Treating Acute Radiation Sickness with Mesenchymal Stromal Stem Cells
William R. Prather RPh, MD, Senior VP Corporate Development; Pluristem Therapeutics, Haifa, Israel
Drug Discovery & Development - June 22, 2011
The recent nuclear crisis in Japan has highlighted the urgent need to develop products for the treatment of acute radiation sickness (ARS) and radiation exposure.
Acute radiation sickness (ARS)—also known as radiation poisoning—occurs after accidental radiologic or nuclear exposure to a high dose of radiation over a short period of time. The U.S. unit of measurement for a radiation dose is the rem (roentgen equivalent in man) and most people in the United.States receive approximately 0.25 rem per year from normal background radiation. Flying for 12 hours at 39,000 feet exposes a person to approximately 0.006 rem, while a mammogram exposes patients to approximately 0.3 rem.
The onset and types of symptoms that are caused by radiation depend on the amount of the radiation exposure. At 5 to 10 rem, changes in blood chemistries occur, while gastrointestinal symptoms begin at approximately 50 rem. Half of the people exposed to 500 rem will die within 30 days. The annual dose limit for workers at nuclear plants in the United States is 5 rem.1
Depending on the level of exposure, bone marrow aplasia may be combined with gastrointestinal (GI) involvement, cutaneous burns, muscle radiolysis, lung injury, and/or central nervous system failure, among other conditions.2 The prodromal phase consists of GI symptoms that include abdominal pain, nausea, vomiting, and diarrhea lasting an average of five days. During the latent phase, which occurs over the ensuing several days, the patient appears to be recovering. However, over the next several days to weeks, patients suffer a hematopoietic crisis from the depletion of erythropoietic, thrombocytopoietic, and leukopoietic precursors within the bone marrow. The illness phase is characterized by immunosuppression and multiple organ failure with death occurring within months following the initial exposure, usually from infection. Hematological malignancies, such as leukemia, can also occur years after exposure.3
Damage to the whole organism is related to a systemic inflammatory response. Different target organs are affected due to the activation of the innate immune system, resulting in a significant release of inflammatory cytokines,4 with the pathophysiology resembling the “cytokine storm” seen in graft-versus-host disease (GvHD).5 The longer-term effects of ionizing radiation have been related to persistent inflammatory signs, e.g. increased levels of tumor necrosis factor-a (TNF-a), interferon-b, interleukin-6, and C-reactive protein.6 The management of patients afflicted with ARS, therefore, relies on those therapies that both mitigate inflammation7 and are able to aid in the hematopoietic repopulation of the bone marrow.
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Figure 1: Mechanism of action of MSCs in the inflammatory and ischemic environment. (Source: Pluristem Therapeutics)
Based on these characteristics, mesenchymal stromal cells (MSCs) would, therefore, seem to be likely candidates as therapeutics for ARS. MSCs have been shown to be immune-privileged without the need for HLA matching even after repeat injections7 and have been documented to home specifically to radiation-injured tissues.8 In addition to reducing apoptosis,9 MSCs have been shown to secrete an abundance of therapeutic proteins, including anti-inflammatory and angiogenic cytokines and hematopoietic growth factors that are involved in the prevention and treatment of ARS by the reduction of inflammation and the support of angiogenesis10,11,12 (Figure 1). Additionally, MSCs have also been shown to promote hematopoietic recovery after lethal irradiation exposure.7,9
With these attributes, it is no surprise that MSCs have proved to be effective in animal studies of ARS2,8,9,13 leading to governmental funding to expand the research and development of MSCs for this indication. Osiris Therapeutics, a U.S.-based biotechnology company that uses MSCs derived from bone marrow, secured a contract with the U.S. Department of Defense in January 2008 for approximately $225 million. $200 million of this amount will be used for purchasing and stockpiling cell product after efficacy has been demonstrated in two different animal species and safely documented in humans. This approval process was employed because it would be unethical to expose people to high levels of radiation in clinical trials.
While MSCs are usually harvested from bone marrow, they can also be obtained from other sources such as adipose tissue and peripheral blood. One of the more recently discovered sources of MSCs that seems to be highly appropriate is the placenta. The placenta is essentially medical waste with a ubiquitous supply. Moreover, placental cells can be easily and inexpensively expanded ex vivo, and be made available as an allogeneic “off-the-shelf” product.
As with bone marrow-derived MSCs, placental-derived MSCs have been shown to possess favorable hypo-immunogenic properties, act via the secretion of anti-inflammatory and angiogenic factors,14 and potentially provide greater healing powers than older tissue sources.15 While ARS animal trials are still ongoing, early results have demonstrated that placental-derived MSCs enhance the engraftment of hematopoietic stem cells (HSCs) contained in cord blood when the MSCs and cord blood are administered concurrently.16 This would allow ARS patients to obtain cells for therapy immediately after exposure, as well as potentially use cells along with cord blood at a later date to repopulate the bone marrow if necessary.
In summary, MSCs derived from bone marrow and placentas are actively being investigated as therapy for ARS. When available, MSCs will be cryopreserved. Although other cells such as myeloid progenitors are also being studied as a remedy, MSCs are the only cells being investigated that would address the entire clinical spectrum and multi-organ involvement from radiation exposure. A clinical case of ARS has yet to be treated with MSCs, but these cells have been administered systemically in patients for graft-versus-host disease (GvHD) and other indications without significant adverse side effects.
About the Author
Dr. Prather has been with Pluristem Therapeutics since 2006. He received his BS in Pharmacy and medical degree from the University of Missouri. Besides holding senior healthcare research positions for a variety of investment banks, Dr. Prather co-founded Panacos, Inc., a public pharmaceutical company.
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References
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