New retinoid treatment partially restores sight in adult mice

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Scientists are looking for treatments to recover sight and reverse blindness in adults. Vradiy Art/Stocksy
  • Researchers investigated whether synthetic retinoid drugs could improve vision in adult mice with an inherited form of blindness.
  • They found that the treatment increased the activation of vision-related neurons in the brain and retina.
  • Further studies are needed to understand if and how these findings translate to humans.

Leber congenital amaurosis (ACL) is a rare genetic eye disease that begins at birth or in early childhood. Symptoms include significant visual impairment, involuntary eye movements, and discomfort in bright light.

ACL primarily affects retinal photoreceptors, neurons that convert light into electrical signals for interpretation in the brain. At least 27 genetic variants can lead to this condition.

In recent years, many strategies to treat childhood blindness have been studied, including gene editing approaches, gene replacement therapyand pharmacological agents.

Studies have shown that synthetic retinoid treatments are well tolerated and rapidly improve visual function in some children with ACL. However, the extent to which these pharmaceutical methods can improve visual circuitry in adults remains unclear.

Recently, researchers tested the effects of synthetic retinoids in an adult mouse model of ACL.

They found that administration of retinoid compounds resulted in higher activation of neurons associated with vision in the brains of adult mice.

The study was published in current biology.

Commenting on the results, Dr. Rando Allikmets, professor of ophthalmic sciences in the Department of Pathology and Cell Biology at Columbia University, who was not involved in the study, said Medical News Today:

“The study showed that some brain plasticity remained in the mice born blind, which could help restore vision, i.e. the brains of people born blind can still receive and process the visual signals.”

“This goes against the common perception that if the brain is ‘untrained’ in individuals who have never had acceptable vision, there is no hope. This study suggests that there may be [indeed be some hope, and that is the] new and exciting part of the conclusion of the study.
— Dr Rando Allikmets

For the study, the researchers administered a synthetic retinoid known as 9-cis-retinyl acetate – which has previously been shown to improve vision in children – to adult mouse models of ACL.

The mice received injections for seven consecutive days and were monitored thereafter.

The researchers noted that the mice that received the drug experienced more electrical activity in their retinas when exposed to light and higher optomotor reflexes (OMRs) – orientation behavior related to visual movement – ​​by report to witnesses.

Previous studies have shown that cone photoreceptors completely degenerate in mouse models of ACL at postnatal day 42.

Based on immunostaining tests, the researchers noted that mice treated with retinoid treatments likely experienced increased retinal electrical activity and OMR from restored photoreceptor function.

They further noted that the treatment resulted in more primary visual cortex activity and that this was maintained for at least nine days after treatment, with the therapeutic effects remaining for 27 days. OMR improvements were also maintained for at least 19-20 days after treatment.

Although primary neurons in the visual cortex that responded to light stimulation from the eye on the opposite side doubled after treatment, they became less responsive over time.

Meanwhile, signals from the ocular pathway on the same side increased the number of neurons activated immediately after treatment and during the post-treatment period by a factor of 5.

“It is traditionally thought that if the brain does not receive electrical signals from the eyes during early development, it never ‘learns’ the ability to process visual stimuli – a sort of ‘use it or lose it’ situation at the cellular level,” said Dr. Tim Corson, Merrill Grayson Senior Professor in the Department of Ophthalmology at Indiana University School of Medicine, who was not involved in the study. DTM.

“Patients (or mice) with ACL type 14 cannot produce a chemical ‘retinoid’ needed by photoreceptor cells in the retina to convert light energy into electrical signals. It is known that treating animals or humans with this retinoid circumvents this problem, allowing the retina to partially function,” he added.

“What is surprising about this new study is that retinoid treatment not only rescued retinal function in mice with ACL type 14, but also boosted activity in the part of the brain where signals visuals are processed. This suggests that neural pathways in the eyes of adult mice with ACL can still “learn” to process information from the retina, resulting in fairly good vision after treatment. »
— Dr. Tim Corson

The researchers concluded that their findings demonstrate the plasticity of the adult central visual system as well as the potential of retinoids to treat adults with retinal diseases.

Asked about the limitations of the study, Dr. Corson noted that because vision improvements were only evident for a few weeks, repeat doses of retinoids would be needed for long-term treatment.

“More behavioral analyzes are needed in the future to determine what this means functionally, and the full picture of how these vision improvements would appear to human ACL patients remains to be seen,” he said. -he declares.

“Finally, only one model of ACL disease – type 14 – was studied. It is likely that these findings could translate to other forms of stroke and retinal blindness, but this will need to be explored,” he said. -he adds.

Dr. Abigail Hackam, professor of ophthalmology at the University of Miami Miller School of Medicine, who was also not involved in the study, pointed out that the study was only conducted in animals. .

“A limitation, of course, is that the study was conducted on mice. Many results from experimental studies performed on rodents can be extrapolated to humans, but certainly not all. identify the underlying mechanisms that lead to the rescue of visual function, which could also lead to the development of new effective treatments that would eventually be tested in patients using carefully designed clinical trials.

Dr. William Merigan, professor of ophthalmology at the University of Rochester Medical Center, who was not involved in the study, said:

“Retinal therapies such as those described [one] here are quite effective in restoring restored vision to affected children, and one may be interested to see if giving this treatment to adults will also work or if recovery will be blocked by the deprived brain. This remains complicated since the photoreceptors involved here [were] degenerate in the mouse disorder studied in this manuscript.

Dr Merigan acknowledged that the data from this vision restoration study was carefully collected, but did not yield “a strong take-home message that cannot be changed by future work”.

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