An Israeli company is engaged in the development of an innovative substitute to overcome the shortage of bone marrow doses for the treatment of cancerous blood diseases. Preclinical trials have shown optimistic results
24.9.2006
By: Ora Burger and Zami Aberman, Scientific American *
Illustration from the Pluristem website
Treatment through bone marrow transplantation is used as a solution in a variety of malignant hematological diseases. The difficulty in finding a suitable donor leaves tens of thousands of incurable patients every year. In recent years, it has become clear that the umbilical cord blood of fetuses, which was previously considered medical waste, contains mature stem cells of the blood system, suitable for bone marrow transplants. Collecting umbilical cord blood at birth and keeping it deep frozen, allows the establishment of an extensive and available pool of mature stem cells that will be used in the future as a source for bone marrow transplants. The pool may solve the lack of donors and open up many possibilities for saving lives.
However, the amount of stem cells in umbilical cord blood is too small. In the conventional process of bone marrow transplantation, approximately 170,000 hematopoietic stem cells (stem cells of the blood system) are injected into the patient per kilogram of body weight. The experience gained to date shows that an amount smaller than this will considerably reduce the chances of the graft being accepted.
How to make the limited resource usable?
In order to treat an adult patient, therefore, more than 12 million cells are required, but in a typical umbilical cord blood portion there are at most 5-4 million hematopoietic stem cells. Therefore, it is impossible to use umbilical cord blood for transplants in patients who weigh more than 35 kg. Because of this, only about 6,000 transplants of stem cells derived from umbilical cord blood have been performed to date, most of them in children. The limited amount of cells resulted in the fact that during the last decade many studies were conducted all over the world that dealt with the question: how to utilize the limited resource, and make it suitable for the entire population?
Today, several approaches are available to increase the number of hematopoietic stem cells in a portion of umbilical cord blood. One of the common methods is ex-vivo expansion of the stem cells. In this approach, it must be ensured that the proliferating cells retain the properties of the original stem cells and can restore the damaged blood system of the patient, similar to their role in a healthy person. In a normal state, a stem cell of the blood system divides in most cases asymmetric division: one of the daughter cells retains its properties as a stem cell, while the other daughter cell begins the processes of differentiation, and becomes an adult cell with a defined role in the blood system: a red blood cell, a white blood cell, or a platelet .
As the mature and sorted cell ages, it dies and is replaced by a "new" cell that has undergone the same process. This life cycle occurs every day in the body of a healthy person. Without the stem cell pool in the bone marrow, the body has no ability to replace the aging and dead cells of the blood system with new ones. Therefore, a tissue transplanted into a cancer patient containing cells that have already started the differentiation process, will not be able to long-term restore the blood system in his body, and will not be able to save his life. Hence the enormous importance of the proliferation of stem cells without differentiation.
In the extracellular proliferation methods, growth factors and synthetic substances (recombinant cytokines) are used to accelerate proliferation. But at the same time as this process, the unwanted differentiation process also begins, so differentiation-inhibiting chemicals are also added to the culture. Varhat believed that the use of synthetic substances of various kinds could cause genetic instability of the stem cells and other side effects over time.
Another method that aims to overcome the small amount of cells, is the transplantation of two portions of umbilical cord blood originating from two different donors. First clinical results obtained in dozens of patients show that only one dose is absorbed - the first dose injected.
The startup began with a doctoral thesis
The Israeli company Pluristem (Pluristem Life Systems) is engaged in the development of biological products that will allow the use of umbilical cord blood as a substitute for bone marrow transplantation to cure cancerous blood diseases. The company was founded in 2003 by Dr. Shai Maretzky based on his doctoral thesis which was done in collaboration between the Weizmann Institute of Science and the Technion and it operates in the Matam Park for Advanced Technology in Haifa.
Recently, the company reported on successful pre-clinical trials of an innovative product, which offers a third method to overcome the problem, the transplantation of which together with the hemopoietic stem cells derived from the umbilical cord blood leads to an increase in the rate of graft acceptance, thus compensating for the small amount of cells. The product contains mesenchymal infrastructure cells (stroma) extracted from the placenta and encourage the absorption of the rare hematopoietic stem cells in the patient's body. The cells of the mesenchymal infrastructure are part of the natural tissue that builds the bone marrow in the healthy body, a tissue that creates the appropriate conditions for the occurrence of the processes in which the hematopoietic stem cells are preserved and new blood cells are formed.
This innovative product, known as PLX-1, is based on the growth of mesenchymal cells, which originate, as mentioned, in the placenta, in an environment that simulates the three-dimensional physiological structure of the bone marrow. The placenta is considered medical waste and is disposed of at the end of the birth. The advantage of the placenta as a source of life-saving medicine is that it is a human tissue whose use does not involve ethical problems. From each placenta, a pool of cells is extracted and built in a process that begins with an initial sorting of the desired cells. For multiplication, the cells are seeded at a later stage on a three-dimensional substrate of inert material (not biologically active).
These conditions allow the tissue culture to multiply and reach a high density, which roughly simulates the natural density of cells in the body's skeleton. The growth of the dense culture is made possible by providing adequate feeding and ventilation conditions in a 1D growth facility (bioreactor) called PluriX. After two to three weeks, the cells are collected from the bioreactor, divided into portions and frozen in liquid nitrogen. Each dose contains a dose of mesenchymal cells, supporting graft uptake, and is ready for thawing and transplantation. This dish is actually the product called PLX-XNUMX.
The preclinical experiments conducted in a multisystem in mice lacking an immune system show that the injection of the PLX-1 cells in addition to the hematopoietic stem cells from the umbilical cord blood increases the efficiency of the transplant by at least three times compared to the control group, in which the stem cells were transplanted without PLX-1. The preclinical experiments demonstrate both the increase in absorption efficiency of the umbilical cord hematopoietic stem cells, which are limited in number, and the reduction of the need for extracellular proliferation of the stem cells. This solution will make it possible to use a portion of umbilical cord blood as a substitute for a bone marrow transplant in older patients.
* Zami Aberman is the CEO of Pluristem and Dr. Ora Burger is the company's Vice President of Research and Development. The article was brought at the initiative and with the assistance of Bernard Ditchek, the editor of the online magazine dealing with the Israeli life sciences industry.
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