how did you come to use this technology?” and “How many patients have been treated?” and “What kind of negative effects is it having?”

Costello: I read that you scattered Jesse’s ashes at Mt. Wrightson, outside Tucson where he grew up. I wondered if you ever return up there and if you do, what are your thoughts when you’re standing there?

Gelsinger: I haven’t been there in about four years because my knees started giving me so many problems. One of my goals is to be able to hike up to that mountain again. And I know they had to do clinical research to develop the implants that would make that possible.

Costello: So your message isn’t stop clinical trials. Your message is get it right.

Gelsinger: Absolutely. Get it right. Go about it with the same intent that my son had. He had a heart of gold. What he did wasn’t for himself, it was for others. Hopefully the system can work the same way he did.

https://sm.stanford.edu/archive/stanmed/2011spring/article2.html

Joseph Stealin

https://t.me/RGiuliani/1103