New research shows that patients with infantile Batten disease exhibit significant early disease in the spinal cord and that combined treatment of the spinal cord and the brain has significant therapeutic effects.
The study titled, “Synergistic effects of treating the spinal cord and brain in CLN1 disease,” was published in the Proceedings of the National Academy of Sciences of the United States of America.
INCL (inflantile neuronal ceroid lipofuscinosis), also called infantile Batten disease, develops due to a deficiency in the enzyme PPT1. Researchers have established mouse models that lack PPT1 to study this disease in animal models.
INCL was believed to be a consequence of disease that happened only in the brain. However, treating just the brain was found to have very few beneficial effects on most patients, which indicated the disease may be occurring outside the brain. Studies have also shown that mouse models of INCL have deficits in motor and sensory pathways of their bodies, which suggests there might be an issue with the spinal cord.
Researchers at Washington University School of Medicine in St. Louis, Missouri, hypothesized there was a component of the disease that may be occurring in the spinal cord, as it is central to sensory and motor pathways.
Researchers first showed there was significant disease pathology in the spinal cord by using tissue obtained from children with INCL. Then, by looking at spinal cords obtained from mouse models of INCL at different ages, they showed early evidence of disease in all parts of the spinal cord. In fact, these features of the disease occurred before the disease was observed in the brain.
This finding prompted researchers to determine the therapeutic effect of treating the spinal cord. They used adeno-associated virus (AAV)-mediated gene therapy, which is one of the most promising methods that have been shown to treat these types of diseases. In this type of gene therapy, a virus vector is used to deliver the deficient protein into cells.
They administered two types of AAV injections to the mice models of INCL; one was injected into the spine and the other was injected into the brain. Results from this study showed that targeting the spinal cord alone did result in an improvement of the disease.
Interestingly, researchers showed that when the gene therapy was administered in the brain and the spinal cord together, there was essentially no pathology of INCL in either the brain or the spinal cord. And when targeting both the spine and the brain, the mouse model of INCL displayed significant improvement in motor function and a significantly longer lifespan.
Results from this study suggest that INCL begins in the spine and that it can be targeted to improve motor symptoms and lengthen the lifespan of patients.
“These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders,” the authors concluded.