Haifa-based Pluristem has been working with researchers in Fukushima, the site of nuclear meltdowns in 2011, to treat acute radiation syndrome
Once it was Three Mile Island, then Chernobyl – but today, the name that evokes the horror of nuclear radiation is Fukushima, the site of a tragic 2011 incident in which an earthquake and subsequent tsunami led to three nuclear meltdowns, hydrogen-air explosions, and the massive release of radioactive material into the air.
Seven years later, the Japanese government says that the cleanup of the site is nearly complete, and that it is safe to return to Fukushima.
It is not known how many people died or got sick due to radiation at Fukushima, but a WHO report predicted a rise in some cancer rates in contaminated areas.
At the completion of several four-year studies, Haifa-based Pluristem Therapeutics has reported positive results that show that its placenta-based PLX-R18 cells are effective as a treatment for radiation damage to the gastrointestinal tract and bone marrow.
PLX-R18 RESCUE OF HEMATOPOIESIS IN VIVO
PLX-R18 efficacy in rescuing hematopoiesis was tested in a well-characterized model of lethal irradiation in collaboration with NIAID and with Hadassa Medical Center. Administration of PLXR18 intramuscularly to mice 1 and 5 days after total body irradiation (LD70/30) significantly increased survival and rescued-radio-induced weight loss relative to vehicle-injected controls. Similar results were seen when cells were injected on days 2 and 5 after irradiation, indicating that a window of time exists during which therapy can still be effective in case of lethal irradiation.2 In addition, cell treatment significantly increased the number of colony-forming hematopoietic progenitors in the bone marrow and raised peripheral blood cellularity to values near those of un-irradiated control values.
In vivo secretion studies indicate that PLX-R18 cells responded to radiation-induced hematopoietic failure by transiently secreting haematopoiesis-related proteins to enhance reconstitution of the hematopoietic system. The PLX-R18 cells secreted factors that induced the early secretion of endogenous (mouse-derived) hematopoietic factors (such as KC, IL-6, and G-CSF) in irradiated mice. These factors were secreted on days 2-14 after irradiation in treated mice (peaking on day 4-9), whereas in untreated animals they peaked much later (at around day 16) in those animals which survived to this time point. Secretion of exogenous (PLX-R18-derived) and endogenous (mouse derived) factors enables an earlier increase in the number of multi-lineage hematopoietic precursor cells (HPCs) in the bone marrow and enables the migration of bone marrow cells. Higher levels of cellularity in the bone marrow can be seen on days 4-9 following PLX-R18 treatment, allowing earlier hematopoietic rescue after irradiation. Proliferation, differentiation, and migration of HPCs ultimately leads to an elevation in the levels of multiple blood lineages in the peripheral blood (with significant differences visible on day 23 after treatment). The end result of this regenerated hematopoietic system is a higher survival rate in PLX-R18-treated irradiated mice.
In vitro studies have indicated that PLXR18 lacks the ability to differentiate into osteocytes or adipocytes, supporting their proposed mechanism of action of endocrine protein secretion. PLX-R18 cells were proven to have a stable karyotype and to reach senescence, supporting their safety for clinical use. PLX-R18 cells do not express HLA class II molecules or co-stimulatory molecules, supporting their use as an off-the-shelf allogeneic product. Safety studies in vivo have indicated no treatment-induced toxicity or pathologies, and biodistribution studies indicate that the PLX-R18 cells remain localized to the site of injection within the muscle. Therefore, clinical use of PLX-R18 by intramuscular administration is not expected to have any associated safety concerns.
Under a memorandum of understanding with Pluristem, the Fukushima Global Medical Science Center of Fukushima University has been developing targeted animal models of acute radiation sickness and testing these models to evaluate the efficacy of PLX-R18 in treating radiation damage to the GI tract and bone marrow of mice.
Data from the studies showed that PLX-R18 cells significantly increase survival rates, preserve GI stem cells activity that enhance the recovery of the GI system and prevent severe damage to the intestinal lining, suggesting PLX-R18 potential as a multi-organ therapy for acute radiation syndrome, the company said.
Pluristem has for the better part of the last decade been working on a cure for acute radiation syndrome, also known as radiation disease, the mass destruction of tissues and cells caused by exposure to extremely high levels of radiation, such as could occur in a nuclear catastrophe, and incorporating potentially lethal damage to the gastrointestinal tract, lung, skin and bone marrow, as well as other systems.
Previous tests conducted in Israel and the US on animals (mostly mice), which were subjected to total-body irradiation and injected with human cytokines, showed significantly increased survival rates when treated with Pluristem’s PLX-RAD cells, with the treatment essentially reversing the effects of radiation disease – which is especially hard on bone marrow – to a great extent.
While there are many companies today harvesting stem cells to develop therapeutic products, Pluristem was the first, and is still one of the only, companies harvesting from human placenta.
According to Pluristem researchers, the placenta contains mesenchymal-like adherent stromal cells, which have been found by researchers to have significant therapeutic potential.
The cells promote tissue repair, possibly by secreting biologically active substances, including cytokines, that modulate immune response, along with factors that enhance the growth of blood vessels.
These cells stimulate the body’s own mechanisms to heal damaged tissues.
And, because placental cells themselves are immunoprivileged (meaning that they do not elicit an immunological response from the body, as other cells do), they can be used freely for any purpose, without requiring tissue matching.
Pluristem “harvests” the placenta from a hospital in northern Israel, where it is donated by women undergoing caesarean section births.
The births are planned in advance, allowing the company to set up the equipment needed to ensure that the placenta is still living and not contaminated by the environment.
It is then rushed to Pluristem’s facility, where it is then processed into PLX (PLacental eXpanded) cells, for use in a variety of applications.
In the Fukushima studies, data showed that treatment with PLX-R18 (a version of PLX cells developed specifically for treating radiation sickness) following exposure to high level of ionizing radiation (14 Gy, where 6 Gy or greater exposure generally leads to death within two weeks), with partial shielding of the bone marrow, led to a 50% increase in survival, significantly reduced weight loss and increased white blood cell and platelet counts as compared to the control groups.
GI tract damage in acute radiation syndrome typically includes damage to, or reduction of, local stem cells, as well as a breach of the lining of the GI tract, leading to life threatening diarrhea and sepsis. Among the effects of PLX-R18 cells, the studies showed, is the mitigation of severe damage to the intestinal lining and enhanced regeneration of local stem cells, thus enhancing the repair process and giving patients a better chance to survive.
The study was conducted in cooperation with Fukushima University. According to Dr. Akihiro Inano of the university, “we were impressed by PLX-R18’s ability to increase survival by mitigating the damage of high levels of radiation on these organ systems. The development of this animal model enabled us to evaluate the efficacy of treating ARS in both the GI system and bone marrow simultaneously.”