CLN1 enzyme replacement therapy shows promise in animals | Motor Dysfunction Attenuated by Batten ERT in Mouse and Sheep Models

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An experimental enzyme replacement therapy (ERT) – injected directly into the brain – has been shown to reduce motor dysfunction and nerve cell death in mouse and sheep models of childhood Batten disease, a new study reports.

Pharmaceutical Collaborations, known as CPI, recently received nearly $3 million in funding from the National Institutes of Health (NIH) to support toxicology studies of the ERT candidate. These studies should support a request for permission from regulatory authorities to begin human testing of the therapy.

“This work will set the stage for future clinical studies,” said Sean Ekins, PhD, CEO of CPI, in a company press release.

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Ekins noted that CPI is looking to collaborate with pharmaceutical or other companies to advance the development of ERT.

“CPI holds orphan drug and rare disease designations from the Food and Drug Administration for this potential treatment that we are focused on bringing to market. We welcome discussions with other rare disease societies and potential partners who would be interested in learning more,” said Ekins.

The study, “Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheepwas published in The Journal of Clinical Investigation.

Enzyme replacement test in animals

Infantile Batten disease, also called CLN1 disease, is caused by mutations in the gene that provides instructions to make an enzyme called palmitoyl-protein thioesterase-1 (PPT1). The goal of enzyme replacement therapy, also called ERT, is to administer a working version of this enzyme to “replace” the dysfunctional one.

Scientists at the University of Texas Southwestern Medical Center have been working to develop a recombinant or lab-made version of human PPT1, called rhPPT1.

Now, researchers at CPI and other institutions have tested this ERT potential in animal models of childhood Batten disease.

First, in a mouse model, mice received rhPPT1 monthly via intracerebroventricular infusion – an injection of the experimental ERT directly into fluid-filled cavities inside the brain. After six months, the mice’s brains and spinal cords were removed for analysis.

Batten mice given inactive vehicle treatment had virtually undetectable levels of PPT1 activity. But people treated with rhPPT1 had about 64% typical activity in the brain and 38% in the spinal cord, according to the data. The treated Batten mice also had less nerve cell loss and less activation of inflammatory brain cells.

Without treatment, mice in this Batten model will typically begin to show pronounced abnormalities in gait or walking ability, beginning at around four months of age. In contrast, mice treated with rhPPT1 demonstrated “overall gait performance closer to wild-type controls,” the researchers reported.

Mice treated with rhPPT1 also performed similarly to wild-type mice on the stationary rotarod test – a measure of balance and coordination – while untreated mice showed marked impairment at age. six months.

In another series of experiments, the researchers tested other methods of delivering rhPPT1 in mice, specifically intrathecal injection, in which the therapy is delivered into the spinal cord. However, treatment effects were generally strongest with intracerebroventricular administration.

“Compared to intracerebroventricular administration, there was less overall therapeutic benefit to the brain after intrathecal administration of rhPPT1,” the researchers wrote. “Fractionating the same total dose of rhPPT1 across both routes of administration was also less effective against all outcome measures, suggesting that a certain threshold of rhPPT1 activity must be reached for ERT to be efficient.”

“These results suggest the efficacy and feasibility of repeat ICV [intracerebroventricular] delivery of the recombinant enzyme and is an important next step before clinical testing,” Ekins said.

The scientists then tested the rhPPT1 treatment in a sheep model of infantile Batten disease. Similar to the results from the mouse model, the data suggests that the treatment increases enzyme activity and reduces nerve cell death in the brains of sheep.

“Our data show that repeated administration of rhPPT1 is an effective therapy in animal models of CLN1 disease in different species. These results represent a key step towards clinical testing of ERT in children with CLN1 disease” , the researchers concluded.

This study was supported by grants from the NIH and several academic and charitable organizations.

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