Page 226 - 2014 Printable Abstract Book
P. 226
Exposure to ionizing radiation (IR) from medical procedures has increased sharply in the last three
decades. Recent epidemiological studies suggest a direct relationship between exposure to IR and health
problems including cancer incidence. Therefore, minimizing the impact of IR in patients has become a
priority in the development of future clinical practices. Crucial players in IR-induced DNA damage include
reactive oxygen species (ROS), but the sources of these have remained elusive. We show here for the first
time that two members of the ROS-generating NADPH oxidase family (NOXs), NOX4 and NOX5, are
involved in IR-induced DNA damage. Depleting these two NOXs in human primary fibroblasts resulted in
reduced levels of DNA damage as measured by levels of IR-induced foci, a marker of DNA double-strand
breaks (DSBs) and the comet assay coupled with increased cell survival. NOX involvement was
substantiated with Fulvene-5, a NOXs specific inhibitor. Moreover, Fulvene-5 mitigated IR-induced DNA
damage in human lymphocytes ex-vivo. Our results provide the evidence that the inactivation of NOXs
protects cells from both IR-induced DNA damage and IR-induced cell death. These findings suggest that
NOXs inhibition may be considered as future pharmacological targets to help minimize the negative
impacts of radiation exposure for millions of patients each year.
(PS3-67) Development of a myeloid progenitor cell therapeutics for treatment of HS-ARS. Jennifer
Maxey, MS; Gregory Boucher, MS; Jennifer Adrian; Kitman Sharis-Yeung, MS; Tim C. Fong, PhD; Anna K.
Sedello, PhD; Cellerant Therapeutics, Inc., San Carlos, CA
Exposure of the hematopoietic system to lethal doses of radiation results in severe neutropenia
increasing susceptibility to opportunistic infections. Exposed individuals may survive if they receive timely
supportive care until autologous hematopoietic recovery occurs. We have developed a method to
generate a large number of mouse myeloid progenitor cells (mMPC) from purified mouse hematopoietic
stem cells in serum-free culture conditions in vitro to produce a cell-based product for the treatment of
severe neutropenia. We have previously shown that cryopreserved mMPC pooled from several major
histocompatibility complex disparate donors engraft across allogeneic barriers and provide cell-dose
dependent radioprotection in lethally irradiated mice at supralethal radiation doses (9-15 Gy) and when
administration is delayed for up to 7 days post irradiation. We now demonstrate that mMPCs engraft
transiently to provide survival benefit at lower radiation doses (6-7 Gy) that result in hematopoietic
syndrome of acute radiation syndrome (HS-ARS). We further show that mMPC generate functional
myeloid progeny including neutrophils in vitro and in vivo. These results show proof-of-concept in a mouse
model that myeloid progenitor cells generated in vitro are a versatile therapeutic capable of providing
myeloid hematopoietic support for HS-ARS. Cellerant Therapeutics is currently developing a human
myeloid progenitor cell product, CLT-008, as an effective bridging therapy for neutropenia associated with
chemotherapy, cord blood transplants, and HS-ARS.
1
(PS3-69) A useful by-product of rice production for radiation protection. Kimberly J. Krager, PhD ; Mary
2
2
3
3
Kordsmeier, M.S. ; Luke R. Howard, PhD ; Philip J. Breen, PhD ; Cesar M. Compadre, PhD ; Martin Hauer-
1
1;4
Jensen, MD, PhD ; Nukhet Aykin-Burns, PhD ;Division of Radiation Health, Department of
Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock,
2
1
AR ; Department of Food Science, University of Arkansas, Fayetteville, AR ; Department of Pharmaceutical
224 | P a g e
decades. Recent epidemiological studies suggest a direct relationship between exposure to IR and health
problems including cancer incidence. Therefore, minimizing the impact of IR in patients has become a
priority in the development of future clinical practices. Crucial players in IR-induced DNA damage include
reactive oxygen species (ROS), but the sources of these have remained elusive. We show here for the first
time that two members of the ROS-generating NADPH oxidase family (NOXs), NOX4 and NOX5, are
involved in IR-induced DNA damage. Depleting these two NOXs in human primary fibroblasts resulted in
reduced levels of DNA damage as measured by levels of IR-induced foci, a marker of DNA double-strand
breaks (DSBs) and the comet assay coupled with increased cell survival. NOX involvement was
substantiated with Fulvene-5, a NOXs specific inhibitor. Moreover, Fulvene-5 mitigated IR-induced DNA
damage in human lymphocytes ex-vivo. Our results provide the evidence that the inactivation of NOXs
protects cells from both IR-induced DNA damage and IR-induced cell death. These findings suggest that
NOXs inhibition may be considered as future pharmacological targets to help minimize the negative
impacts of radiation exposure for millions of patients each year.
(PS3-67) Development of a myeloid progenitor cell therapeutics for treatment of HS-ARS. Jennifer
Maxey, MS; Gregory Boucher, MS; Jennifer Adrian; Kitman Sharis-Yeung, MS; Tim C. Fong, PhD; Anna K.
Sedello, PhD; Cellerant Therapeutics, Inc., San Carlos, CA
Exposure of the hematopoietic system to lethal doses of radiation results in severe neutropenia
increasing susceptibility to opportunistic infections. Exposed individuals may survive if they receive timely
supportive care until autologous hematopoietic recovery occurs. We have developed a method to
generate a large number of mouse myeloid progenitor cells (mMPC) from purified mouse hematopoietic
stem cells in serum-free culture conditions in vitro to produce a cell-based product for the treatment of
severe neutropenia. We have previously shown that cryopreserved mMPC pooled from several major
histocompatibility complex disparate donors engraft across allogeneic barriers and provide cell-dose
dependent radioprotection in lethally irradiated mice at supralethal radiation doses (9-15 Gy) and when
administration is delayed for up to 7 days post irradiation. We now demonstrate that mMPCs engraft
transiently to provide survival benefit at lower radiation doses (6-7 Gy) that result in hematopoietic
syndrome of acute radiation syndrome (HS-ARS). We further show that mMPC generate functional
myeloid progeny including neutrophils in vitro and in vivo. These results show proof-of-concept in a mouse
model that myeloid progenitor cells generated in vitro are a versatile therapeutic capable of providing
myeloid hematopoietic support for HS-ARS. Cellerant Therapeutics is currently developing a human
myeloid progenitor cell product, CLT-008, as an effective bridging therapy for neutropenia associated with
chemotherapy, cord blood transplants, and HS-ARS.
1
(PS3-69) A useful by-product of rice production for radiation protection. Kimberly J. Krager, PhD ; Mary
2
2
3
3
Kordsmeier, M.S. ; Luke R. Howard, PhD ; Philip J. Breen, PhD ; Cesar M. Compadre, PhD ; Martin Hauer-
1
1;4
Jensen, MD, PhD ; Nukhet Aykin-Burns, PhD ;Division of Radiation Health, Department of
Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock,
2
1
AR ; Department of Food Science, University of Arkansas, Fayetteville, AR ; Department of Pharmaceutical
224 | P a g e
