Amit Srivastava, Abstract Co-Author: Nothing to Disclose

Sarah Gross, Abstract Co-Author: Nothing to Disclose

Camille Bulte, Abstract Co-Author: Nothing to Disclose

Akshata Almad, Abstract Co-Author: Nothing to Disclose

Nicholas Maragakis, Abstract Co-Author: Nothing to Disclose

Jeff W.M. Bulte PhD, Presenter: Research Grant, Koninklijke Philips NV Founder and co-owner, SenCEST, LLC

The first Phase I clinical trials have shown that neural stem cell (NSC) therapy represents a possible new treatment for Lou Gehrig’s disease (ALS), a motor neuron disease for which there is no cure. Monitoring the the survival of transplanted cells is imperative for determining the therapeutic success. The purpose here was to monitor graft survival as related to the progression of motor deficits.

Allogeneic luciferase-transfected NSCs were transplanted bilaterally (100,000 cells) into the cervical spinal cord (C5) of presymptomatic SOD1(G93A) transgenic ALS mice (n=9) and wild type littermates (n=5) via laminectomy. Mice were immunosuppressed by using FK506/rapamycin (1 mg/kg, i.p.) daily. Bioluminescence imaging (BLI) and computed tomography (CT) were performed for several weeks post-transplantation using a dual-mode Perkin Elmer Spectrum/CT. Rota rod test was performed to determine motor deficits. Disease onset was defined by decline in motor skills and weight loss.

BLI showed no excessive proliferation of transplanted cells (Fig. 1A). The first sign of disease onset was observed in 84 days old ALS mice. Motor skills continued to decline further, Compared to day 1, a 60% decline in BLI signal was observed in ALS mice after four weeks of transplantation (at the time of disease Anchoronset) (p<0.05) (Fig. 1B). The decrease of cell survival preceded the decline in motor skills and, interestingly, showed the same overall time course pattern. There was a complete loss of BLI signal at the end point. In contrast, only 10% decline in the BLI signal was observed in wild type littermates after four weeks of transplantation. Anti-Iba1 (red) and anti-luciferase (green) staining showed the presence of activated microglia around engrafted cells in the spinal cord of symptomatic ALS mice (Fig. 1C).

The disease onset and progression adversely affect the survival of engrafted NSCs in ALS. This poor survival is likely a result of the pathological microenvironment in the spinal cord of ALS mice.

The hostile microenvironment of the spinal cord in ALS represents a significant barrier for successful clinical therapy.

Srivastava, A, Gross, S, Bulte, C, Almad, A, Maragakis, N, Bulte, J, Amyotrophic Lateral Sclerosis: Impact of Disease Progression on Intraspinal Stem Cell Survival.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14010682.html