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As genetic therapy for neurologic diseases moves toward the mainstream, a key challenge that must be addressed is the need to deliver genes to the central nervous system (CNS) and ensure that the functional protein will be expressed. In a novel technique, researchers have successfully transfected ependymal cells in nonhuman primates with subsequent expression of the protein at high levels. Most importantly, functional protein was secreted into the cerebrospinal fluid (CSF). Both protein expression and activity were maintained for over 20 weeks. These data were presented at the WORLDSymposium in February, 2019.
In this study, the gene encoding lysosomal enzyme tripeptidyl peptidase-1 (TPP1) was inserted into the adeno-associated virus vector and delivered to ependymal cells via a unilateral injection into the ventricle. Mutations in TPP1, result in a progressive neurodegenerative disease with pediatric onset, late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). Children with CLN2 have seizures, loss of motor control and vision, progressive cognitive impairments, and typically die within the first 2 decades of life.
Study author, David Anderson of Spark Therapeutics, Philadelphia, PA said, ““With this method, we have been able to use a single administration to achieve durable expression of functional protein and delivery to multiple brain areas through secretion into the CSF. We are hopeful that this can potentially treat not only CLN2 but also other neurologic illnesses in which a single protein mutation affects multiple brain regions; diseases that, so far, have been quite difficult to address with gene therapy.”
Regina Krel, MD; and Paul G. Mathew, MD, DNBPAS, FAAN, FAHS
Mary Motwani, PhD; and Deena Kuruvilla, MD
Emmanuelle A. D. Schindler, MD, PhD; and Christopher Gottschalk, MD