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ELSI Panel Dives Into Germline Gene Editing at Biology of Genomes

COLD SPRING HARBOR, NY (GenomeWeb) – Germline genome editing looks increasingly as if it could become a reality, prompting a panel at the Biology of Genomes meeting here this week to discuss its potential ethical and societal effects.

The ethical, legal, and social implications panel, moderated by the National Human Genome Research Institute's Nicole Lockhart, discussed how advances in somatic DNA editing could lead to germline editing, which is fraught with additional ethical considerations. The panel — made up of the Altius Institute for Biomedical Sciences' Fyodor Urnov, Johns Hopkins Berman Institute of Bioethics' Debra Mathews, Ryan Fischer from the Parent Project Muscular Dystrophy, and Rosario Isasi of the University of Miami — also addressed how the possibility of germline gene editing is raising safety, consent, and equity concerns.

While gene editing has been around in various forms for years, the panelists noted that developments in and the relative ease of CRISPR-based gene editing are pushing the field along quickly.

The first gene editing clinical trial — using zinc finger nucleases — started in 2009, according to Urnov. Sangamo Therapeutics, where he used to work, targeted the CCR5 gene for disruption in a bid to treat HIV as the virus relies on the protein that gene encodes to enter cells. In 2015, another clinical trial used TALENs to target immune genes in children with leukemia. Last year, the first in vivo clinical trial of ZFN-based gene editing for Hunter syndrome began. And, this year, he noted, a CRISPR-based gene-editing trial in patients with beta-thalassemia is set to begin.

But what about the next generation, Urnov asked. For instance, variants causing beta-thalassemia could be edited out of the germline and reduce the public health burden. However, he noted that other approaches, such as carrier screening and pre-implantation genetic diagnosis, could likewise limit the transmission of the condition.

Therefore, he said, the question must be asked: "In what specific context will it be medically appropriate to use embryo editing?"

Thus far, embryo editing has been limited to non-viable embryos. In 2015, researchers from Sun Yat-sen University in Guangzhou, China, edited the beta-globin gene involved in beta-thalassemia in non-viable embryos, as they reported in Protein & Cell at the time.

This, Hopkins' Mathews added, touched off a flurry of opinion pieces that argued that gene-editing technology isn't yet ready for prime time and that more discussions of germline gene editing were needed.

However, she noted that that conversation has been going on for decades, pointing to a 1982 report on the social and ethical issues of genetic engineering in humans. In these previous discussions, Mathews said the main conclusions have been to not perform germline editing of people, as it's not safe.

"But now we can see a path to safety with CRISPR," she added, noting that researchers are working on limiting off-target effects and mosaicism.

And patients and parents want it, Fischer, from the muscular dystrophy organization, said. He noted that somatic gene editing seems promising for treating conditions like muscular dystrophy, which is an X-linked, pediatric-onset condition. He said that when he told a parent that he'd been on a panel to discuss the ethics of CRISPR, her response was, "Ethics, shmethics, my son needs a therapy now." This was only partly said in jest, he added.

But, as Mathews noted, somatic gene editing isn't as concerning to people as germline editing is. "People are much more comfortable editing people in front of them than future people," she said.

That, Miami's Isasi added, is exemplified by the varying legal status of embryo research around the world. She and her colleagues surveyed 16 countries to examine the global climate of embryo research. For human germline genetic modification, they found a range of policies, from permissive ones in China to intermediate ones in the US and restrictive ones in Canada and France, as they wrote in Science in 2016.

Editing of embryos also raises consent issues, Mathews said. There are concerns that editing would then limit that person's right to an open future, possibly affecting their future treatment choices. And what might be medically or socially acceptable at one point in time may later change.

Fischer further noted that patients and parents may also be so caught up in the promise of gene editing to provide a cure that they may consent too readily without taking in the risks.

Judging by the cost of gene therapy, gene editing is also likely to be expensive, which may limit treatments based on it to the affluent, the panelists said. The new gene therapy to treat retinal dystrophy, Spark Therapeutics' Luxturna, costs $850,000 for both eyes. Kite Pharmaceuticals' Yescarta, a CAR T-cell therapy for lymphoma, has a price tag of $373,000 and Novartis' CAR T-cell therapy for pediatric acute lymphoblastic leukemia, Kymriah, is $475,000. However, gene therapy companies have been considering alternate payment models, such as pricing based on how well the treatment works.

But as of now, germline CRISPR editing is likely going to be for rich people who want genetically related children and who can't have them today, Mathews said. When asked how researchers could try to make it more equitable, she said they could keep concerns like ease of use or refrigeration in mind when developing new technologies so that treatments aren't limited to large academic medical centers or are easier to store in more areas.

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