Encouraging Results for New Strategy to Treat Juvenile Batten Disease

A treatment for juvenile Batten disease has been tested in a mouse model and shown to reduce symptoms and improve longevity. The results of the study were published in Nature Communications. The researchers involved in the study were from Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, and King’s College London.

Various forms of Batten disease have been attributed to more than 400 different mutations in 14 segments of DNA. Juvenile Batten disease affects males and females in equal numbers and occurs in just 3 of every 100,000 births.

"Patients with juvenile Batten disease are born healthy and reach the expected developmental milestones of the first 4 to 6 years of age," senior author Marco Sardiello, PhD, assistant professor of molecular and human genetics at Baylor, said in a statement. "Then, these children progressively regress their developmental achievements; they gradually lose their vision and develop intellectual and motor disabilities, changes in behavior and speech difficulties. Most people with this condition live into their 20s or 30s. This inherited, rare disease has no cure or treatment other than palliative care."

Batten disease is a lysosomal storage disorder. Lysosomes are in charge of clearing out the waste produced by cells, and when they fail to do their job, cellular waste accumulates, causing disease. In Batten disease, brain cells are affected by the accumulation of cellular waste, leading to disruption of cell processes, cell death, and a regression of motor, physical, and intellectual abilities.

"A few years back we discovered a protein in cells called TFEB, a master transcription factor that stimulates the cell to produce more lysosomes and degrade cellular waste more effectively," said Sardiello. "So we thought about counteracting the accumulation of cellular waste in Batten disease by acting on TFEB."

Thus, the researchers focused on how to activate TFEB with a drug.

"We discovered that TFEB is under the control of another molecule called Akt, which is a kinase, a protein that can modify other proteins," said Michela Palmieri, PhD. At the time of the study, Palmieri was a postdoctoral fellow in Sardiello’s lab and is now at the San Raffaele Scientific Institute in Milan, Italy. "Akt has been studied in detail. There are drugs available that can modulate the activity of Akt."

Akt adds a chemical group to TFEB that inactivates it, so the researchers wanted to inhibit Akt in order to keep TFEB more active, thus countering the accumulation of cellular waste. They tested trehalose in a mouse model of juvenile Batten disease, examined the brain cells of the mice under the microscope, and found that trehalose was successfully inhibiting Akt.

Allowing more TFEB to remain active results in increased lysosomal activity and a subsequent decrease in the accumulation of cellular waste and reduced tissue inflammation. The treated mice lived significantly longer.

"We are very excited that these findings put research a step closer to understanding the mechanisms that underlie human lysosomal storage diseases," said Palmieri. "We hope that our research will help us design treatments to counteract this and other human diseases with a pathological storage component, such as Alzheimer's, Huntington's, and Parkinson's diseases, and hopefully ameliorate the symptoms or reduce the progression of the disease for those affected."