(Grantome.com) http://grantome.com/grant/NIH/R01-NS091110-05

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder without a cure. Patients who suffer from ALS typically die within two-to-five years of diagnosis. Recent progress in regenerative medicine has raised hope for a breakthrough. The significant role of glia for the proper function of motor neurons has been recently reported, and efficient methods to isolate glial-restricted precursors (GRP) have been established. It has been shown in rodent models that GRPs of fetal origin display the highest therapeutic potential among all other sources, because they are characterized by extensive engraftment, differentiation, and robust therapeutic effect.

In this project, we propose to use fetl GRPs for the treatment of ALS. The Allografting of GRPs in pigs is particularly attractive, as it will be performed in a clinically relevant setting, including utilization of catheter-based cell delivery, with a clinical MR scanner for cell tracking and assessment of immunogenicity/immunoprotection.

The application of the latest developments in neurobiology, interventional neuroradiology, and regenerative medicine should result in a long-awaited cure for ALS.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease, with most patients dying within three-to-five years of diagnosis and effective treatment not available. The application of stem/progenitor cells offers the greatest potential for restoration of lost neurological function. Accordingly, we propose to focus our project on regenerative medicine and the application of glial progenitor cells for the treatment of ALS.

(Grantome.com) http://grantome.com/grant/NIH/R01-NS102675-01A1

Over the last few decades, we have witnessed exceptional progress in the fields of regenerative medicine and oncology in terms of defining molecular mechanisms of disease, developing research tools (molecular biology, imaging, transgenic animals) and identifying treatment strategies. While these two fields have overall divergent targets they are can be envisioned as being complementary. Further interfacing is needed: in particular, the field of neuro-oncology may greatly benefit from exploiting all the recent achievements in regenerative medicine.

Glioblastoma multiforme (GBM) accounts for approximately 65% of all primary brain tumors and is characterized by low survival, with only 10% of patients surviving >5 years. Radiation therapy dose escalation has been explored but now abandoned due to radiation-induced brain injury, which is primarily manifested by damage to white matter and cerebral vasculature. We believe we can make significant advancements in developing a better cure for GBM.

Our preliminary experiments indicate that tumors can be completely eradicated with radiation therapy provided that the dose is sufficiently high. We have shown complete elimination of tumors without reoccurrence with a single dose of 40 or 80 Gy. Importantly, the injury as manifested by white matter damage and the occurrence of hemorrhage as seen on magnetic resonance imaging (MRI) was detectable after 2-3 months, providing an ample time window for therapeutic intervention.

We propose to perform a detailed characterization of radiation-induced brain injury following high dose radiation therapy and to test the feasibility of regenerative approaches aiming at reversing or preventing the injury to the most vulnerable components (white matter and vasculature). To this end, we will use a state-of-the art multimodal intravital imaging platform with MRI, bioluminescence imaging (BLI) and two-photon microscopy (2PM).

Public Health Relevance

Glioblastoma remains untreatable and is one of the most deadly brain malignancies and while more aggressive radiotherapy could potentially improve efficacy, radiation-induced damage to the white matter and the vasculature mandates a ceiling for the maximum radiation dose. We propose to exploit recent developments in regenerative medicine, which make it feasible to repair the white matter and the vascular compartment, potentially allowing an elevation of the maximum tolerated dose of radiotherapy, which would permit complete eradication of glioblastoma. We will use multimodality intravital imaging to rapidly and accurately assess both radiation damage and treatment responses.