CLN1 Enzyme Replacement Therapy Shows Promise in Animal Models
ERT found to lessen motor dysfunction in mouse, sheep models
An experimental enzyme replacement therapy (ERT) — one injected directly into the brain — was found to lessen motor dysfunction and nerve cell death in mouse and sheep models of infantile Batten disease, a new study reports.
Collaborations Pharmaceuticals, 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 are expected to support an application seeking permission from regulators to start in-human testing of the therapy.
“This work will set the stage for future clinical studies,” Sean Ekins, PhD, CEO of CPI, said in a company press release.
Ekins noted that CPI is seeking to collaborate with pharmaceuticals or other companies to advance the ERT’s development.
“CPI holds the orphan drug and rare disease designations from the Food and Drug Administration for this potential treatment which we are focused on commercializing. We welcome discussions with other rare disease companies and potential partners that would be interested in learning more,” Ekins said.
The study, “Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep,” was published in The Journal of Clinical Investigation.
Testing enzyme replacement in animals
Infantile Batten disease, also called CLN1 disease, is caused by mutations in the gene that provides instructions for making an enzyme called palmitoyl-protein thioesterase-1 (PPT1). The aim 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 worked to develop a recombinant or lab-made version of human PPT1, referred to as rhPPT1.
Now, researchers at CPI and other institutions tested this potential ERT in animal models of infantile Batten disease.
First, in a mouse model, mice were given 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 collected for analysis.
Batten mice given an inactive vehicle treatment had virtually undetectable levels of PPT1 activity. But those treated with rhPPT1 had about 64% of typical activity in the brain, and 38% in the spinal cord, the data showed. The treated Batten mice also had less loss of nerve cells and less activation of inflammatory brain cells.
Without treatment, mice in this Batten model typically will begin to exhibit pronounced abnormalities in gait, or walking ability, starting around four months of age. By contrast, mice treated with rhPPT1 demonstrated “an overall gait performance more like 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 six months of age.
In another set of experiments, the researchers tested other methods of rhPPT1 administration in mice, particularly intrathecal injection, in which the therapy is administered into the spinal cord. However, the effects of treatment were generally strongest with intracerebroventricular administration.
“Compared to intracerebroventricular delivery, there was less overall therapeutic benefit upon the brain after intrathecal rhPPT1 delivery,” the researchers wrote. “Splitting the same total dose of rhPPT1 across both delivery routes was also less effective against all outcome measures, suggesting that a certain threshold of rhPPT1 activity must be reached for ERT to be effective.”
“These results suggest the efficacy and feasibility of the repeated ICV [intracerebroventricular] delivery of the recombinant enzyme and are an important next step before clinical testing,” Ekins said.
The scientists next tested rhPPT1 treatment in a sheep model of infantile Batten disease. Similarly to results in the mouse model, data suggested that the treatment increased enzyme activity and reduced nerve cell death in the sheep’s brains.
“Our data show that repeated dosing of rhPPT1 is an effective therapy in CLN1 disease animal models across different species. These results represent a key step towards clinical testing of ERT in children with CLN1 disease,” the researchers concluded.
This study was funded by grants from the NIH and from several academic and charitable organizations.