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Published on: June 12, 2018
Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model
Keigo Takahashi1, Elizabeth M Eultgen1, Sophie H Wang1
1Department of Pediatrics.
Abstract:
Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.
Insights
Researchers characterized neurological and neuropathological changes in Cln2R207X mice, a model for neuronal ceroid lipofuscinosis type 2 (CLN2 disease). Gene therapy improved seizures, gait, and lifespan, highlighting the need for effective CLN2 disease treatments.
Area of Science:
- Neuroscience
- Genetics
- Biomedical Research
Background:
- Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) pathophysiology is poorly understood, limiting therapeutic development.
- A validated disease-modifying therapy exists, but more effective treatments are needed.
- The Cln2R207X mouse model carries a common human mutation but requires further characterization.
Purpose of the Study:
- Investigate neurological and neuropathological changes in Cln2R207X mice.
- Establish a clinically relevant phenotype for evaluating therapeutic interventions.
- Assess the efficacy of AAV9-mediated gene therapy in this CLN2 disease model.
Main Methods:
- Long-term electroencephalography (EEG) recordings to detect epileptiform activity.
- Histological analysis of brain and spinal cord tissue for neuronal loss, microglial activation, and astrogliosis.
- Neonatal administration of adeno-associated virus serotype 9 (AAV9) gene therapy.
Main Results:
- Progressive epileptiform abnormalities and spontaneous seizures were observed in Cln2R207X mice.
- Seizures correlated with loss of cortical neuron populations and early microglial activation preceding neuron loss.
- AAV9 gene therapy ameliorated seizures, improved gait, extended lifespan, and reduced neuropathology.
Conclusions:
- Cln2R207X mice present a robust model for studying CLN2 disease progression and evaluating therapies.
- Early neuropathological changes include microglial activation and astrogliosis, with distinct regional and temporal patterns.
- AAV9 gene therapy shows significant therapeutic potential for CLN2 disease, underscoring the value of clinically relevant outcome measures.
