At the Oregon National Primate Research Center there’s a colony of macaques that have been around since the 1960s when the Japanese government made a gift of the monkeys to the center. But when members of the colony more recently began developing motor difficulties, signs of ataxia, and tremors, initial thoughts were that some of the macaques may have developed a form of multiple sclerosis.
When the macaques were autopsied, pathologists found the brains were noticeably different than those of other macaques. Tissue samples of the deceased animals showed signs of a lysosomal storage disorder. The pathologists then turned to geneticists and neuroscientists at the center to help figure out what was going on.
Researchers began extensive genetic testing of the population and in July, in a study published in the journal Neurobiology of Disease, they reported that the macaques had a naturally-occurring mutation to the CLN7 gene that caused a neurodegenerative disease that is similar to a human form of Batten disease, a rare and fatal condition. Though the researchers didn’t set out to develop an animal model for the condition, they appear to have stumbled on one that could have implications beyond just this one form of Batten disease.
“It’s significant, but it’s also unique. At least to our knowledge, we have the only non-human primate model of any lysosomal storage disease in the world,” said Jodi McBride, lead author and assistant professor at the Oregon National Primate Research Center and OHSU. “We really feel this is a significant discovery because when we move forward to start creating a gene therapy construct, we will be working with a brain anatomy so similar to humans that it will provide a better opportunity to work out the biodistribution and surgical parameters. We think it’s an amazing model.”
The discovery has the potential to accelerate the development of therapies for CLN7 Batten disease. It also may help identify new imaging biomarkers that could provide a means for diagnosing and monitoring patients not just with CLN7 disease, but a range of lysosomal storage disorders with central nervous system involvement.
“Batten’s disease” refers to a group of neurodegenerative conditions caused by mutations in one of several different genes including CLN7. These conditions, also known as neuronal ceroid lipofuscinoses, are considered lysosomal storage disorders. The genetic mutation driving these conditions causes an enzyme deficiency that prevents the ability to properly breakdown metabolic waste. As waste fragments accumulate in the lysosomes of the cells in the brain and elsewhere in the body, they impair function.
CLN7 is a late infantile form of Batten disease that begins to manifest itself between the age of 2 and 4. Seizures are often the first symptoms that sends families in search of medical help. As the condition progresses, language delays are followed with dementia, the loss of the ability to walk and talk, and blindness. Children with the condition usually live just into late childhood or early teenage years.
Last year, BioMarin won approval for an enzyme replacement therapy to treat patients with the CLN2 form of the disease. It was the first and still the only treatment approved in the United States for any form of Batten disease. There are therapies addressing other forms of the disease in clinical development.
In all, the OHSU researchers confirmed 12 Batten disease cases in the macaque colony to date, four of which are young affected monkeys that will enable the development and testing of treatments for the disease. Additionally, the researchers have identified 28 other macaques in the colony that are carriers of the mutated CLN7 gene. Through directed breeding strategies, scientists at the research center expect more affected animals being born each year to help advance a potential therapy for children suffering from Batten disease.
Trevor McGill and Martha Neuringer, two OHSU co-authors of the study, have already begun evaluating a proof-of-concept gene-therapy strategy for Batten disease in the retina. Neuringer will soon expand her work to include noninvasive gene therapies capable of reaching the entire brain by administering the therapy into cerebral spinal fluid.
As for McBride, her lab is turning its attention to identifying a biomarker that could be used as a measure of the accumulated metabolic waste in the lysosomes of brain cells.
“What my lab is going to start doing is working with radiochemist at OHSU so that we can start figuring out if we are able to image the lysosomal storage junk material that gets built up so that when we go into clinical trials, we’ve got a nice biomarker in hand to tell if we are clearing out the junk,” she said. “This would be applicable not just to CLN7 Batten disease, but to any lysosomal storage disease. The broad applicability there would serve dozens and dozens of lysosomal storage diseases.”
July 31, 2018
Japanese macaques at the Oregon National Primate Research Center. (OHSU/Kristyna Wentz-Graff)