Optogenetics trial participants must be aware of ‘large range’ of risks
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Although optogenetics may partially restore vision to patients with severe vision loss, there are ethical issues and risks that clinical trial participants must be made aware of, according to a published review.
“While there are many novel technologies entering clinical trial which may have profound benefits to individuals and society, clinicians and trial participants must not be blind to their potential short- and long-term risks of harm,” Alexander R. Harris, MD, of the University of Melbourne, and Frederic Gilbert, PhD, of the University of Tasmania in Australia, wrote in Graefe's Archive for Clinical and Experimental Ophthalmology.
New technology like optogenetics, which uses the application of light to genetically modify target cells, offers treatment potential for conditions such as retinitis pigmentosa, Parkinson’s disease, addiction, schizophrenia, autism and depression, according to the authors, who stress that clinical trial participants “must be made aware of the large range of short- and long-term risks to ensure they can provide appropriate informed consent.”
A current phase 1/2a trial aims to assess the 1-year safety and tolerability of a single dose of adeno-associated viral vector to deliver genes coding for an optogenetic protein. While the trial will provide critical information regarding safety and efficacy, Harris and Gilbert note that protein expression and function may vary among recipients receiving equal doses.
“Participants who receive some therapeutic response may only have activation in small regions of the retina, limiting their field of view,” they wrote. “It is also unknown how long protein expression will persist or if phototoxic effects will occur, so a therapeutic dose may degrade over time. As a result, some patients may require multiple doses to achieve a therapeutic response. This raises the risk of a potential immune response which is not being assessed in the current trial.”
According to Harris and Gilbert, other concerns include the inability for participants to withdraw from the trial after inoculation or to seek more effective treatment options in the future, due to the irreversibility of optogenetics. They note that attempting to reverse the procedure may result in “severe harm,” such as scar tissue formation and surgical trauma.
In addition, unexpected consequences, such as the premature termination of a trial, may leave participants irreversibly inoculated or without access to resources the trial provided to help them retain vision, including goggles that deliver a high-intensity image.
Harris and Gilbert conclude that if optogenetics is deemed effective and safe for neurodegenerative diseases, there is a “strong chance” it will impact life expectancy and disease trajectory but may also induce iatrogenic harm, making it critical that clinical trial sponsors provide resources and ongoing support for participants. Further, optogenetic interventions should be distributed by the public health care system wherever possible to “ensure a fair and equitable approach over all strata of the population, eliminating potential injustice in treatment administration.”
Perspective
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Our duty as clinicians is not only to diagnose retinitis pigmentosa, but to educate patients and manage their condition. This includes discussion and potential recommendation of novel clinical trials available for participation.
Optogenetics is a form of gene therapy that induces irreversible changes. Although it has the potential for partial recovery of visual function, practitioners must address the ethics surrounding risks and informed consent in ongoing experimental optogenetics trials.
The current trial involved delivery of genes through an adeno-associated viral vector, after which participants wore goggles that delivered a high-intensity image to the treated retina. The primary outcome was safety and tolerability of a single viral dose over a 1-year period. Risks of treatment include development of an immune response if patients require multiple doses to achieve therapeutic response, alongside variability and unpredictability of side effects associated with gene therapy. Moreover, patients should be made aware of their right to withdraw in clinical trials, because reversibility of optogenetics is limited, and participation may prevent eligibility for future treatment. Post-trial obligations must also be discussed, such as access to goggles and facilities. Ultimately, participants must be fully informed of the short and long-term risks that these optogenetics clinical trials pose
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