Enzyme Treatment Slows Decline Caused by Common Form of Batten Disease

Study also indicates early treatment may provide best outcomes

(From the June 2018 issue of Research Now)

With every diagnosis of CLN2 Batten disease, Emily de los Reyes, MD, a neurologist and director of the Nationwide Children’s Batten Disease Center of Excellence, had a difficult conversation with parents.

“I always told parents this is a brain disorder that will result in the early death of your child and that you may see your child melt before your eyes,” says Dr. de los Reyes. “Now, I can tell them that we have a treatment. Or maybe even a cure if children get the treatment before they lose function.”  

Dr. de Los Reyes and Lenora Lehwald, MD, an attending neurologist at Nationwide Children’s and co-investigator of the CLN2 trials, led the U.S. portion of an international study that shows an enzyme treatment delivered directly to the brains of children with CLN2 significantly slows motor and language declines. The response rate of 87 percent at 96 weeks.

The study is published in the New England Journal of Medicine.

CLN2, also called neuronal ceroid lipofuscinosis type 2, is a rare lysosomal storage disorder caused by the lack of the enzyme tripeptidyl peptidase 1 (TPP1).

“Lysosomes are like the vacuum cleaners of the brain,” Dr. de los Reyes explains. But without a functioning TPP1 enzyme, lysosomal storage material accumulates and causes degeneration throughout the central nervous system.

Most children with the disease function normally until they’re 2 to 4 years old. Then, they typically begin with language delay followed by seizures that are difficult to control. A rapid decline in motor, language, cognitive and visual function follows. Most die by early adolescence.

In this study, 23 children, age 3 to 16, received an infusion of cerliponase alfa, a recombinant proenzyme form of human TPP1, every two weeks for at least 96 weeks. The researchers infused the enzyme directly into the right lateral ventricle of each child’s brain, through an implanted Rickham reservoir.

During the 96 weeks, none of the treated children suffered an unreversed 2-point decline on a CLN2 clinical rating scale of their language and motor skills. The medical records of comparable untreated children, called historical controls, show they reached a mean 2-point decline in skills at just under a year.

The decline rate among treated children was a mean of was 0.27 points per 48-week period versus 2.12 points for the historical controls per 48-week period.

The difference in measurements of motor, language, cognitive and visual function between the treated and untreated children grew over time, indicating the treatment benefit persisted, Dr. de los Reyes says.

Adverse events included convulsions, vomiting, hypersensitivity reactions, failures of the intraventricular device and infection. They resolved themselves or were treated medically, but none required children to stop receiving treatment.

All 23 children continue to receive the infusions, more than four years after the study began.

The youngest two participants had no signs of impairment due to CLN2 at the beginning of the study and continue to have none. That suggests early treatment may provide the greatest benefit, Dr. de los Reyes says.

To test that theory, the researchers are now studying the treatment in children younger than 3.

Citation: Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschütter A; CLN2 Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. New England Journal of Medicine. 2018 May 17;378(20):1898-1907. doi: 10.1056/NEJMoa1712649. Epub 2018 Apr 24.