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A single injection into the brain of an experimental gene therapy currently in clinical trials partially prevented retinal degeneration and vision loss in a mouse model of CLN6 Batten disease, according to a study.

These findings mark the first report of brain-delivered gene therapy reaching both the brain and the eyes, and may help optimize gene therapies for CLN6 disease and other neurodegenerative diseases affecting the retina – the ocular layer. which sends vision signals to the brain.

The results also add to previous data showing that this treatment prolonged the lifespan of mice and decreased their motor and cognitive impairments, underscoring the potential overall benefits of the therapy, which is being evaluated in a phase clinical trial. 1/2 (NCT02725580) of CLN6 disease. the patients.

The study, “Intracranial administration of AAV9 gene therapy partially prevents retinal degeneration and visual deficits in mice with CLN6-Batten disease, ”Was published in the journal Molecular therapy – Methods and clinical development.

CLN6 Batten disease – also known as a variant of late childhood CLN6 disease – belongs to a group of disorders called neuronal ceroid lipofuscinosis, in which waste molecules build up inside cells, primarily affecting the central nervous system (brain and spinal cord) and retina.

A thin layer of nerve cells lining the back of the eye, the retina picks up light through its photoreceptors and sends vision signals to the brain through the optic nerve (its only connection to the brain).

In a previous study, an experimental gene therapy using a modified and harmless adeno-associated virus to deliver a functional copy of CLN6, the mutated gene in Batten disease CLN6, has been shown to result in promising survival and clinical benefit in a mouse model of the disease.

The treatment was given directly into the ventricles of the brain – called intracerebroventricular injection (ICV) – of newborn (1 day old) mice. The ventricles of the brain are chambers filled with cerebrospinal fluid (CSF), the fluid that bathes the brain and spinal cord.

The therapy also appeared safe and remained active for six months when given directly into the spinal canal (reaching the CSF) of monkeys.

These positive results prompted the launch of a Phase 1/2 trial by Amicus Therapeutics testing the experimental therapy – named AT-GTX-501 when given into the spinal canal – in children with Batten disease CLN6 .

Data from interim trials showed that AT-GTX-501 was generally safe and stabilized motor and language function in these patients. These data, published at the end of 2020, reflected the condition of the patients two years after the single treatment.

“Although directing gene therapy to CSF ​​is a logical approach to treating the brain manifestations of the disease, it has always been considered unlikely to exert a therapeutic effect on the retina because CSF does not does not come into direct contact with ocular structures other than the optic nerve, “the researchers wrote.

Now, researchers from Amicus and several American institutions and universities have shown that delivering gene therapy directly to the cerebral ventricles filled with CSF not only reaches the retina, but also to some extent prevents retinal damage and blood loss. vision loss in a mouse model of the disease.

Similar to the previous mouse study, one day old mice received a single ICV injection of gene therapy (treated mice) or saline (untreated mice).

The results showed that the therapy completely prevented the loss of nerve cells associated with Batten in the visual processing centers of the brain. Compared to the untreated group, the treated mice also showed the presence of CLN6, CLN6-resulting protein, in the retina, which was associated with the preservation of photoreceptors in the central retina.

However, peripheral photoreceptors were gradually lost between 3 and 9 months, despite treatment, and were similar to the overall loss of photoreceptors seen in untreated mice. The reasons for these differential effects between retinal regions remain unclear, the team noted.

In addition, the treatment partially prevented vision loss in these mice, particularly in female mice, which had intermediate visual acuity compared to healthy mice and untreated mice. Yet their visual acuity showed significantly less decline over time than that of untreated mice.

The researchers suggest that further analysis of visual function over time might find additional benefits not detected with the technique used in their study.

These results demonstrated that a single dose of the therapy led to “marked preservation of neurons in both the central retina and central visual pathways of the brain” and “partial visual function” in these mice, wrote the researchers.

The data also suggests that “the IVC route of administration could potentially provide some benefit for retinal manifestations of CLN6 disease instead of follow-up injections directly treating the eye,” they added.

“We report the first case of damage and rescue of a viral gene delivered by the CSF [disease-associated features] both in the brain… and retinal neurons, thus partially slowing visual deterioration, ”the researchers wrote.

They also noted that these promising results could help develop more effective gene therapy strategies for CLN6 disease and other similar neurodegenerative diseases. Further studies, they added, are needed to clarify how such therapy delivered by the brain can reach the retina.


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