Presymptomatic, symptomatic CLN5 sheep aided by gene therapy

Evidence suggests higher doses of NGN-101 are likely to be more effective

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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CLN5-targeted gene therapy safely preserved clinical function, prolonged survival, and prevented brain tissue atrophy in a sheep model of CLN5 disease, a form of late-infantile Batten disease, in a recent study.

The benefits were observed in sheep at both pre- and post- symptomatic stages, and the evidence suggests higher doses are likely to be more effective, particularly for those already exhibiting symptoms.

“This study indicates great translational promise for extending and improving the quality of life in post-symptomatic CLN5 patients,” the researchers wrote in “Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease,” which was published in Frontiers in Genetics.

The therapy, called NGN-101, has entered a Neurogene-sponsored Phase 1/2 clinical trial (NCT05228145), based on these and other preclinical findings. It’s recruiting about six children, ages 3-9, with genetically confirmed CLN5 disease at two sites in New York and London. The children will receive one of two doses and will be monitored for safety over five years.

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What does NGN-101 gene therapy do?

The gene therapy should provide a healthy version of the CLN5 gene. Mutations in the gene are the cause of CLN5 disease and result in a lack of the CLN5 protein that helps break down cellular waste products called lipofuscins.

As in other types of Batten disease, lipofuscins accumulate in cells, leading to symptoms such as vision loss, neurodegeneration, and seizures.

The naturally occurring sheep model of CLN5 disease was previously used to develop the gene therapy, which is delivered via injection into the fluid-filled cavities of the brain. This is called an intracerebroventricular (ICV) infusion.

The one-time gene therapy was found to slow clinical disease progression and brain volume loss when delivered to the sheep at 3 months of age, which corresponds to a presymptomatic disease stage. This supported the launch of the Phase 1/2 trial. The researchers have published additional long-term safety and efficacy data from the sheep model that were used to support the request to the U.S. Food and Drug Administration to begin clinical testing.

In these experiments, sheep at three different disease stages, presymptomatic (3 months), early symptomatic (6-7 months), and late symptomatic (9 months), were administered one of three different doses and monitored for clinical disease progression.

More than a year of post-treatment monitoring indicated the therapy was generally well-tolerated and most animals saw clinical benefits.

Survival was prolonged in 12 of 19 treated animals, several of which lived to more than double their natural life expectancy and reached similar weights as healthy sheep.

While declines in clinical status were observed over time in untreated CLN5 sheep, seven of nine asymptomatically treated sheep and five of seven early symptomatic treated sheep saw significant delays in clinical disease progression. Many sheep in these two groups had only mild symptoms for a long time after receiving the gene therapy before eventually declining.

One of the three animals treated at advanced disease stages who were already having substantial symptoms saw a significant slowing of disease progression. Vision was not preserved at any dose or administration age.

Other effects of NGN-101 gene therapy

The treatment also significantly delayed brain tissue loss for many animals and there was evidence of lower neuroinflammation and reduced accumulation of waste products in the brain.

The treatment was associated with increased CLN5 protein levels in the brain, which was virtually absent in untreated sheep. Higher doses of gene therapy were linked to more CLN5 in brain tissue and better efficacy outcomes in symptomatic sheep.

“Overall, these studies … demonstrate the long-term efficacy of ICV … gene therapy when delivered at pre-symptomatic, early symptomatic, and more advanced symptomatic disease stages at the doses administered,” wrote the researchers, who noted that CLN5 disease is usually not diagnosed until patients develop symptoms, which would correlate with the early symptomatic sheep in this study.

Use of ICV delivery was motivated by the fact that the most significant symptoms of CLN5 disease are neurological. The lack of effect on vision could be combated by simultaneously delivering the treatment to the eye. Indeed, preclinical studies indicate the effectiveness of an eye-targeted gene therapy against ocular symptoms in sheep, which scientists are continuing to investigate as a treatment strategy.

It’s possible that tissues outside the eyes and brain are affected, however. CLN5 sheep exhibit significant gastrointestinal involvement, for example.

“Future therapeutic strategies may be required for other pathologies,” the scientists wrote.