New Findings in Batten Disease Drug Research

According to RUSH researchers, the FDA-approved lipid-lowering drug gemfibrozil may stop the progression of juvenile Batten disease. The Journal of Neuroscience recently published the study’s findings.
Researchers discovered that gemfibrozil, also known by the brand name Lopid, helps to remove the autofluorescent pigment deposits that are a characteristic of the condition from the brain. The lipid-protein fragments that make up autofluorescent pigment deposits build up in the brain over time and suffocate healthy cells by depriving them of oxygen, which causes neuronal death.

Childhood-onset juvenile Batten disease is an uncommon but severe neurodegenerative condition that results in seizures, visual loss, and progressive neurological degeneration, which is the loss of brain structure and function. In the US, it affects two to four out of every 100,000 babies, according to estimates. Batten disease is inherited in an autosomal recessive pattern and is caused by the deletion of the CLN3 gene, which codes for the production of a protein that is present in all bodily tissues. There is currently no medication that can stop or slow the development of the condition. “Finding an effective drug to protect the brain and stop the progression of Batten is an important area of research,” said Kalipada Pahan, Ph.D., the Floyd A. Davis professor of neurology.

Children with Batten disease eventually go blind, become comatose, and develop mental illness. A condition that shortens life is juvenile Batten disease. The type or variation can affect life expectancy. Depending on how quickly the disease develops, death typically happens in the 20s.”We have found that oral gemfibrozil successfully reduces inflammation in the brain, decreases brain accumulation of toxic autofluorescent pigment deposits, and improves locomotor activities in mice that are missing the CLN3 gene,” Pahan said.

Effective lysosomes that aid in removing deposits from any part of the body are needed to remove hazardous substances from the brain, as is the transcription factor EB (TFEB), which is in charge of producing functional lysosomes. This is the control of fundamental cellular functions that help the body get rid of hazardous waste.

Researchers at RUSH University Medical Center have found a new mechanism for the molecule PPAR, which is present in the liver, fatty acids, and different regions of the brain, to stimulate TFEB. This discovery was made as part of the development of a new mouse model for studying juvenile Batten disease. The removal of waste by the TFEB molecule from the brain and other parts of the body may assist to halt future brain damage. “We were excited to see that oral gemfibrozil activates TFEB in the brain, which is the beginning of the process for clearing out dead cells from the body,” Pahan said.

Oral gemfibrozil remains unable to increase TFEB, or decrease autofluorescent materials in the brain and improve locomotor performance of Cln3 mice that lack peroxisome proliferator-activated receptor alpha (PPARα).

The major role of PPARα is to control fat metabolism in the liver. “Our mechanistic finding suggests that gemfibrozil may not be beneficial for Cln3 brain that is lacking PPARα,” Pahan said. “The drug was only effective in a Cln3 brain that had PPARα.

Gemfibrozil is scheduled for clinical trial in patients with juvenile Batten disease.

“If these results are replicated in patients, it would open up a promising avenue of treatment of this devastating disease and stop the disease in its tracks,” Pahan said.

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