Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuronal disorder characterized by neuronal degeneration and currently no effective cure is available to stop or delay the disease from progression. Transplantation of murine glial-restricted precursors (mGRPs) is an attractive strategy to modulate ALS development and advancements such as the use of immune modulators could potentially extend graft survival and function. Using a well-established ALS transgenic mouse model (SOD1G93A), we tested mGRPs in combination with the immune modulators synthetic PreImplantation Factor (sPIF), Tacrolimus (Tac), and Costimulatory Blockade (CB). We report that transplantation of mGRPs into the cisterna magna did not result in increased mice survival. The addition of immunomodulatory regimes again did not increase mice lifespan but improved motor functions and sPIF was superior compared to other immune modulators. Immune modulators did not affect mGRPs engraftment significantly but reduced pro-inflammatory cytokine production. Finally, sPIF and CB reduced the number of microglial cells and prevented neuronal number loss. Given the safety profile and a neuroprotective potential of sPIF, we envision its clinical application in near future.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuronal disorder characterized by degeneration of the upper and lower motor neurons of the cortex, the brain stem, and the spinal cord
We aimed to evaluate the potential of synthetic PreImplantation Factor (sPIF), Tac and Costimulatory Blockade (CB) in combination with murine glial-restricted precursors (mGRPs) transplantation using the S OD1G93A transgenic mouse model
We hypothesized that mGRPs transplantation in combination with immune modulatory therapeutics will impact the graft function and modulate the course of ALS5,23
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuronal disorder characterized by degeneration of the upper and lower motor neurons of the cortex, the brain stem, and the spinal cord. Testing of new therapeutic approaches is essential and one well-defined animal model is the SOD1G93A transgenic mouse model[2]. In this model, mice express a G93A mutant form of human SOD1 and develop progressive loss of upper and lower motor neurons. The neuroprotective property of sPIF was further underscored by its ability to mitigate neuronal loss and microglial activation in murine model of immature brain injury as well[9,12,13,17]. Immune-modulatory therapeutics in combination with stem cell transplantation possess the potential to enhanced cell protection/regeneration in ALS. We aimed to evaluate the potential of sPIF, Tac and CB in combination with mGRPs transplantation using the S OD1G93A transgenic mouse model
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