Gene therapy shows benefit in late infantile Batten disease model
Treatment seen to slow disease progression, preserve vision in sheep model
Delivering a CLN5-targeted gene therapy simultaneously to the brain and eye in a sheep model of late infantile Batten disease was found to slow or even halt disease progression, a study reported.
The disease was slowed in sheep treated in the pre-symptomatic stages — before showing any signs of the genetic disorder — with a moderate dose of the treatment. Disease progression was delayed or halted in animals with early or advanced symptoms that received a high dose of the gene therapy, with visual function being preserved in both cases.
These results could potentially translate into people, the researchers noted, saying that the data supported the launch of the first-in-human clinical trial testing the gene therapy in children with CLN5 disease.
“These findings hold translational promise for extending and improving the quality of life in both pre-symptomatic and symptomatic CLN5 patients,” the team wrote.
The Phase 1/2 trial (NCT05228145) is testing NGN-101, Neurogene’s CLN5-targeted gene therapy, in about six children, ages 3-9, with genetically confirmed CLN5 disease. Children will receive one of three doses of the CLN5-targeted gene therapy delivered a single time into the brain and eye on the same day. Patients will be monitored for five years to assess long-term treatment safety and efficacy.
The findings of the animal study were detailed in “Efficacy of dual intracerebroventricular and intravitreal CLN5 gene therapy in sheep prompts the first clinical trial to treat CLN5 Batten disease,” published in the journal Frontiers in Pharmacology.
Late infantile Batten disease now lacks treatment
CLN5 disease, a form of late infantile Batten disease, is a neurodegenerative disorder that can cause vision loss, intellectual disability, developmental regression, and premature death in children. The condition, caused by mutations in the CLN5 gene, currently lacks treatment. Yet, due to its genetic cause, CLN5 disease is considered an attractive potential target for gene therapy.
Researchers in New Zealand in a previous study assessed the therapeutic benefits of a CLN5-targeted gene therapy when injected into the brain of a naturally occurring sheep model of CLN5 disease.
The gene therapy was found to safely delay disease progression, prevent brain tissue loss, and prolong sheep survival. Although treatment also delayed vision loss, the treated sheep eventually became blind.
Now, researchers assessed the therapeutic benefits of simultaneously administering the one-time gene therapy into the brain, by intracerebroventricular (ICV) injection, and into the eye, by intravitreal (IVT) injection. The sheep were in three different stages of the disease: pre-symptomatic; early symptomatic; and late symptomatic.
ICV injections were administered to both sides of the brain, with IVT injections given only to the left eye. The right eye served as a control.
Pre-symptomatic sheep received a moderate dose of the therapy, while early and late symptomatic animals were given a high dose. Each treatment group was composed of three sheep. Healthy sheep and sheep with CLN5 disease who were given no treatment also were included as controls.
CLN5-targeted gene therapy shows benefits at all disease stages
Over the course of two years, the therapy was generally well-tolerated, with most animals showing clinical benefits.
While declines in clinical status were observed over time in untreated CLN5 sheep, disease progression was slowed in pre-symptomatic animals that had been treated with a moderate dose of gene therapy.
In sheep at early and advanced symptomatic stages, a high dose of the gene therapy delayed or even halted disease progression.
Compared with untreated CLN5 sheep whose vision steadily declined, a high dose of the gene therapy preserved vision function for two years in sheep at early and advanced stages of the disease.
Collectively, these findings indicate great translational promise for extending and improving vision and other core symptoms in both pre-symptomatic and symptomatic CLN5 [late infantile Batten disease] patients.
In pre-symptomatic sheep, the gene therapy was less effective: two of the three sheep were deemed to be functionally blind and the third was running into objects. However, these sheep received a 10 times lower dose of the gene therapy given by ICV injection (the dose administered by IVT injection was identical).
Further maze tests confirmed these findings. Cognitive and visual function was sustained in the early symptomatic sheep, with the animals completing the maze as fast as healthy sheep (average time of 28.8 vs. 27 seconds). Two of the three sheep with advanced symptoms also completed the maze within an average time of 27.3 seconds over their lifetime.
Only one of the three pre-symptomatic sheep completed the maze, within an average time of 28.3 seconds. Untreated CLN5 sheep failed to complete the maze starting at 19 months of age, and were unable to do the test once they reached the age of 21 months.
Treatment also delayed brain tissue loss across all groups. This was in contrast with untreated animals that rapidly developed brain atrophy, or shrinkage. Evidence of lower neuroinflammation and reduced accumulation of waste products in the brain also were found in the treated animals.
Increases were seen with treatment in the levels of the CLN5 protein in the brain and spinal cord of treated sheep, which was virtually nonexistent in untreated sheep.
“Collectively, these findings indicate great translational promise for extending and improving vision and other core symptoms in both pre-symptomatic and symptomatic CLN5 patients,” the researchers wrote.
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