Radiation and Cancer Biology

SS 19 - Biology 4 - Normal Tissue Radiobiology

145 - Total Body Irradiation and Bone Marrow Transplant Significantly Extends the Paralysis Free Interval in Amyotrophic Lateral Sclerosis Mice (SOD1G93A)

Tuesday, October 23
7:45 AM - 7:55 AM
Location: Room 008

Total Body Irradiation and Bone Marrow Transplant Significantly Extends the Paralysis Free Interval in Amyotrophic Lateral Sclerosis Mice (SOD1G93A)
J. S. Greenberger1, R. Fisher2, C. Donnelly2, S. Watkins2, M. Ross2, L. Rigatti2, and M. Epperly3; 1UPMC-Shadyside Hospital, Pittsburgh, PA, 2University of Pittsburgh, Pittsburgh, PA, 3UPMC Hillman Cancer Center, Pittsburgh, PA

Purpose/Objective(s): ALS is a fatal neuromuscular disease caused by the progressive nerve degeneration of motor neurons in the brain and spinal cord. While the cause of ALS is unclear, 10 to 15% of patients have a familial history of the disease, while the majority of cases (85 – 95%) develop the disease sporadically. There are nearly forty genetic mutations associated with ALS, the second most common of which is a mutation in the Superoxide Dismutase-1 (SOD1) gene. The well-established SOD1G93A mouse model, which replicates ALS in human patients, and shows progressive muscle wasting, paralysis, and death. Current antioxidant therapies, biological response modifiers, cytokine inhibitors, cytokine receptor antagonists, and an introduction into the spinal cord of neurotrophic growth factors or mesenchymal stem cells engineered to produce neuroleukines have been largely unsuccessful.

Materials/Methods: Since most ALS patients are diagnosed after onset of symptoms, we carried out experiments with 90 day old SOD1G93A mice demonstrating level 1 paralysis. Mice received 9.0 Gy total body irradiation (TBI) Cesium source 340 cGy per minute, and intravenous bone marrow transplantation with 1 x 106 C57BL/6 GFP+ donor bone marrow. Control C57BL/6NTac mice were transplanted at the same age with SOD1G93A ALS bone marrow. Spinal cord sections were analyzed by single photon, confocal, ribbon-scanning microscopy for bone marrow origin cells. Blood/brain barrier permeability was analyzed by I.V. perfusion with 0.2 µm Fluorospheres (F8810, Invitrogen).

Results: The results demonstrated significant prolongation of paralysis free survival in bone marrow transplanted SOD1G93A mice from 100 to over 250 days (p=0.0018). In contrast, control mice transplanted with SOD1G93A bone marrow showed no evidence of paralysis. Marrow transplanted SOD1G93A mice demonstrated bone marrow origin, GFP+ M2 microglial cells surrounding degenerating anterior horn motor neurons at days 120, 200, and as late as day 280. Blood/brain barrier permeability was detected in SOD1G93A, but not control mice, or bone marrow transplanted SOD1G93A mice.

Conclusion: Total body irradiation and bone marrow transplantation is a potentially valuable therapeutic option for treating ALS. Further studies are required to determine whether whole spine or segmental spine irradiation, brain and/or spine irradiation, or TBI will provide a therapeutic effect in the absence of marrow transplantation. The subset of donor bone marrow cells (hematopoietic stem cells, committed granulocyte/macrophage progenitors, or mesenchymal stem cells) required to provide the therapeutic effect must also be determined.

Author Disclosure: J.S. Greenberger: None. R. Fisher: None. C. Donnelly: None. S. Watkins: None. M. Ross: None.

Joel Greenberger, MD, FACRO

University of Pittsburgh Cancer Institute

Disclosure:
Employment
UPCI: Professor and Chairman: Employee

Biography:
I am a principal investigator managing an independent research program on lung cancer models over the past 35 years, have supervised over 20 postdoctoral fellows, junior faculty at the assistant professor level, and medical students. As a principal investigator, I have maintained uninterrupted NIH funding since 1977 and am a National and International manuscript reviewer in areas of lung cancer, radiation biology, stem cell transplantation, and stem cell plasticity. I have been investigating effects of irradiation on normal tissue responses and protecting normal tissue.

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