A Multimodal MRI Approach for Probing ALS Pathophysiology and Neurorepair

Bulte, Jeff

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating disease with near 100% mortality. An important role has been assigned to (over)activated astrocytes. Given the few available treatment options, stem cell therapy is now actively being pursued as a new treatment paradigm, aimed at either immunomodulation (using mesenchymal stem cells - MSCs), astrocyte replacement (using glial progenitors), or motor neuron restoration, with several clinical trials currently in progress. Our goal is to pursue a two-pronged approach using co- transplantation of both MSCs and glial-restricted precursor cells (GRPs) to achieve simultaneous immunosuppression and glia restoration. Central to our transplantation studies is the development of imaging biomarkers that can non-invasively report not only on the fate of transplanted cells but also on changes in the ALS host environment. To this end, we aim to interrogate 1) the activation state of host cells in vivo using manganese-enhanced magnetic resonance imaging MRI (MEMRI); 2) the in vivo survival of transplanted GRPs using conventional bioluminescent imaging (BLI) as gold standard with 19F MRI cell tracking as an exploratory but clinically applicable surrogate marker; 3) and the disease outcome using time of onset, animal survival, behavioral, and compound muscle action potential (CMAP) measurements. Three transgenic SOD1 and two age-matched wild type cohorts of animals will be enrolled in these studies. Luciferase-transfected and fluorinated hGRPs and unlabeled human MSCs will be transplanted at day 60, i.e., about 30 days before onset of the disease. All animals will be monitored weekly for weight, behavioral scores, and end survival. Randomized groups will undergo BLI, CMAP, and 19F MRI and MEMRI at 1 day, and 1, 2, and 3 months after transplantation up until approximately 150 days. Immunohistological analysis of neuroinflammation, motor neuron degeneration, astrocyte pathology, and grafted cell survival will be used to validate the imaging findings and to compare the potential therapeutic benefit of MSC co-transplantation.

Public Health Relevance

Using a transgenic mouse model, we aim to develop novel imaging biomarkers for stem cell treatment of ALS. To this end, we will follow the location and survival of transplanted glial restricted precursor cells, and determine the location and amount of astrocyte activation. For assessment of these three parameters, we will use magnetic resonance imaging (MRI), which is already used in patients for diagnosis of ALS.