Michelle Hastings, PhD, director, Center for Genetic Diseases, was recently awarded a $2.3 million grant from the National Institutes of Health to address an urgent need to discover treatments for CLN3 Batten disease, a fatal neurodegenerative disease affecting young children.

CLN3 Batten disease is a lysosomal storage disorder (LSD) among about 50 such inherited metabolic disorders caused by a defect in any of a number of different genes, all of which encode a component of cells critical for digestion and recycling of cellular material. Children with CLN3 Batten disease carry a defect in their genetic code that disrupts the CLN3 gene, a key factor in the cellular waste management process, which is particularly important to neuronal function.

... studies suggest that our approach may provide an effective treatment in patients

Dr. Hastings is an expert in modulating gene expression, including the development of antisense oligonucleotide (ASO) technology or genetic “patches,” a therapeutic platform with potential applications for a large number of inherited diseases.

Scientists at RFU, including Dr. Hastings and Jessica Centa, the project lead and a graduate student in her lab, recently published a study in Nature Medicine, showing that disease symptoms in murine models with CLN3 Batten disease can be lessened through the application of ASOs designed to attach specifically to the disrupted CLN3 gene product.

“Our study tested a novel approach to therapeutically target the expression of the most common cause of the disease using small modified nucleic acid sequences — ASOs — directed to the mutated form of the gene,” Dr. Hastings said. “These results are a critical step toward our long-term goal of developing a treatment of CLN3 Batten disease.”

When rodents were injected with the therapeutic CLN3 corrector, their lifespan was extended, motor skills improved and waste buildup in the brain was lessened. Dr. Hastings, lead author of the study, describes the work as “a surprising demonstration that partial correction of the defective CLN3 gene can lead to meaningful improvements in an animal model with this disease.”

The researchers also demonstrated that human cells cultured from CLN3 Batten patients respond to treatment in a manner that indicates a reversal of cellular defects.

“We have work to do before this therapeutic will be ready to test in humans, but the animal studies suggest that our approach may provide an effective treatment in patients,” Dr. Hastings said.

Further development of the therapeutic approach is supported by the new NIH grant, which was awarded in partnership with colleagues in the Pediatrics and Rare Diseases group at Sanford Research, Sioux Falls, SD, led by neuroscientist Jill Weimer, PhD.

“Our team of scientists has vast expertise in protein interaction analysis and cell and animal models of Batten disease to ensure our success in fulfilling our aims,” Dr. Hastings said. “Those aims include understanding CLN3 function, determining the requirements for recovering function, advancing a therapeutic ASO for treating CLN3 Batten disease, and informing therapeutic approaches for other LSDs.”