Sex-split analysis of pathology and motor-behavioral outcomes in a mouse model of CLN8-Batten disease reveals an increased disease burden and trajectory in female Cln8mnd mice

• Published in: Orphanet journal of rare diseases 2022-11, Vol.17 (1), p.1-411, Article 411
• Main Authors: Holmes, Andrew D, White, Katherine A, Pratt, Melissa A, Johnson, Tyler B, Likhite, Shibi, Meyer, Kathrin, Weimer, Jill M
• Format: Article
• Language: English
• Subjects: Age; Alzheimer's disease; Cognitive ability; Convulsions & seizures; Cortex (somatosensory); Development and progression; Enzymes; Epilepsy; Females; Gender differences; Gene expression; Gene therapy; Genetic aspects; Glial fibrillary acidic protein; Gliosis; Males; Medical research; Motor ability; Motor task performance; Mutation; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neuronal ceroid lipofuscinosis; Pathology; Pediatrics; Proteins; Rare diseases; Seizures; Sensorimotor integration; Sex differences; Thalamus
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-022-02564-7

CLN8-Batten disease (CLN8 disease) is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 results in characteristic Batten disease symptoms and brain-wide pathology including accumulation of lysosomal storage material, gliosis, and neurodegeneration. Recent investigations of other subforms of Batten disease (CLN1, CLN3, CLN6) have emphasized the influence of biological sex on disease and treatment outcomes; however, little is known about sex differences in the CLN8 subtype. To determine the impact of sex on CLN8 disease burden and progression, we utilized a Cln8.sup.mnd mouse model to measure the impact and progression of histopathological and behavioral outcomes between sexes. Several notable sex differences were observed in the presentation of brain pathology, including Cln8.sup.mnd female mice consistently presenting with greater GFAP.sup.+ astrocytosis and CD68.sup.+ microgliosis in the somatosensory cortex, ventral posteromedial/ventral posterolateral nuclei of the thalamus, striatum, and hippocampus when compared to Cln8.sup.mnd male mice. Furthermore, sex differences in motor-behavioral assessments revealed Cln8.sup.mnd female mice experience poorer motor performance and earlier death than their male counterparts. Cln8.sup.mnd mice treated with an AAV9-mediated gene therapy were also examined to assess sex differences on therapeutics outcomes, which revealed no appreciable differences between the sexes when responding to the therapy. Taken together, our results provide further evidence of biologic sex as a modifier of Batten disease progression and outcome, thus warranting consideration when conducting investigations and monitoring therapeutic impact.