Germline Gene Editing for Deafness : The Hearing Journal

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Germline Gene Editing for Deafness

Nalley, Catlin

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The Hearing Journal 73(2):p 28,30,31, February 2020. | DOI: 10.1097/01.HJ.0000654908.10936.e1
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In November 2018, it was revealed that He Jiankui, a Chinese biophysicist, utilized CRISPR technology to gene edit human embryos in an effort to make them immune to HIV infection. They were then implanted, leading to the birth of twin girls. This announcement was met with condemnation across the scientific community, bioethical discussions on the safety and ethical implications of his work, and calls for a worldwide moratorium on human germline gene editing.

shutterstock/Pan Andrii, genetics, deaf, hearing loss, gene editing.

Despite the outrage at He—who was convicted of “illegal medical practice” in December 2019—and his experiments, another scientist recently announced his intention to utilize CRISPR in a similar manner, this time targeting hereditary deafness. In July 2019, Denis Rebrikov, a molecular biologist from Russia, shared his plans to prevent children from inheriting a form of deafness caused by mutations in the GJB2 gene. He told Nature that he has started gene editing eggs that were donated by hearing women to learn how to allow some deaf couples to have children without the genetic mutation associated with deafness. This research, he believes, will lay the framework for further clinical work; however, Rebrikov has noted that he will not move forward without the necessary regulatory approvals.

According to the CDC, 50 to 60 percent of hearing loss in babies is due to genetic causes. Researchers have identified a number of genes associated with hearing loss, including the GJB2 gene, which contains instructions for the connexin 26 protein. This protein is imperative for cochlear function. Another connexin gene, GJB6, is linked to hearing loss. This gene provides instructions for creating connexin 30.

The works of He and Rebrikov have incited intense discussions regarding the appropriate use of CRISPR/Cas9 technology, which can be utilized for both somatic and germline gene editing. Somatic gene editing is limited to the somatic cells; therefore, the changes only affect certain tissues and are not passed from one generation to the next. On the other hand, germline gene editing alters the genes in eggs or sperm cells or those of an embryo, which could be passed on to future generations. This is where ethical concerns arise.


It can be done, but should it? This is a question that many are debating when it comes to heritable genome editing, especially with regard to a non-life-threatening condition, like deafness.

“The frenetic pace at which CRISPR-based technologies have not only taken over basic research but also reached the clinic has given us little time to ponder the societal and ethical implications of using this technology on humans,” Rodolphe Barrangou, PhD, the editor-in-chief of The CRISPR Journal, wrote in a recent editorial. “Once again, technological innovation has outpaced the dialogue—even though, as we reviewed last year, there has been an awful lot of dialogue about guidelines and principles to manage the implementation of CRISPR, especially relating to its potential use in the human germline” (CRISPR J 2019;2[5]:247-8).

An important discussion surrounding the use of this technology for deafness and hearing loss centers around the question: Is deafness something that needs to be fixed?

“It has been made clear by different governing bodies that this technology really needs to focus on pertinent therapeutic diseases,” said Natalie Kofler, PhD, a trained molecular biologist and a lecturer in bioethics at Yale University and Harvard Medical School. “The challenge is where the line gets drawn between this and non-life-threatening applications, such as deafness.

“There is a lot of diversity in thinking about whether deafness is something that needs to be corrected—and whether correction is even the right word,” she continued. “It's unfortunate that this is the genetic mutation [Rebrikov] decided to focus on.”

As a historian of science, technology, and medicine who specializes in disability technologies, Jaipreet Virdi, PhD, an assistant professor at the University of Delaware, noted, “My research has shown that each time a new deafness cure is introduced, it is sensationalized widely and promoted as the new hope. What is this hope supposed to be for? Eradicating deafness? Something that most people have adjusted to during their lifetime and managed just fine with the assistance of hearing aids, cochlear implants, lip-reading, or sign language?

“There are rich Deaf cultures and communities that demonstrate how diversity livens our relationships with each other and deepens our understanding of oppression,” continued Virdi, who has been profoundly deaf since age 4 after losing her hearing to bacterial meningitis. “These are communities that, as many scholars and Deaf people have shown, have come a long way from marginalization and demonstrated their unique successes. So why this hope?

“Above all, improvement in science does not necessarily mean that we need to eliminate human variety, let alone human conditions that are absolutely not life-threatening,” she emphasized.


Hand in hand with these ethical considerations are the potential medical consequences of this approach. Since deafness and hearing loss do not pose a threat to a person's overall health, is it moral to use a technology that still hasn't been proven to be safe?

“We know from numerous sources that CRISPR-based gene editing, when introduced into a single-cell embryo, does not usually edit the genome right away. Rather, it only edits as the cell divides, which means the DNA may only be edited in one-half, one-quarter, one-eighth, or one-sixteenth of the cells in the baby by the time it is born,” said Brad Walters, PhD, an assistant professor in the department of neurobiology and anatomical sciences and the department of otolaryngology and communicative sciences at the University of Mississippi Medical Center (UMMC). “This means that there is a high likelihood of a gene edit being mosaic and therefore not actually occurring in the cells that will ultimately give rise to the cochleae—so the hearing loss might not actually be prevented.

“More importantly, the gene editing tool is known to cause off-target effects, so it could actually be introducing other mutations into the embryo that could have very serious effects not just in the ear but elsewhere in the body,” he continued.

“On top of the fact that the intervention might not be effective and is fraught with the risk of causing more harm than not intervening, you also have to weigh that there are still other options for those wishing to prevent or treat hearing loss or minimize the risk of having a child that will have a deafness-causing mutation. For example, cochlear implants, the use of a sperm or egg donor, IVF, and genetic screening of embryos, and simply waiting for the technology to be further developed and tested until it is safe.

“I am cautiously optimistic that cases like these, despite grabbing headlines, are rare, and that most researchers and clinicians are going to continue working toward safe and effective options (which may or may not involve gene editing) to prevent or reverse hearing loss,” Walters told The Hearing Journal. “And I think a lot of these potential options will be moving into clinical trials in the near future, and many of them will not involve gene editing, but other forms of genetic manipulation that are significantly less likely to have adverse effects or introduce mutations into the patients’ genomes.”


Many governing bodies and leaders in the field have sought to craft regulations that can keep pace with gene editing advancements and ensure its ethical use.

The World Health Organization has formed an expert advisory committee to “examine the scientific, ethical, social, and legal challenges associated with Human Genome editing. The aim will be to advise and make recommendations on appropriate governance mechanisms.”

An International Commission on the Clinical Use of Germ-line Genome Editing has also been created by the U.S. National Academy of Medicine and National Academy of Sciences and the United Kingdom's Royal Society.

“There needs to be a plan or vision in place to ensure we can utilize these technologies in a way that is indeed ethical and is not leading us toward the path of designer babies,” said Christopher Spankovich, AuD, PhD, MPH, an associate professor and the vice chair of research in the department of otolaryngology and communicative sciences at UMMC.

“It's a very complex and difficult topic,” he added. “Part of me, as a scientist, says let's move this forward. We're not going to figure out what works in humans until we do, and there's a lot of truth to that. However, you can't go into this with a gung-ho approach. We have to be very targeted and meticulous in how this technology moves forward because there are so many ethical considerations that have to be part of the discussion.”

A number of stakeholders have called for a moratorium on the use of this technology until appropriate regulations can be developed. However, some do not believe this is the best approach. In a recent article in The CRISPR Journal, Kerry Lynn Macintosh, JD, of the Santa Clara University School of Law, discussed the potential downsides of instituting a moratorium on heritable genome editing (HGE).

“In this Perspective, I should begin by stating I deplore premature and dangerous uses of HGE. However, I would argue that a moratorium is undesirable for three reasons: it may encourage participating nations to ban HGE or postpone access to it indefinitely; it may deter or delay basic research that could lead to safe and effective HGE; and it may induce participating nations to adopt or maintain laws and regulations that stigmatize children born with genomic modifications,” she explained.

“As an alternative, I recommend that nations regulate HGE for safety and efficacy only and without distinguishing between therapeutic and enhancing modifications” (CRISPR J. 2019;2[5]:272-9).

Kofler emphasized a need for better representation among those making the decisions regarding this technology and its use. “We need to open up these processes in the regulatory space so that we can have meaningful dialogue with different groups of people as well as the public to have more open deliberation about these technologies,” she noted.

“We also have to ensure there is diversity in laboratory research and diversity in leadership,” she continued. “While there has been progress, we still see a huge amount of gender disparity in that space, as well as underrepresentation of people of color and those that identify as having a disability.

“We have to start, in earnest, to create spaces more representative of the society that science is supposed to be improving. If you have a broader swath of people with more diverse lived experiences actually doing the research, that's really what leads to technologies and research that is truly representative of society.”


While gene editing embryos and research like Rebrikov's have gotten a lot of attention, there are a number of other uses for this technology that could one day impact hearing health care services and the patients who receive them.

When it comes to gene editing for deafness and hearing loss, there are a variety of avenues to explore, according to Walters. “For example, in my lab, we operate under this belief that at some point we're going to be able to create a therapeutic intervention to restore or rehabilitate hearing for someone who has sensorineural hearing loss,” he explained.

“Certainly, there's a fair number of people who have lost their hearing and would like to get it back if they can. And so, we are focused on trying to identify the genes that are important in regenerating the sensory cells in the inner ear.”

Walters noted that his team does not exclude the possibility that they will find a chemical or pharmacological tool to achieve this goal. However, he said as technology progresses, it is more and more likely that “at a certain point, it may be more straightforward to edit the genes or change the gene expression to bring about that outcome. There is a lot of hope in the field that there is a path forward where gene therapies or gene editing could be used to either prevent or reverse hearing loss for those who would want that treatment.”

While Walters and his colleagues are dedicated to accelerating discovery, they are cognizant of Deaf cultures and communities. “We're not actively trying to push these technologies and correct any and every hearing loss mutation that we come across,” he said. “We want to discover if it's possible, how it's possible, and present that option clinically. But then it's up to the individual to decide whether they want to live with hearing loss or in cases of progressive hearing loss, allow it to progress.

“Due to the nature of how early the onset of hearing loss is, I don't think the first gene editing or gene therapy approaches that you see for hearing loss are going to relate to embryos at all,” he continued. “I think there's a lot more focus on addressing more progressive or acquired hearing loss.

“So how do we balance technology and discovery while ensuring that we do not deny an identity or a culture that is very much a part of who a person is?” he asked. “We do not want to strip away anyone's identity, and that's something that we definitely try to keep in mind every day.”

When asked what audiologists should be aware of when it comes to this technology, Walters said, “The message for today is keep an eye out for it tomorrow. These technologies—both gene therapy and gene editing—are certainly at the forefront of research and it is moving beyond rodent models, but as of today, I don't think you're going to see anything in the clinic soon. While we can't put an exact timeline on it, I think we're still several years away from seeing these technologies in more clinical trials and even farther away from seeing them in daily practice.”


An important component of hearing health care is advocacy.

“There needs to be a greater awareness that a cure is not always the solution for deafness. Health care providers need to include information from Deaf social workers or ASL teachers when educating hearing parents about options for raising their deaf child,” Virdi recommended. “This is crucial for ensuring that hearing parents are fully educated about both medical and cultural resources so they can make an informed decision about their child.

“At the same time, my research has shown me that people will always seek out cures if they want them. But the kinds of cure that are available are not always safe or even necessary; thus, there should be strict selection procedures about who has access and why,” she continued.

Having audiologists and other clinicians in the room when discussing this technology is important to ensuring that the diverse voices of patients are heard, Spankovich emphasized. “It is our responsibility to support our patients,” he elaborated. “Advocating for Deaf culture is extremely important; we also need to advocate for patients who do want to see this technology move forward in an ethical and safe way.

“And then, we also have to advocate for the profession of audiology,” he continued. “Even with these technological developments and future advancements, there will always be a role for audiologists in enhancing the utilization of these technologies. These approaches will be more likely adjunctive therapies that can improve the system (not cures for hearing loss), and we will need providers who can identify how to best determine candidacy and outcomes alongside other interventions.”

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