Batten Disease Models
Batten disease is not just one disease, but up to 13 variants of lysosomal storage disorders. It is a rare neurological pediatric disease characterized by cognitive impairment, seizures, and progressive loss of vision and motor skills. It is an incurable disease and often fatal. What groups the disease variants together are the common pathology of rampant glial activation and neuronal loss throughout the CNS. Depending on the variant of Batten Disease, the order of symptoms and the age of onset differ.
We are actively working on phenotyping three Batten disease models – CLN2, CLN6, and CLN8 mutations – to identify new biomarker endpoints that can be translated to the clinic. CLN6 and CLN8 are transmembrane neuronal ceroid lipofuscinose (NCL) mutations existing on the endoplasmic reticulum, whereas CLN2 is a lysosomal enzyme with an NCL mutation.
The methods used to identify translatable biomarkers for lysosomal storage disorders include imaging, metabolite measurements using magnetic resonance spectroscopy (MRS), and fine motor kinematic analysis of movement and posture. These methods can help uncover clinically significant changes in animal models that may also be seen in human patients. For example, MRI is used to visualize brain compartments to study structural and functional changes in the disease state as well as in response to therapeutic approaches.
In addition to in vivo imaging and behavioral assessments, we’re actively involved in antisense oligonucleotide (ASO) therapy screening services for Batten Disease and other rare neurological disorders.
Frequently Asked Questions (FAQs) about Batten Disease Studies
What CLN2 Model is Charles River using and for what validation studies?
The most commonly detected nonsense mutation in CLN2 is R208X, which presents itself via disruption of myelin in white matter or corticospinal tracts with mild forebrain atrophy and Purkinje cell degeneration. We’re collaborating with Sanford Research to validate the Cln2R208X mouse model using multiple translational methods, including MRI and MRS, to assess brain metabolites such as glutamate, creatine and phosphocreatine, and fine motor kinematics to assess motor skills.
What CLN6 Model is Charles River using and for what validation studies?
Cln6nclf presents itself with decreased cortical and cerebellar glutamine and GABA. Mutations in the CLN6 gene result in late infantile onset. We’re collaborating with Sanford Research to validate the Cln6nclf model using multiple translational methods including MRI, PET imaging, and MRS to assess metabolic changes and using fine motor kinematics to assess motor skills. These methods also support longitudinal studies to assess specific biomarkers at specific timepoints.
What CLN8 Model is Charles River using and for what validation studies?
The mouse model of CLN8 is Cln8mnd which presents with neuronal death in the hippocampus and spinal cord with GABAergic neuron loss. The main findings that are readily detectable longitudinally in vivo are progressive atrophy in the cortex and whole brain with decreased N-acetyl aspartate and increased glial activation as detected by MRS. PET imaging glucose utilization detects differences only at eight months old and in females with overall gait changes between wild-type and Cln8mnd.