Stem cells lab.
(photo credit: JUDY SIEGEL-ITZKOVICH)
Imagine a magic potion that one could drink to repair all diseased organs and tissues, as if it supplied healthy new spare parts for the human body. It hasn’t happened, and it won’t occur for the foreseeable future, at least in such a form.
But adult stem cells processed from placentas from women who undergo planned cesarean sections and injected into patients show positive signs of treating and even curing diseases by producing missing proteins.
Pluristem Therapeutics Inc., a publicly owned biotechnology company (traded on NASDAQ and the Tel Aviv Stock Exchange) founded by Dr. Shai Meretzki of the Technion- Israel Institute of Technology in 2001, aims at being a world leader in the manufacture of human placental cells for commercial use. Meretzki, now involved in another company, developed the initial technology with colleagues from the Weizmann Institute of Science in Rehovot.
Pluristem has been issued some 30 patents and fully owns over 100 pending patent applications. Although the company concentrated on the development of medical equipment, it changed direction in 2005 when mechanical engineer and businessman Zami (Zalman) Aberman joined Pluristem and became its chairman and CEO.
Pluristem’s president and chief operating officer since this past February is also a non-scientist – Yaky Yanay has a degree in business administration, is a certified public accountant and was chief financial officer of Elbit Vision Systems.
Aberman and Yanay recently held a press tour for health and science journalists at Pluristem’s headquarters in Haifa’s Matam industrial park – showing off the impressive clean rooms with staffers in white overalls, their heads covered with sterile gear to prevent them from infecting the cells as they are grown and handled.
Its PLX (PLacental eXpanded) stem cells are a drug delivery platform that releases a cocktail of therapeutic proteins in response to a large variety of local and systemic inflammatory and ischemic diseases (in which there is an inadequate blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular function, such as a heart attack, peripheral artery disease or stroke). PLX cells are grown using the company’s proprietary 3-D micro-environmental technology and are an “off-the-shelf” product that doesn’t require the matching of tissues between the donor and recipient.
The cells have undergone clinical trials (proof of concept, pre-clinical, phase 1 and phase 2 to treat peripheral arterial disease (PAD) and are being readied for phase 3 trials in various parts of the world in the coming year or more. Pluristem has 160 employees, including three physicians and 17 people with doctorates.
“We do a lot of research in addition to producing the stem cells,” explained Aberman.
THE COMPANY’S Good Manufacturing Practice- certified manufacturing facilities efficiently produce commercial quantities of homogeneous PLX cells suitable for clinical studies, making it the only company so far to manufacture large quantities of placenta- based cell products using a “bioreactor.”
These shiny glass-and-metal containers, invented by Pluristem, create a three-dimensional micro-environment for the controlled, large-scale growth of cells at a fraction of the cost of traditionally expanding cells using culture dishes. Their processes have approval from the US Food and Drug Administration (FDA) and regulatory authorities in Israel, Germany, Australia, Singapore and elsewhere.
“We believe that cell therapy will be significant in the future. A number of major companies such as Genentech, Amgene and Genzyme were established decades ago.
Every biopharma company is working in the field of biological therapy,” said Aberman. “A quarter of a century ago, everybody thought embryonic stem cells produced from fetuses were the next big thing. But at Pluristem, we believe in adult stem cells from placentas to create drugs adapted to the patient himself.”
“Embryonic stem cells produce factors such as white cells or red cells for a certain specific condition. But we use a different technique, taking cells from placentas and producing universal therapeutic cells. We want to be the world’s leading company in developing and manufacturing cell therapies. We had offers from big firms that wanted to buy us, but we refused,” added Aberman, waving a little bottle of pink liquid, containing PLX cells. They are deep-frozen and sent around the world for testing and eventual use, and defrosted using a patented warmer developed at Pluristem that does not cause them any harm.
For treating HIV/AIDS patients and turning the once-fatal condition into a chronic illness, a cocktail of biological drugs was developed to treat various problems involved in the infectious disease. This is multifactorial, and this is the new direction in pharmaceuticals, said the company chairman and CEO.
With people living into their 80s and beyond, the population ages and suffer much more from chronic diseases.
“A variety of things in the body go wrong, so they need multifactorial drugs. Cellular therapy like ours is thus needed to restart organs and tissues so they function properly,” he explained.
The placenta is only human tissue in which there is no war of rejection between the mother and the embryos, said Yanay.
Aberman noted that Russian President Vladimir Putin, who just turned 62, owes his youthful figure and activity to his “injections once a year into his backside of some kinds of cells from pregnant sheep” that have nothing to do with Pluristem.
ALTHOUGH THE company’s products have not yet been approved for general marketing, they have been approved for research or even compassionate use for a handful of desperately ill individuals.
In 2011, the FDA gave “orphan drug” status to Pluristem’s PLX cells for the treatment of Buerger’s disease (a recurring progressive disease, usually resulting from smoking, in which the small and medium-sized arteries in the hands and feet suffer from inflammation and clotting and risk amputation.
Two years ago, Pluristem made PLX cells available to the Hadassah University Medical center in Jerusalem’s Ein Kerem for injection into the muscles of a seven-year-old girl from Romania who had bone marrow aplasia. She had undergone two stem cell transplants that had been taken from her own body and treated, but they failed to improve her condition, and she deteriorated.
In desperation, they tried Pluristem’s PLXPAD cells after receiving approval from the Health Ministry. It was the first time stem cells had been injected into the muscle rather than into the circulatory system. Pluristem said the treatment led to a significant increase in the girl’s red cells, white cells and platelets, and reversed her condition. She was able to be sent home soon after.
Later in 2012, Pluristem saved the life of a 45-year-old patient who suffered from acute myeloid leukemia, also at Hadassah.
He received two injections of the stem cells into a muscle and was well enough to be discharged.
The cells have also been approved in Japan, Singapore and other places to treat children with host vs. graft disease, a complication that can follow a stem-cell or bone-marrow transplant and occurs when the donor cells attack the transplant patient’s body.
The company’s first product, named PLXPAD and made mostly from maternal cells, is being used in clinical trials for a variety of conditions; a second one, called PLX-RAD and made mostly from fetal cells, has been added. This one, in pre-clinical development, is meant for blood conditions and acute radiation exposure. Two years ago, Pluristem signed a cooperation agreement with the US National Institutes of Health’s National Institute for Allergies and Infectious Diseases for animal-model research aimed at treatment of acute radiation diseases. The US agency invested millions of dollars in the study because it was eager to have therapies for victims of radiation exposure from an accident or war.
“We first tried to get the Israeli government interested, but they weren’t, so we turned to the NIH,” said Aberman, who maintained that the cells are “effective in treating life-threatening complications to the blood caused by exposure to large doses of radiation.”
Other animal studies shows that placental cells can reduce scar tissue in the hearts of mice models of acute myocardial infarction (heart attacks) and improve the pumping function in their hearts by causing the formation of new blood vessels.
In the orthopedic field, they have been shown in rats to significantly improve the recovery of muscles that suffered physical trauma. As for lung function, Pluristem was able to normalize oxygen saturation levels and reduce collagen deposition to the lung tissue of mice suffering from pulmonary fibrosis.
PROF. RAPHAEL Gorodetsky, the chief researcher in the biotechnology and radiology lab at Hadassah’s Sharett Institute of Oncology, said that pre-clinical studies he conducted showed that the placental cells have the potential to quadruple survival rates of animals exposed to a fatal level of radiation, compared to a control group.
Exposure to excess radiation damages the bone marrow and causes a serious reduction in red and white blood cell production, which increases the risk of infection and bleeding can be fatal. It can also affect the digestive system.
The placentas from which the cells are produced are obtained from women who give birth by planned cesarean sections at Bnai Zion (formerly Rothchild) Hospital and Rambam Medical Center in Haifa. As the placentas are discarded after birth, the women are almost always happy to donate them for research after the uterus expels them following birth. It’s forbidden by law to pay women for their placentas.
PROF. RON Gonen, head of Bnai Zion’s obstetrics branch, told reporters that human placentas “are a raw material that will exist forever and constitute the most accessible human raw material in the world. It is alive for nine months, weighs (without the fetus) about 500 grams and undergoes rapid growth. It transmits oxygen and food from the mother to the fetus and removes carbon dioxide and other wastes. It also has protection against rejection by the mother.”
The placenta also produces various hormones to ensure the fetus’s proper development and uses membranes to prevent the mixing of the mother’s blood with that of the fetus.
“If the placenta’s implantation after conception is not normal, it can result in preeclampsia, a potentially fatal condition for both the fetus and mother that causes hypertension and the release of protein in the woman’s urine. This can cause her multisystem organ failure and damage to the eyes, kidneys and abnormal blood clotting.” There is no cure, he added, except for abortion.
Pre-eclampsia occurs in three percent to 5% of pregnancies.
But Pluristem research on mice found that the human PLX cells can bring about the normalization of blood pressure, reduce the amount of protein in the urine and improve the functioning of the blood vessels, placenta and immune system without hurting the fetus.
“So far,” said the Bnai Zion physician, ”it has proven itself in mice, but it could become the drug to treat pregnant women.”
DR. EREZ Kachel, a cardiac surgeon in Sheba Medical Center at Tel Hashomer and Pluristem’s medical safety officer, said that placentas can release cytokines (small proteins important in cell signaling that affect the behavior of other cells, growth factors and other useful substances involved in building and curing the body).
“They can remain as stem cells or become specific other cells that could eventually be used to treat cardiovascular disease, autoimmune disease, cancer, sports and other orthopedic injuries and physical trauma,” said Kachel. “There have been over 500 studies in cell therapy in the world so far, and the world recognizes it as very important. The apparatus at Pleuristem is to give the body the ability to cure itself by releasing specific cells. Regenerational cells will be the future of medicine,” he concluded.