Neural Program:
Can human neural stem cells be used to treat neurological diseases and injuries?
In 1997, StemCells' scientists invented a reproducible method for growing human central nervous system (CNS) stem and progenitor cells in culture as clusters of cells called 'neurospheres' as invented originally by Reynolds and Weiss for rodent cells. These cells can be expanded for a number of generations in culture and can become all three of the major cell types of the brain and spinal cord—neurons, astrocytes, and oligodendrocytes. In collaboration with Dr. Anders Bjorklund of Lund University, Sweden, we showed that cells from these cultures could be successfully transplanted into the brains of rodents. The cells migrated and specialized into different cell types depending on their surroundings (Fricker, et. al. 1999; Englund, 2002).
In 2000 we were the first to identify, isolate, and purify well-characterized, normal human CNS stem cells (HuCNS-SC) from brain tissue using monoclonal antibodies against cell surface antigens. Because the cells are normal, genetically unmodified, and highly purified human CNS stem cells, they may be safer and more effective than cancer cells or unpurified mixtures of cell types as potential cell-based therapeutics.
The Company's scientists expanded HuCNS-SC to generate cell banks, and transplanted them into the brains of thousands of immunodeficient mice, where they migrated and differentiated into the three major CNS cell types, i.e., neurons, astrocytes and oligodendrocytes. The HuCNS-SC survived over the long term in the mouse brains, and a portion of them resided in the endogenous stem cell niche where they continued to divide. Thus, the Company's proprietary HuCNS-SC can adapt in host brain environments and behave like host neural cells, dividing, migrating and differentiating.
We currently have collaborations with a number of experts in order to test the effects of transplanted HuCNS-SC in preclinical animal models of neurological disease and injury, such as lysosomal storage disease, spinal cord injury, demyelinating diseases and Alzheimer's disease
ˆTop
What neurological diseases and injuries might be treatable by stem cell transplantation?
Neuronal Ceroid Lipofuscinosis (Batten disease)
Batten disease is named after the British pediatrician who first described the juvenile form of neuronal ceroid lipofuscinosis (NCL) in 1903. The name is now commonly used to encompass three forms of NCL—infantile, late infantile and juvenile onset. All forms have the same basic cause—lack of a lysosomal enzyme—and have a similar progression and outcome. The different forms of NCL have traditionally been classified by age of onset, but today the disease is more precisely classifiable in terms of mutations in the specific gene and enzyme causing the disease. Children with Batten disease suffer seizures, progressive loss of motor skills, sight and mental capacity, eventually becoming blind, bedridden and unable to communicate. Today, Batten disease is always fatal.
Infantile and late infantile NCL are brought on, respectively, by inherited mutations in the CLN1 gene, which codes for palmitoyl-protein thioesterase 1 (PPT1) or in the CLN2 gene, which codes for tripeptidyl peptidase I (TPP-I). The consequence of these mutations is either a defective or a missing enzyme that leads to accumulation of lipofuscin-like fluorescent inclusions in various cell types. Presumably, these non-degraded lysosomal substrates accumulate to the point where they interfere with normal cellular and tissue function and ultimately lead to the pathological manifestations of the disease. One way to treat the disease may be to provide the brain with a replacement source of functional enzyme that can be taken up by the enzyme-deficient cells. Read about our Phase I clinical trial in NCL and our preclinical proof-of-concept.
Batten disease is one of about 40 lysosomal storage disorders (LSD). LSDs are caused by genetic errors that lead to the accumulation of toxic material within the lysosomes. These conditions, which together affect about 5 million people in the United States, currently have no cure.
Disorders of Myelination
The myelin sheath is an extended cell membrane that wraps around axons (which conduct electrical nerve impulses between neurons) in small segments called internodes. Myelin provides insulation for axons; small gaps between internodes allow the rapid, non-degrading “saltatory” propagation of the action potential down the axon. The result is a system of axons that conduct nerve impulses rapidly in a small space with low energy requirements.
CNS myelination is accomplished by glial cells called oligodendrocytes. Multiple sclerosis is a progressive disorder of myelination, resulting in extensive muscle and organ malfunction. We believe some function may be restored in such cases by transplantation of HuCNS-SC that become oligodendrocytes and form myelin sheaths. Periventricular leukomalacia (PVL), a kind of cerebral palsy, is a disease caused by errors in myelination. In these cases function may be restored if transplanted HuCNS-SC can become oligodendrocytes and replace those that are lost. Our preclinical research with “Shiverer” mice (which have a mutation in the gene for myelin basic protein, MBP, that results in disordered myelination and shivering behavior) has shown that HuCNS-SC can survive, migrate, generate oligodendrocytes and actually myelinate damaged host axons.
Read about our Phase I clinical trial in Pelizaeus-Merzbacher Disease (PMD) a fatal myelination disorder and our preclinical proof-of-concept.
ˆTop
Spinal Cord Indications
Spinal cord indications are often associated with neuron loss and demyelination. To determine whether transplanted HuCNS-SC could become neurons and oligodendrocytes in the injured spinal cord of immunodeficient mice, we initiated a collaboration with Dr. Aileen J. Anderson and Dr. Brian J. Cummings of the Reeve-Irvine Center at the University of California. Spinal cord-injured mice transplanted with HuCNS-SC showed improved motor function compared to control animals. In addition, the transplanted HuCNS-SC migrated along the spinal cord to the point of injury, and matured into both neurons and oligodendrocytes. Researchers also found that the animals with the most surviving cells had the greatest recovery in walking. Based in part on these data, StemCells was awarded a one-year $342,000 Small Business Innovation Research grant from the National Institute of Neurological Disease and Stroke (NINDS) to pursue its work in the treatment of spinal cord injuries.
Age-related Macular Deneneration
Currently afflicting 25-30 million people worldwide, age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in people over the age of 55. As of today, there is no cure for AMD.
Our preclinical data demonstrates the therapeutic potential of our human neural stem cells to treat diseases of the eye such as AMD. Studies conducted with the Casey Eye Institute as part of an ongoing research collaboration show that, when transplanted into the eye of the RCS (Royal College of Surgeons) rat, a well-established animal model of retinal degeneration, our human neural stem cells protect the retina from progressive degeneration and preserve visual function long term as measured by two separate visual tests. The transplanted cells also exhibit robust, long-term protection of both rod and cone photoreceptors.
The ability to protect cones, in particular, is significant in regard to AMD, since it is the progressive deterioration of these specific cells (which are highly concentrated within the macula of the human eye) that ultimately results in the vision loss caused by this disease. The protection of both rods and cones is important in considering the potential of using human neural stem cells as a treatment for retinitis pigmentosa and other retinal degenerative disorders.
We are pursuing additional preclinical studies of our neural stem cells in the hope of one day achieving a breakthrough in treating retinal degenerative diseases such as AMD and retinitis pigmentosa.
For more information on our work in this area, download our Fact Sheet on AMD.
Alzheimer's Disease
Alzheimer's disease is a complex, fatal disease involving progressive cell degeneration, beginning with the loss of brain cells that control thought, memory and language. The disease, which currently has no cure, was first described in 1906 by German physician Dr. Alois Alzheimer, who discovered amyloid plaques and neurofibrillary tangles in the brain of a woman who died of an unusual mental illness. Today these tangles and plaques are considered hallmarks of Alzheimer's disease, which is the leading cause of dementia and currently affects approximately 4.5 million Americans.
StemCells received a Small Business Technology Transfer (STTR) grant from the National Institutes of Health (NIH) to fund studies on the use of the Company's proprietary HuCNS-SC in Alzheimer's disease. These studies are to be conducted in the laboratory of Dr. George A. Carlson of the McLaughlin Research Institute in Great Falls, Montana.
Dr. Carlson's work testing HuCNS-SC in mouse models for Alzheimer's disease could determine the feasibility and utility of treatment using neural cell transplants. The Company has been working with Dr. Carlson over the past few years to develop the necessary animal models and reagents for this study. The model is an immunodeficient transgenic mouse that over-expresses the human A peptide, which accumulates and forms amyloid plaques seen in Alzheimer's patients. The mouse model therefore should provide a meaningful opportunity to study the effect of transplanted HuCNS-SC in an environment similar to that found in the human disorder.
Other Potential Applications for the Neural Stem Cell
HuCNS-SC may be able to replace acetylcholine-producing nerve cells in Alzheimer's disease, restore lost motor neurons in ALS (amyotropic lateral sclerosis, also known as Lou Gehrig's disease), or produce inhibitory cells to help block inappropriate electrical activity in epilepsy patients. In addition to the potential of the human neural stem cells in transplant-based therapies, we envision many other uses of our cells:
They may help identify and characterize factors that affect the nerve supply and modulators of such factors.
They may express unique molecules and signaling pathways that could serve as targets for new drugs.
Cultured neural stem cells can be induced to differentiate (specialize) into various types of neural cells (e.g., neurons, astrocytes, oligodendrocytes) that may prove useful in drug-discovery efforts, for instance:
- Neural stem cells or differentiated cells derived from them may be used to evaluate the biologic effect (pharmacology) and possible toxic effects (toxicology) of drugs, thus reducing the use of animal testing and making animal and human testing safer.
- High-throughput screening can be conducted on drug libraries with human neural stem cells to learn what effects drugs have on cell differentiation pathways.
- Neural stem cells may be used for gene-expression profiling to discover rare genes that are only expressed in stem cells and to examine gene expression when stem cells are exposed to various stimuli, including CNS-acting drugs.
ˆTop
|
