A gene therapy designed to provide a functional version of the CLN8 gene – the one mutated in people with CLN8, a form of Batten disease in late childhood – prolonged survival, reduced brain features associated with the disease, and partially corrected motor problems in a mouse model.
The results, possibly representing one of the most successful rescues reported in this animal model of the disease, highlight the potential of this type of genetic approach in the treatment of CLN8 and support its further development for this patient population. served, the researchers noted.
The study, “AAV9 gene therapy increases lifespan and treats pathological and behavioral abnormalities in mouse model of CLN8-Batten disease, ”Was published in the journal Molecular therapy.
CLN8 disease belongs to a group of disorders called neuronal ceroid lipofuscinosis, also known as Batten disease, in which waste molecules build up inside lysosomes, primarily affecting the central nervous system (the brain and spinal cord) and retina.
Lysosomes are small structures inside cells that break down waste and unused protein into smaller components to throw away or recycle.
A rare form of Batten’s disease, CLN8 is caused by mutations in the CLN8 gene, which provides instructions for making CLN8, a protein involved in transporting enzymes to lysosomes to break down waste.
In the absence of CLN8, lysosomes are depleted of key enzymes, which leads to the characteristics of Batten: toxic buildup of waste products inside cells, activation of glial cells, and neurodegeneration. Glial cells are non-neuronal cells that support and protect nerve cells.
Symptoms of CLN8 disease, which can appear between ages 2 and 10, include seizures, cognitive decline, vision problems, tremors, and difficulty walking. Patients generally have a reduced life expectancy.
“Various small molecule treatments have shown some efficacy in animal models of CLN8 disease, but none have been adopted clinically, resulting in an unmet need to stop or reverse disease progression.” The researchers wrote.
Gene therapy has shown promise in animal models of several types of Batten disease, some being tested in clinical trials, but this approach has not been tested in CLN8 disease.
Now a team of researchers in the United States, in collaboration with Therapeutic Amicus, evaluated the effects of gene therapy designed to increase CLN8 levels in a mouse model of CLN8 disease.
Notably, two candidates for Amicus gene therapy are currently being evaluated in clinical trials: one in another form of late childhood Batten disease (CLN6) and the other in juvenile Batten disease (CLN3).
CLN8-led gene therapy uses a modified and harmless adeno-associated virus serotype 9 (AAV9) to deliver a functional copy of CLN8 which has been modified to promote the production of CLN8 primarily in cells of the central nervous system (brain and spinal cord).
The treatment was given directly into the ventricles of the brain – called intracerebroventricular injection – of newborn (1 day old) mice. The ventricles of the brain are chambers filled with cerebrospinal fluid, the fluid that surrounds the brain and spinal cord.
The results showed that a single injection of gene therapy effectively promoted the production of CLN8 in all brain regions assessed, as well as in the spinal cord and kidneys, and over a period of 24 months (approximately two years).
The treated mice lived significantly longer than the untreated mice (median of at least 24 months versus 10 months) and showed survival comparable to that of healthy mice. This far exceeded the maximum 16% increase in survival reported to date for potential therapy in this mouse model, the team noted.
Gene therapy also resulted in a significant reduction in waste buildup inside cells and glial activation over 24 months, reaching levels indistinguishable from healthy mice on several occasions.
However, the treated mice still showed an increase in waste accumulation and glial activation between eight and 24 months, which, although they never reached those of untreated mice, suggest that the effect of rescue is incomplete.
Additionally, mice that received gene therapy performed similarly to unaffected mice and did significantly better than those that did not receive therapy in a number of motor tests, and showed almost complete absence. tremors associated with the disease. In complex behavioral tests, there was also evidence of potential improvements in vision with gene therapy.
The treatment was found to be safe and well tolerated, with no signs of side effects.
“These results demonstrate, by far, the most successful degree of rescue reported in an animal model of CLN8 disease, and they support the further development of gene therapy for this disorder,” the researchers wrote.
“This dosing regimen would be most representative of early postnatal treatment in humans rather than symptomatic stages, and the future adoption of neonatal screening for CLN8 mutations could make this type of treatment both realistic and feasible,” he added. ‘team.
Still, they noted that more studies are needed to optimize dose levels and timing, and to improve the effectiveness of therapy.