LAUSR

We’d like to thank Lindner for his response “The thin line between seeing risks and venturing scientific progress” [1] to our article “Restoring vision using optogenetics without being blind to the risks” [2]. Our article highlighted some potential risks of a clinical trial of optogenetics treatment for retinitis pigmentosa which showed significant potential after a first-in-human trial demonstrated partial recovery of visual function in a blind patient [3]. In highlighting the potential risks to first-in-human trial participants, we referenced some well-known adverse events from previous clinical trials and other risks discussed in the scientific literature or mass media. A potential immune response to the viral vector is only one risk associated with these types of trials. Lindner has correctly pointed out the difference between adeno-associated virus (AAV) and adenovirus vectors and that the current COVID-19 vaccines are in fact adenovirus vectors, and not AAVs. However, these examples were not intended to raise specific concerns about individual viral vectors but rather to demonstrate that the risks associated with these types of trials may be difficult to predict or unexpected, can have very low occurrence rates, or appear at time intervals long after initial treatment. Even when a similar therapy has successfully passed through clinical trial, a novel therapy can have a different risk profile. So while AAV2.7m8 might have shown greater transduction efficacy in preclinical studies compared to the already approved wildtype AAV2, it may yet induce unexpected side effects and not receive regulatory approval. A main concern for these types of trials is their irreversibility, which prevents patient’s right to withdraw from the trial and affects their opportunity and eligibility for future treatments [4]. From this standpoint, running irreversible clinical trials for “the sole purpose of novelty” would be unethical. For instance, a company trialling a novel AAV that aims to replicate the performance of AAV2.7m8 only to evade intellectual property rights would place a patient at risk with limited benefit. In the current optogenetics trial, AAV2.7m8 was shown to have better efficacy than the already approved wildtype AAV2. Therefore, we believe that the use of AAV2.7m8 in the clinical trial was ethically justified. However, given the knowledge already available from previous clinical trials, we question whether the trial structure used for testing AAV2.7m8 was the most appropriate for minimising participant risk and maximising trial benefit. For instance, were the number of participants, length of the trial, and viral dosage study appropriate? What support is available to the participants at the conclusion of the trial whether it was successful or not? It also raises concerns about development of newer vectors or optogenetic sequences; what amount of improvement in preclinical trial data would justify a new vector or optogenetic sequence being trialled in humans and how should that trial be structured? At what level of development of optogenetics, bionic vision devices (or other therapies) would trials of novel therapies for vision loss become unethical? Lindner points out that COVID-19 and HIV are highly emotional topics and that raising documented adverse events from large-scale clinical trials of viral vector use may plant unnecessary concerns in potential optogenetics trial participants. However, all patients suffering from progressive, untreatable diseases are likely to be highly emotional, regardless of the disease prevalence or media coverage. And it is difficult to obtain accurate, long-term risk data from * Alexander R. Harris [email protected]