Mitigation of the Hematopoietic and Gastrointestinal Acute and Delayed Radiation Syndromes Using Combination Therapy with Pegylated Hematopoietic Growth Factors
Abstract
The growing threat of terrorist events involving radiation, as well as the potential for radiation accidents at nuclear power plants, aboard nuclear powered vessels, or involving military nuclear weapons, underscores the need for medical preparedness for effective treatment of radiation victims. The aftermath of radiological/nuclear (RN) accident/event will be predictably chaotic and the logistics for providing medical care will be challenging. Military personnel and first responders will likely be among the first to arrive on the scene of a RN event and will require drugs that prevent death or illness from radiation exposure, as will civilians. Personnel exposed to high-dose radiation will experience life-threatening infections, bleeding, and dehydration due to damage to the blood forming system in the bone marrow and cells that make up the gastrointestinal (GI) system. The hematopoietic system that forms all blood cells is the most sensitive tissue to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) after significant exposure. The GI system is the next most sensitive tissue to radiation, resulting in the GI-ARS, a malabsorption syndrome leading to severe diarrhea, dehydration, and death if untreated. Survivors of ARS are plagued later in life by delayed effects of radiation exposure (DEARE), chronic illnesses that affect multiple organ systems, including hematopoietic, GI, cardiovascular, pulmonary, and renal. There are currently no drugs approved to treat severely irradiated personnel, and doctors would rely on medications used to treat radiotherapy patients, such as Neupogen. Neupogen has been shown by our group to significantly increase survival in H-ARS animal models and is likely to be the first drug licensed by the FDA to treat severely irradiated personnel. However, Neupogen requires >16 consecutive daily injections to increase survival in animal models, posing a logistical challenge to using Neupogen in the chaotic aftermath of an RN event. Additionally, despite improving survival and recovery from the acute effects of radiation on blood cell production, Neupogen has not shown activity against DEARE. Thus, there is an unmet medical need for effective drugs to treat both acute and delayed effects of radiation exposure. To address the problem of challenging dosing regimens and lack of drugs for DEARE, our team has developed three novel drugs (Bolder Biotech s peg-G-CSF, peg-GM-CSF, and peg-IL11) that require only a single injection 24 hours after irradiation to significantly increase survival in animal models. This "triple combo" appears to have positive effects on the radiation-damaged bone marrow and GI system, which would make it the first therapy to have dual-activity. In addition, our preliminary data suggest that the triple combo may have positive activity in DEARE on the hematopoietic system. The goals of this proposal are twofold: (1) to determine the mechanisms by which the triple combo is acting to increase survival in H-ARS and have positive effects on hematopoietic DEARE. We will investigate these questions at the level of the hematopoietic stem cell (HSC), the rare bone marrow cell that is responsible for making all the blood elements and which, when damaged by radiation, fails to provide hematopoietic support resulting in H-ARS and hematopoietic DEARE; and (2) to determine whether the triple combo possesses positive effects on GI-ARS and to investigate the mechanisms of these effects. Better understanding of how radiation damages HSC and GI cells and leads to H-ARS, GI-ARS, and DEARE, will help scientists design treatments with more directed activity for the damaged cells and tissues, which means fewer side effects and more effective drugs. If successfully completed, the outcome of this work will be the identification of Bolder Biotech s peg-GCSF, peg-GM-CSF, and peg-IL11 as effective combination therapy against the dual syndromes of H-ARS and GI-
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510635
Entities
People
- Christie Orschell
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army