Naturally occurring primate model of late-infantile Batten identified

Study authors note primates could help in development of treatment for CLN2

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

Share this article:

Share article via email
A young man shouts into a megaphone cone.

Researchers have discovered a new naturally occurring nonhuman primate model of late-infantile Batten disease, or CLN2 disease.

The primates, all of whom had a mutation in the CLN2 gene — the known cause of late-infantile Batten — also exhibited signs of the human condition including motor dysfunction, brain tissue atrophy, neuroinflammation, and the buildup of toxic waste products in nerve cells.

As noted by the authors, the new model is “expected to open up new avenues for developing novel therapeutic strategies and preclinical trials of CLN2 disease.”

The study, “Cynomolgus macaque model of neuronal ceroid lipofuscinosis type 2 disease,” was published in Experimental Neurology.

Also known as neuronal ceroid lipofuscinoses, all forms of Batten disease are caused by genetic mutations that lead to the toxic buildup of fatty waste products called lipofuscins inside cells, to which nerve cells are particularly sensitive.

Late infantile Batten is most commonly caused by mutations in the CLN2/TPP1 gene, leading to a deficiency in the TPP1 enzyme needed to help clear lipofuscins.

Symptoms including vision loss, seizures, motor problems, and cognitive regression typically begin to emerge in young children between the ages of 2-4.

Recommended Reading
An illustration of a brain with lightning bolts emanating from it.

Mini pig model may help scientists to better study late infantile Batten

Nonhuman primates frequently used in biomedical research

Preclinical models are critical for studying disease mechanisms and identifying new treatment targets. Nonhuman primates are frequently used in biomedical research due to their similarities to humans, particularly in terms of brain structure and function.

Now, the scientists have identified a new, naturally occurring model of CLN2 disease in cynomolgus macaques — a type of nonhuman primate — bred and maintained at a facility in Japan.

Among a large family of these macaques, the researchers identified three animals exhibiting symptoms similar to Batten disease, including limb tremors and gait disturbances, at about 2 years of age that progressed to impaired balance, instability, and frequent falls.

These three animals also had difficulty feeding independently and progressively lost weight.

The scientists found that the electrical activity in their eyes was reduced relative to unaffected animals, and they exhibited significant signs of brain atrophy on MRI scans by age 3.

An analysis of their brain tissue revealed significant nerve cell degeneration, and evidence of the buildup of lipofuscin waste products in the brain. The brain’s cerebellar cortex appeared particularly vulnerable to cell loss, which has been previously reported in other Batten models.

Changes to nerve cell structure and signs of neuroinflammation were also observed.

Because all of the findings observed in the animals are hallmarks of Batten disease, the researchers believed them to have some form of the condition.

DNA sequencing identifies CLN2 gene mutation in primates

The scientists performed DNA sequencing on the affected animals, identifying a mutation in the CLN2 gene. The scientists could not detect the TPP1 protein in the animals’ tissues, even while it was evident in animals without symptoms.

For two of the three macaques for which the appropriate analysis was available, the CLN2 mutation was found in both copies of the gene, consistent with the known inheritance pattern of CLN2 disease.

The scientists then performed DNA sequencing on 95 asymptomatic macaques descended from the same great-grandfather who was thought to pass along the mutation to the affected animals.

Of them, 49.5% carried one copy of the mutation and were considered disease carriers, whereas 50.5% did not have the mutation at all.

Overall, findings in the macaques, “recapitulated most of the pathological features observed in CLN2 patients,” the researchers wrote, suggesting the model is “suitable for assessing disease pathology.”

Additional analyses from any future affected animals born in the colony will help to further establish the model, according to the scientists.

As such, the team noted a need to continue breeding the animals for “further systematic quantification and characterization of motor functions and behavioral analyses using validated outcome measures.”