Anti-ceramide Single-Chain Variable Fragment Mitigates Gastrointestinal-Acute Radiation Syndrome and Improves Marrow...

Area of Science:

• Radiation biology
• Medical countermeasures
• Gastrointestinal-acute radiation syndrome (GI-ARS) research

Background:

• Post-9/11 nuclear threat necessitates medical countermeasures for acute radiation syndromes (ARS).
• Hematopoietic-ARS is treatable with bone marrow-supportive drugs, but GI-ARS lacks effective mitigation strategies.
• Current treatments fail to preserve the gastrointestinal tract, a critical issue in mass casualty scenarios.

Purpose of the Study:

• To investigate the long-term consequences of preventing acute GI-ARS lethality using anti-ceramide scFv.
• To evaluate the efficacy of anti-ceramide scFv in mitigating GI-ARS and its impact on survival and overall health.
• To explore the potential of anti-ceramide scFv in improving bone marrow reconstitution post-irradiation.

Main Methods:

• C57BL/6J male mice were subjected to 15 Gy whole-body irradiation, a lethal dose for GI-ARS.
• Mice were treated with anti-ceramide scFv, bone marrow transplantation (BMT), or a combination thereof.
• Long-term outcomes, including survival, physiological function, and tissue health, were assessed up to 90 days post-irradiation.

Main Results:

• Anti-ceramide scFv treatment rescued small intestinal stem cells and mitigated GI-ARS lethality.
• Mice receiving both BMT and anti-ceramide scFv showed normalized blood counts by day 12.
• At 14 Gy, anti-ceramide scFv significantly improved marrow engraftment, reducing the required survival-conferring marrow dose.
• Long-term survivors (90 days) exhibited normal appearance, behavior, and near-normal physiology across 42 tissues.

Conclusions:

• Anti-ceramide scFv is a promising therapeutic agent for mitigating GI-ARS lethality.
• This scFv enhances bone marrow reconstitution, contributing to improved survival rates.
• The treatment leads to prolonged survival with remarkably normal physiological function post-acute radiation exposure.