BrainStorm is developing cellular therapeutics based on stem cell technologies. The medical benefits promised by stem cell therapies offer hope to millions of patients suffering from many types of degenerative diseases, including PD, ALS and MS.
The aim of cell therapy is to “repair” damaged tissue and organs by augmentation with healthy cells provided by stem cell transplants. Bone marrow stem cell transplants for replacement and restoration of the hemopoeitic system (blood and lymph) of cancer patients have been successfully used for the past 20 years. Moreover, some types of stem cells, including cells from cartilage and skin, are already being used successfully.
Stem cells are generally described as cells that are capable of both self-renewal and differentiation. Stem cells have the ability to undergo asymmetric division such that one of the two daughter cells retains the properties of the stem cell, while the other begins to differentiate into a more specialized cell type. Stem cells are therefore central to normal human growth and development and a potential source of new cells for the regeneration of diseased and damaged tissue. There are two primary sources for stem cells:
�� Embryonic stem cells (ESC) are among the easiest to grow and
culture. However, their use has generated much legal and ethical
debate, surrounding the use of early human embryos.
�� Adult stem cells (ASC) are derived from bone marrow, umbilical
cord, and progenitor cells from various adult tissues. Their use does
not involve ethical issues but does entail challenges involving the
development of efficient methods for their proliferation and
differentiation. Bone marrow is an especially attractive source, since it
can be sourced from the patient himself or herself, obviating the need
to find suitable donors and avoiding the use of risky
immunosuppressive therapy.
Stem cells have been used successfully in bone marrow transplants for many years, primarily for treating leukemia, immune deficiency diseases, severe blood cell diseases, lymphoma and multiple myeloma. Bone marrow is the tissue where differentiation of stem cells into blood cells (hematopoiesis) occurs. Bone marrow transplant success rates are now between 40% to 60% and improving.
Studies of neurodegenerative diseases suggest that symptoms that arise in afflicted individuals are secondary to defects in local neural circuitry and cannot be treated effectively with systemic drug delivery. Consequently, alternative approaches for treating neurodegenerative diseases have emerged, such as transplantation of cells capable of replacing or supplementing the function of damaged neurons. For such cell replacement therapy to work, implanted cells must survive and integrate both functionally and structurally, within the damaged tissue without affecting other areas of the brain.
Stem Cell Therapy for Parkinson’s Disease
In PD animal models, researchers have transplanted non-neuronal cells, including monocytes, bone marrow stem cells, myoblasts, fibroblasts, astrocytes and Sertoli cells1, with and without engineering them with growth factor genes (glial-derived and brain-derived growth factors) to enhance survival rates, or with dopamine synthesis genes2. However, these cells failed to fully acquire the structural and functional characteristics of the damaged neuron cells and consequently proved to be therapeutically ineffective3.
In contrast, transplantation of neural progenitor cells such as fetal brain cells from the area of the brain rich in dopamine-containing cell bodies — and the area most affected in PD patients — has been shown to be partially effective in animals, reversing the behavioral deficits induced by selective dopaminergic neurotoxins.4
PD is the first disease of the brain for which intracerebral cell replacement therapy has been used in humans. Since the 1980s clinical experiments using cell transplantation as a therapy for PD have been conducted. Several attempts have been made to provide the neurotransmitter dopamine to cells of the diseased basal ganglia of PD patients by homografting adrenal medullary cells to the brain.5
To date, about 300 PD patients in several Western countries have undergone transplantation of fetal cells. The studies showed that the embryonic dopamine cell transplants survive in nearly all patients regardless of age and without immunosuppressants. Among younger patients (60 years old or younger), standardized tests of PD revealed significant improvement in the transplantation group as compared with the sham-surgery group when patients were tested in the morning before receiving medication.
However, no significant clinical improvement occurred in the older patients. In addition, in about 15% of the cases, transplanted patients suffered from severe dyskinesia, probably caused by overproduction of dopamine. The partial results have been attributed to the heterogeneity and lack of control on the fetal tissue source. Some experts have proposed that neuro-transplantation should be attempted earlier in the clinical course of PD to prevent disease progression. In any event, the low availability of human fetal tissue substantially limits the number of patients who could benefit from fetal cells transplantation.
Adult bone marrow stromal cells (BMSc) are non-hematopoietic cells that can differentiate into neuron-like cells. Transplantation of BMSc into mouse and rat models of PD was previously shown to result in beneficial effects.6
However, engrafted BMSc may uncontrollably release neurotransmitters, even dopamine, which in turn may cause severe side effects such as “runaway” dyskinesia. Consequently, there is a widely recognized need for generating in vitro neuronal-like cells that controllably produce dopamine and to use these for transplantation and integration into damaged neuronal tissue to effectively and safely treat neurodegenerative disorders.
Overview
