Combined Anti-inflammatory and Neuroprotective Treatments Have the Potential to Impact Disease Phenotypes in Cln3−/− Mice

Abstract

Batten disease, or juvenile NCL, is a fatal neurodegenerative disorder that occurs due to mutations in the CLN3 gene. Because the function of CLN3 remains unclear, experimental therapies for JNCL have largely concentrated upon the targeting of downstream pathomechanisms. Neuron loss is preceded by localized glial activation, and in this proof-of-concept study we have investigated whether targeting this innate immune response with ibuprofen in combination with the neuroprotective agent lamotrigine improves the previously documented beneficial effects of immunosuppressants alone. Drugs were administered daily to symptomatic Cln3−/− mice over a 3 month period, starting at 6 months of age, and their impact was assessed using both behavioral and neuropathological outcome measures. During the treatment period, the combination of ibuprofen and lamotrigine significantly improved the performance of Cln3−/− mice on the vertical pole test, slowing the disease-associated decline, but had less of an impact upon their rotarod performance. There were also moderate and regionally dependent effects upon astrocyte activation that were most pronounced for ibuprofen alone, but there was no overt effect upon microglial activation. Administering such treatments for longer periods will enable testing for any impact upon the neuron loss that occurs later in disease progression. Given the partial efficacy of these treatments, it will be important to test further drugs of this type in order to find more effective combinations.

Comparative proteomic profiling reveals mechanisms for early spinal cord vulnerability in CLN1 disease

“…As already discussed, whether this is due to inherent cell-type defects or as a reaction to regional cues is yet to be determined, but these data help us understand the cause of such regional differences in vulnerability. Furthermore, our data raise the possibility of spinal cord targeted regional therapeutic interventions such as anti-inflammatories or neuroprotective agents 57,58 to improve disease outcome.…”

“…It is now apparent that CLN1 disease does not just affect the brain. Characterizing and subsequently targeting the early inflammatory response observed in Ppt1 −/− spinal cords may therefore prove to be an effective strategy either alone or in combination with other therapies, as has become increasingly common across the NCLs 57,59,60 . Such characterization of the pathomechanisms of CLN1 disease and other forms of NCLs can directly inform therapeutic efforts in order to significantly improve disease outcomes.…”

Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation

“…A number of novel therapies, including small molecule 5,29-33 , antisense oligonucleotides 34 , and gene replacement 35,36 strategies are under development for CLN3 disease. These approaches will not target all cell types equally.…”

“…The brains of CLN3 disease mouse models demonstrate progressive storage accumulation, predominantly comprised of subunit C of the mitochondrial ATP synthase (SCMAS) 2 3 , mirroring what occurs in CLN3 disease patients 4 . Therefore, most drug development efforts rely on histopathologic markers of efficacy, including reduction of storage material, reactive astrocytosis and microgliosis 2,4,5 . However, whether these histopathologic changes cause disease, augment the disease process, or are simply harmless epiphenomenon is unclear.…”

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

“…Three full KO models of Cln3 have thus far been established all displaying hallmarks of CLN3 such as progressive neurodegeneration (Mitchison et al, 1999;Cotman et al, 2002;Eliason et al, 2007). To date there has been research using these models in alleviating CLN3 pathology with administration of various antiinflammatory and neuroprotective compounds such as ibuprofen and lamotrigine to modulate intracellular inflammatory conditions (Mirza et al, 2019;Tarczyluk-Wells et al, 2019). 4.…”