Friday, May 30, 2008
How Stem Cells Could Fight Lou Gehrig's Disease
Kerry A. Dolan and Robert Langreth
Used with permission from Forbes.com
Patients with Lou Gehrig's disease face a dismal prognosis. The only approved drug, Sanofi-Aventis's Rilutek, slows the fatal muscle-wasting disease by just a few months. Numerous experimental drugs have flopped in trials.
Can stem cells break the logjam?
That's the hope behind a path-breaking new collaboration between California Stem Cell, a biotech company in Irvine, Calif.; the charitable ALS Association; and a small Belgian drug discovery company. The concept is to use motor neuron cells the biotech firm has generated from embryonic stem cells to hunt for new drugs to treat amyotrophic lateral sclerosis, more commonly called ALS, or Lou Gehrig's disease.
The ALS Association, a patient advocacy group based in Calabasas Hills, Calif., will fund the research as part of its initiative to speed up the discovery of new drugs and therapies for ALS. Funding could amount to several million dollars if the research proceeds as planned, says Dr. Lucie Brujin, science director for the ALS Association.
"We're very excited about what this can do for us," says Brujin. "Before, we were using motor neurons from mice or rats."
Even then, adds Brujin, it was difficult to get a large enough quantity of the cells to use for research purposes. California Stem Cell's ability to deliver large quantities of human motor neuron cells is "a valuable new tool to use in the drug discovery process," says Brujin.
Embryonic stem cells offer the hope of providing an unlimited supply of living human cells for use in drug discovery and cell transplant therapy. The hard part is coaxing stem cells to turn into the various types of cells that are needed for research--muscle, bone, neuron, liver cell pancreas and so on.
"The hope of stem cells is just a hope and nothing more" without an efficient method of turning them into different types of adult cells, says Hans Keirstead, a stem cell researcher at University of California, Irvine, and a member of California Stem Cell's scientific advisory board.
He says the premise behind California Stem Cell is to create an efficient process for generating large, pure batches of various types of brain cells and other cells from embryonic stem cells. So far, his company has created motor neurons, heart muscle cells, neuronal progenitors and heart pacemaker cells.
Under the deal, California Stem Cell will ship batches of its motor neuron cells to BioFocus DPI, a U.K. company that provides research services to pharmaceutical and biotech companies. (BioFocus is a unit of Belgian drug discovery company Galapagos.) BioFocus will develop a test to screen the motor neurons against some 11,000 different gene-silencing fragments that will shut off a gene in the motor neuron cells.
"The aim is to rescue the cells from cell death, since ALS is a disease of cell death," says Katherine Hilyard, vice president for biological sciences at BioFocus DPI.
This process, which should take about a year, should allow BioFocus DPI to come up with a handful of drug targets. The next steps would be to determine if they translate into good drugs and, if so, develop a drug aimed at one or more targets.
Hilyard says BioFocus DPI previously worked with another company attempting to produce human motor neurons, but that company couldn't successfully turn the embryonic stem cells into motor neuron cells. "It would be impossible to do this research" without these motor neuron cells, she says. "We're all very pleased with this development."
Separately, the New York-based charity Project ALS is independently working on a similar project with researchers at Columbia University and the Harvard Stem Cell Institute. The Columbia and Harvard researchers it sponsors have already made billions of motor neurons from embryonic stem cells and hope to begin using them in drug screens this year, says Project ALS Research Director Valerie Estess.
With Kevin Eggan, a cellular biologist at Harvard, Project ALS is also making progress in taking skin biopsies from ALS patients and reprogramming those to become motor neurons. This will create cells in the lab dish that are genetically identical to those in the spines of ALS patients.
Until now, Estess notes, researchers have had to test their experimental ALS drugs on mice that have been genetically engineered to get the disease. Too often, the drugs work great in the mice and then "failed miserably in people," she says. "What stem cells will provide us in the very short term is much better disease models. They will allow us to screen drugs more effectively … and will represent human disease more accurately."
Patients with ALS typically live for a mere three to five years after the disease is diagnosed. The disease attacks and kills motor neurons, the nerve cells responsible for movement. As motor neurons die, muscles grow weaker, and ALS patients have trouble speaking, chewing, swallowing and breathing. In its devastating last stages, people can become "locked in"--alive and conscious but unable to move an eyelash or communicate with the outside world in any way. ALS affects an estimated 30,000 people in the U.S.
There are several drugs now being tested to treat ALS, but all of them were first approved for some other disease. With any sort of luck, this new initiative could eventually lead to the first drug developed specifically to treat ALS.
In addition to its work in ALS, California Stem Cell is working with another charity, Families of Spinal Muscular Atrophy, to use motor neuron progenitor cells made from embryonic stem cells to treat this disease. SMA is a genetic disease that strikes children and causes muscles to waste away because they cannot make a crucial protein needed for motor neurons to survive. A trial for this therapy could begin next year.
By MARCO SIBAJA, Associated Press WriterThu May 29, 10:31 PM ET
Brazil's Supreme Court ruled Thursday that scientists can conduct embryonic stem cell research, which holds the promise of curing Parkinson's disease and diabetes but raises ethical concerns about the limits on human life.
Six of the court's 11 justices upheld a 2005 law allowing embryonic stem cell research and turned down a petition filed that same year by then-Attorney General Claudio Fontelles, who argued the law was unconstitutional because it violates the right to life.
The remaining five judges argued that while the 2005 law is constitutional, research should only be carried out "with restrictions" such as not allowing the embryo to be destroyed and submitting each case for the approval of an ethics commission.
The ruling drew immediate fire from church officials in the world's largest Roman Catholic country.
The National Conference of Brazilian Bishops issued a statement saying it "regretted" the ruling, comparing it to a death sentence. The bishops' conference said its position "is not a matter of religion, but of the defense of human life, beginning with conception."
The law opens the way for research with embryos resulting from in-vitro fertilization that have been frozen for at least three years.
Advocates have said that a favorable Supreme Court ruling could make Brazil Latin America's leader in stem cell research.
They praise Brazilian scientists for their work with adult stem cells for the treatment of cardiovascular diseases and Type 1 diabetes, and have said that similar breakthroughs could be achieved with embryonic stem cells.
Wednesday, May 28, 2008
Canwest News ServicePublished: Tuesday, May 27, 2008
VANCOUVER -- Researchers say it might be possible to slow, maybe treat, amyotrophic lateral sclerosis -- a fatal neurodegenerative disease known as ALS -- by stimulating the body's own stem cells.
A team, led by neurologist Dr. Neil Cashman at the University of British Columbia, announced yesterday that it has found a "safe pathway" for activating bone-marrow stem cells in ALS patients.
The idea is to use a growth-factor stimulant to increase the number of stem cells in the body, in the hope they will travel to the site of motor-neuron injury and slow down the disease's progression, says Cashman.
His team recently completed a small trial involving eight patients that showed a growth stimulant is well tolerated and can be safely used in people with ALS. Cashman says he's working to build support for a much larger trial involving ALS treatment centres across Canada to see whether there is a therapeutic benefit.
If it works, Cashman says the treatment could sidestep the use of stem cells made from human embryos, which is fraught with ethical problems.
But much research is needed to find out if stimulating the body's own stem cells will work.
ALS is a progressive neurodegenerative disease that kills one in 1,000 adult Canadians. Most die within five years of their first symptom.
There is no cure for ALS, and Cashman says finding one is "a very tall order."
© Times Colonist (Victoria) 2008
Monday, May 26, 2008
Stem Cell Research Goes Beyond Biology
The Georgia Institute of TechnologyLiveScience.comSat May 24, 10:41 AM ET
This Behind the Scenes article was provided to LiveScience in partnership with the National Science Foundation.
Why is an engineer studying stem cells? This is a question I have routinely been asked during my first three and a half years as an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. The answer: the field of stem cell research needs engineers to translate the potential of stem cells into regenerative therapies and novel diagnostic technologies for biological sensing and pharmaceutical screening.Today, donated organs and tissues are used to replace ailing or injured tissues, but the need for transplantable tissues and organs far exceeds the available supply. Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells to treat many chronic and degenerative diseases including Parkinson's and Alzheimer's diseases, spinal cord injury, stroke, heart disease, diabetes, osteoarthritis, rheumatoid arthritis, muscular dystrophy and ALS (Lou Gehrig's disease).The potential of stem cells is endless - which is why I became increasingly interested in the role of stem cells within regenerative medicine and tissue engineering as I neared the completion of my Ph.D. in bioengineering from the University of Washington. As a result of my curiosity, I immersed myself in stem cell biology research during my postdoctoral fellowship in a cardiac pathology laboratory that focused on cell replacement therapies for myocardial repair.During my postdoctoral fellowship, I would often find that the outcomes of my experiments varied dramatically from week to week even though I followed the same procedures for growing and differentiating the cells. Sometimes my cultures contained many spontaneously and rhythmically beating foci of differentiating cells (evidence of primitive heart muscle formation in a dish), but other times I strained to find a single area of contracting cells and I was left pondering, "What was different this time?"
As an engineer, I was accustomed to controlled systems. The lack of consistency I frequently encountered in my experimental studies while working in this cell and molecular biology laboratory caused me a lot of frustration. General trends and significant differences were clear, but the more subtle changes that frequently seemed to occur went undetected. At the time, I accepted the limitations of the systems we were working with in order to complete my studies and publish the data, but those experiences shaped my views and vision for the future.I began to view stem cell differentiation studies differently. While most investigators studying stem cells were choosing a target cell population a priori and focusing their outcome assessments solely on their ability to obtain a specific cell type of interest, I wasn't. Any instance of failure to differentiate stem cells to a specific cell type represented a potential success in deriving other cell types. This "glass-half-full" perspective suggested to me that global analysis methods are required to truly comprehend how any one stem cell differentiates. Also, if a population of stem cells starts at the same initial point, how do they simultaneously diverge into a broad array of different cell types and what can be done to improve the homogeneity of differentiation?Now that I am an independent investigator with my own laboratory, I try to address these questions through various research projects. I want to better understand the extracellular environmental cues that regulate stem cell fate and develop engineering approaches to exploit these mechanisms to better control stem cell differentiation. For one project, we are studying how different mixing conditions modulate early embryonic stem cell commitment and subsequent downstream differentiation. To do this, we shake a petri dish of embryonic stem cells in suspension culture at different speeds while they are differentiating. We examine how different speeds modify the size, internal morphology and gene expression in "embryoid bodies" - the three-dimensional clumps of embryonic stem cells undergoing differentiation. The results suggest that designing bioreactors to shake at the optimal speed could generate increased yields of desired cell types from embryonic stem cells. In another project, we've developed a method of controlling the presentation of molecules within aggregates of embryonic stem cells to enhance the efficiency and purity of differentiation. Using biodegradable microspheres to release the molecules allows us to control when and where these factors are presented to the stem cells. Engineering the amounts and sequences of certain molecules released from the microspheres may direct differentiation to a specific cell type.We are also examining the molecules that embryonic stem cells spontaneously synthesize during differentiation to see if they can promote tissue regeneration in adult organisms. To do this, we are developing acellular matrices containing these unique factors and assessing their ability to promote tissue regeneration in a variety of wound-healing environments. These studies represent a new application for stem cells that could have broad implications.All of these projects help us better understand the mechanisms regulating stem cell fate and suggest new applications for stem cells to stimulate tissue regeneration. Although we still experience unexplained inconsistencies during the course of our studies because many unknowns remain, the future is bright for stem cell research and particularly for engineers to contribute to translating the potential of stem cells into viable regenerative therapies. (McDevitt presented his stem cell research on April 9 at the 235th American Chemical Society National Meeting. More details about his presentation are available here.) Video: Organ Repair Top 10 Mysterious Diseases What is a Stem Cell?
Editor's Note: This research was supported by the National Science Foundation (NSF), the federal agency charged with funding basic research and education across all fields of science and engineering. See the Behind the Scenes Archive. Original Story: Stem Cell Research Goes Beyond Biology
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Saturday, May 24, 2008
Friday, May 23, 2008
Re: Re: Fwd: Life.........
Thu, 22 May 2008 18:54:13 +0400
Today at 4.20 pm Boris passed away.
California Stem Cell and Biofocus DPI to Collaborate in ALS Association-Funded Research Using Human Motor Neurons
Through its TREAT ALS™ drug discovery and clinical trials program, The ALS Association announces that California Stem Cell (CSC) has signed a contract to supply international drug discovery organization BioFocus DPI, the service division of Galapagos, with its MOTORPLATE™ 96 assay-ready well plates, containing motor neuron progenitors derived from human embryonic stem cells. BioFocus DPI will use the high purity, clinical grade human motor neurons to perform assay development and screening for amyotrophic lateral sclerosis (ALS or “Lou Gehrig’s Disease”).
The Association’s TREAT ALS (Translational Research Advancing Therapy for ALS) program is funding this collaborative research project as part of its global initiative to speed the discovery of new drugs and therapies for ALS.
“The ALS Association is focused on accelerating new and promising developments from the laboratory bench into treatments for ALS,” said Lucie Bruijn, Ph.D., science director and vice president of The Association. “The unique ability of CSC to generate human motor neurons on a large scale, and the target discovery engine provided by BioFocus DPI, will contribute to the development of medicines that may significantly slow the progression of this disease and ultimately lead to a cure.” “BioFocus DPI chose to source human motor neurons from CSC because its multi-well plate format enables us to develop specialized high-throughput assays not previously possible,” said Katherine Hilyard, PhD, vice president of biological sciences, BioFocus DPI. “This the first source of high purity human motor neurons available for use in high-content screening assays. This significant advancement allows us to develop innovative human cell-based assays for the discovery of drugs for ALS and other neurological disorders.”
“CSC is delighted to help our lead customer BioFocus DPI to accelerate its drug discovery programs, and to begin to supply the marketplace with stem cell derived human motor neurons, produced using state of the art, proprietary and commercially scalable manufacturing processes. The potential market for this product in high-throughput and high-content screening analyses for predictive toxicology and drug discovery is very significant,” said Dr. Chris Airriess, CSC chief operating officer. “More importantly, CSC is proud to work toward the common mission of developing a treatment for ALS.”
BioFocus DPI aims to expand its partners’ drug pipelines by accelerating the gene-to-candidate discovery process. This is achieved through a comprehensive discovery platform, which includes target discovery in human primary cells, focused as well as diverse compound libraries, in vitro and cell-based screening, medicinal chemistry and ADME/PK services, supported by unique chemogenomic and informatics tools. As the service division of Galapagos, BioFocus DPI has over 300 employees in five countries worldwide.
California Stem Cell, Inc. is a privately held company focused on the manufacturing of high-purity human cells for therapeutic development and clinical application. Since its founding in 2005, CSC has developed and has intellectual property surrounding methods for scalable production of human motor neurons, neuronal progenitors, cardiac muscle and sino-atrial node cells at its Irvine, Calif. facility. CSC is currently in the pre-clinical development stage of stem cell based therapies for amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s Disease), spinal muscular atrophy (SMA), spinal cord injury (SCI) and coronary heart disease.
The ALS Association is a leader in ALS research and the only national not-for-profit voluntary health organization dedicated solely to the fight against ALS. The mission of The ALS Association is to lead the fight to cure and treat ALS through global cutting-edge research, and to empower people with Lou Gehrig’s Disease and their families to live fuller lives by providing them with compassionate care and support.
Wednesday, May 21, 2008
Monday, May 19, 2008
Anthony G. Payne, Ph.D.
Amyotrophic lateral sclerosis (ALS) is an insidious, mercilessly devastating disorder in which motor neurons that control voluntary movement are progressively lost while those that are involved in cognition and sensation are spared. At this time ALS sufferers have no scientifically validated treatment options available to them. Fifty percent succumb within three years of symptom onset and between eighty and ninety percent within five years.
At this point-in-time ALS has a complex, incompletely understood etiology. Approximately 5- 10% of cases have a genetic basis (familial ALS or fALS), with the remainder having no clearly discernible cause. The best that can be said is that ALS is very likely a multifactorial disorder triggered by any number of exposures such as environmental toxicants, either alone or in combination with specific genetic factors). This is underscored by the fact that an approximately two-fold increase in the risk of developing ALS appeared among military personnel deployed to Southwest Asia during the Gulf War (Aug 1990-July 1991) compared to non-deployed personnel.
Once the ALS disease process is underway, there are a number of pathogenic mechanisms that are felt to bring about the cellular dysfunction and apoptosis in motor neurons that are characteristic of the disease:
(1) Mitochondrial dysfunction involving, in part, oxidative stress.
(2) Excitotoxicity due, in part, to a down regulation of motor neuron glutamate transporters.
(3) A loss of calcium homeostasis in motor neurons.
(4) Disrupted protein synthesis and processing.
(5) Altered neuronal cytoskeletal function and axonal transport.
(6) Dysfunction of astrocytes and glial cells that support the CNS in general, as well as motot neurons.
Current therapeutic intervention is aimed at modulating the various pathogenic processes. Research is ongoing and involves such things as use of intravenous (IV) Ceftriaxone to upregulate glutamate transporter genes and protein expression in motor neurons.
It is proposed by the author that at least some cases of ALS arise due to defective specialized neuroglial cells called ependymal cells, especially modified ependymal cells called choroidal cells that are involved in the synthesis and circulation of cerebrospinal fluid and maintenance of the blood-CSF barrier. These cells may arise, at least in part, as the end result of deleterious mutations or possibly epigenetic influences. As a result of these cellular defects in the choroidal cells, cerebrospinal fluid is synthesized that is laden with compounds that are neurotoxic, especially with respect to motor neurons, as well as rich in inflammatory cytokines and such. It is the circulation of this aberrant CSF that brings some (and in some instances perhaps all) of the pathogenic features that characterize some cases of ALS.
Support for this hypothesis comes from two sources:
(1) Direct: Published studies that show that CSF taken from ALS patients induces neurodegeneration characteristic of ALS in lab animals.
(2) Indirect: Seeming retardation in disease progression in four (4) ALS patients who have been following a regimen that modulates neurodegenerative processes shown to result when CSF from ALS patients is administered to lab animals and used in cell cultures.
Hypothesis Support - Studies
A. In a lab study conducted in India , motor neurons and spinal cord neurons in culture were exposed to CSF from 20 ALS patients and 20 controls. The “Exposure of cells to ALS-CSF drastically decreased the survival rate of motor neurons to 32.26+/-2.06% whereas a moderate decrease was observed in case of other spinal neurons (67.90+/-2.04%). In cultures treated with disease control CSF, a small decrease was observed in the survival rate with 80.14+/-2.00% and 90.07+/-1.37% survival of motor neuron and other spinal neurons respectively.” The die-off of spinal cord cells exposed to CSF from ALS patients was linked to elevation of intracellular calcium, while that of motor neurons to “activation of glutamate receptors, the AMPA/kainate receptor playing the major role.”Sen I, Nalini A, Joshi NB, Joshi PG.
B. “CSF was injected intrathecally into three-day-old rat pups and subsequently the ultrastructural changes in the motor neurons were studied after 48 h, 1, 2 and 3 weeks. We observed that ALS-CSF causes fragmentation of the Golgi apparatus in a considerable number of motor neurons in the spinal cord. This was further confirmed when motor neurons were stained with an antibody against a medial Golgi protein (MG160). Thus, we suggest that the putative toxin(s) present in ALS-CSF may cause impairment in the protein processing leading to motor neuron death. “ Ramamohan PY, Gourie-Devi M, Nalini A, Shobha K, Ramamohan Y, Joshi P, Raju TR.
C. “... earlier studies have shown that cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients causes death of motor neurons, both in in-vitro as well as in-vivo. There was an aberrant phosphorylation of neurofilaments in cultured spinal cord neurons of chick and rats following exposure to CSF of ALS patients (ALS-CSF). Other features of neurodegeneration, such as swollen neuronal soma and beading of neurites were also observed. In neonatal rat pups exposed to ALS-CSF, we observed phosphorylated neurofilaments in the soma of spinal motor neurons in addition to the increased lactate dehydrogenase activity and reactive astrogliosis. The present study examines the effect of ALS-CSF on the expression of glial glutamate transporter (GLT-1) in embryonic rat spinal cord cultures as well as in spinal astrocytes of neonatal rats. Immunostaining suggested a decrease in the expression of GLT-1 by astrocytes both in culture and in-vivo following exposure to ALS-CSF. Our results provide evidence that toxic factor(s) present in ALS-CSF depletes GLT-1 expression. This could lead to an increased level of glutamate in the synaptic pool causing excitotoxicity to motor neurons, possibly by triggering the 'glutamate-mediated toxicity-pathway'. Shobha K, Vijayalakshmi K, Alladi PA, Nalini A, Sathyaprabha TN, Raju TR.
D. “In the present study we show that there is an increased number of astrocytes intensely immunoreactive for glial fibrillary acidic protein (GFAP) in the gray matter of the spinal cords of neonatal rats exposed to ALS CSF. There is also increased expression of GFAP in the astrocytes of the white matter of neonatal rat spinal cords exposed to ALS CSF. Western blot analysis also confirmed the increased expression of GFAP. Accordingly, our study provides for the first time a clear evidence for the pathological response of glia to the circulating toxic factor(s) in the CSF of ALS patients.” Shahani N, Nalini A, Gourie-Devi M, Raju TR.
There are other studies, most cell culture or animal, which directly or indirectly indicate that the CSF of ALS patients contains compounds that are neurotoxic, inflammatory and proinflammatory, and otherwise contributory to pathogenic mechanisms common to ALS.
The impact of these CSF compounds can be summarized briefly as follows:
(1) Intracellular calcium is elevated in spinal cord neurons.
(2) Glutamate levels rise and receptors are activated in motor neurons.
(3) Some appear to lower quinine reductase levels in motor neurons and possibly astrocytes, which results in increased glutamate influx.
(4) Mitochondrial dysfunction occurs and with this compromised motor neuron energetics.
(5) Neuroinflammation increases.
(6) Antioxidant defenses such as glutathione are increasingly at risk of depletion or depleted.
Some of these effects overlap those of other players, both genetic and non-genetic, in ALS. As such, it is likely that therapeutic intervention with respect to modulating synthesis of neurotoxic, etc. compounds in the CSF or their impact on spinal cord and motor neurons, moderates the impact of these other players.
This aside, it follows that if some or most nonfamilial ALS patients owe at least part of their condition to damage wrought by various neurotoxic, inflammatory and proinflammatory, etc. compounds in their CSF, dietary, pharmacologic and nutraceutical measures that lower or otherwise modulate the synthesis of these substances or attenuate their impact on motor neurons will slow disease progression and prolong lifespan.
With this in mind, the author tooled together just such a regimen (2005 with subsequent modifications) consisting of:
CoQ10 (Ubiquinone/ubiquinol): Rationale for use – CoQ10 appears compromised in ALS. Dose: 200 mgs. every 2 hours during the day (1200 mgs daily)
Noni juice or capsules – Rationale for use: Contains a potent quinone reductase inducer – QR reduces glutamate toxicity in cells. Dosage: Juice to be drunk liberally all day long. Capsules – 1 every 2 hours during the day and 1-2 capsules one hour to one-half hour before bedtime.
Tumeric Extract Tablets or Capsules – Rationale for use: Quinone reductase inducer in astrocytes (Lowers glutamate). Dose: 1 (.05 gram) tablet every two hours during the day and 1-2 tablets prior to bedtime.
DEPRENYL: According to a 1994 animal study, “CSF samples from ALS and non-ALS neurological patients were injected into the spinal subarachnoid space of 3-day-old rat pups, followed by a single dose (0.01 mg/kg body weight) of (-)-deprenyl, administered 24 h after CSF injection. After a further period of 24 h, the rats were sacrificed and the spinal cord sections were stained with antibodies against phosphorylated neurofilament (NF, SMI-31 antibody) and glial fibrillary acidic protein (GFAP). Activity of lactate dehydrogenase (LDH) was also measured. (-)-Deprenyl injection resulted in a significant (61%) decrease in the number of SMI-31 stained neuronal soma in the ventral horn of the spinal cord of ALS CSF exposed rats. This was accompanied by a reduction in the astrocytes immunoreactive for GFAP. There was also a significant (35%) decrease in the LDH activity following (-)-deprenyl treatment. These results suggest that (-)-deprenyl may confer neuroprotection against the toxic factor(s) present in ALS CSF.” Shahani N, Gourie-Devi M, Nalini A, Rammohan P, Shobha K, Harsha HN, Raju TR.
Dose: Discretionary with each patient’s physician. Use of patches or oral forms (Pills, tablets or liquid). The typical daily dose was 12 mgs/daily.
IV Glutathione: Rationale – depleted in many ALS patients or at risk of becoming so. The intravenous (IV) dose is determined by each patient’s physician. During 2007 a patented oral form of glutathione became available, one that is absorbed through the oral mucosa and resists breakdown until it reaches the CNS (Th-Queen from Italy ).
PREVAGEN (Aequorin) – Rationale for use: Prevents calcium influx and resultant toxicity in neurons. Dose: One twenty milligram (20 mg) capsules every 2 to 3 hours during waking hours and one to two (1-2) capsules 30-60 minutes before retiring for the night. Aequorin became available commercially during 2007 and was added to the regimen at that time.
Lithium – Rational for use: Glutamate modulation in neurons. Dose: 250 mgs. to 600 mgs Lithium carbonate daily (Dosage determined by each patient’s neurologist or primary care physician). Lithium was added to the regimen during 2007.
Diet: Medium Chain Triglycerides Diet. Rationale: There are many reasons the ketogenic or MCT diets might be of benefit to ALS patients, not the least of which is the fact they tend to increase glutamate transporter gene expression.
Ketogenic & MCT Diet (Epilepsy website)
Hypothesis Support – Clinical Responses (n=4)
Four individuals diagnosed with nonfamilial ALS (3 male, 1 female, ages 35-52) adopted the regimen outlined above beginning during 2005, all with their primary care physician or neurologist’s participation (Note that Prevagen was introduced during 2007 when it became available. Lithium was likewise added during 2007). All four experienced disease progression, however when compared to age- and disease matched controls, the degree of progression is decidedly less. One (male) patient noted that “Every single ALS patient diagnosed at the same time I was (diagnosed) is now dead or on a respirator. I am still walking, talking, eating and living my life. I’ve lost some functioning in my hands and arms, but this is not so great as to rob me of doing things I need to do like driving my car”.
While the responses of these six is far from definitive and cannot be called rigorous in the scientific sense, it is suggestive and offers a very tentative confirmation of the hypothesis put forward.
A greater degree of confirmation will come when, for example, the choroidal cells in the brains of ALS are replaced in whole or part by healthy counterparts produced from stem cells. In accordance with this hypothesis, it is expected that synthesis and circulation of a healthy CSF will result in a significant degree of disease progression or even disease arrest.
See also this variation of the regimen cited in this paper: Retarding ALS Progression
© 2008 by Dr. Anthony G. Payne. All rights reserved. The information contained in this article is provided for informational purposes only and should not be construed as medical advice or instruction. Readers are advised to consult a licensed health care professional concerning all matters related to their health and well being.
Friday, May 16, 2008
Tuesday, May 13, 2008
Neural stem cells are present in the adult human spinal cord
Jean-Philippe Hugnot (teacher-researcher at the University of Montpellier) Alain Privat (Inserm research director) Luc Bauchet (neurosurgeon) and their colleagues at Inserm Research Unit 583 have for the first time demonstrated the presence of neural precursor cells in the adult human spinal cord. The use of these stem cells for therapeutic purposes could potentially contribute to repairing the spinal cord of persons suffering from a traumatic injury, as well as in the case of a degenerative disease involving the motor neurons: amyotrophic lateral sclerosis (ALS). This work is published in The Journal of Neuroscience Research.
Some 40,000 people in France suffer from spinal cord injuries as a result of an accident. Each year there are 1,500 new cases of paraplegia or tetraplegia concerning for the most part 25-30 year-olds. The spinal cord is the part of the central nervous system that extends from the brain inside the spinal column. It ensures the proper working of an entire network of motor neurons that are vital not only to all our movements but also to the transmission of sensory signals and the control of visceral functions. Injuries affecting this neuron wiring are at the present time irreversible.
Researchers throughout the world are today subjecting stem cells to close scrutiny for their ability to differentiate in a given type of cell. They are in fact at the origin of all the cell types of the organism. These undifferentiated cells are present in the embryo. They are also present in the adult but are far less common and less pluripotent: adult stem cells present in tissue cannot, as a general rule, give a type of tissue other than their own.
The presence of neural stem cells in the brain and the spinal cord of adult rodents was shown several years ago, but it had not previously been possible, on the strength of current techniques, to detect such cells in the human spinal cord. Thanks to close cooperation with the Montpellier University Hospital and the Agence de Biomédecine, the researchers from Inserm have been able to work with tissues of excellent quality. Using techniques combining immunologic markers and electron microscopy, they have proved the presence of neural stem cells in the human adult spinal cord. Moreover, by cultivating these cells in vitro, the Inserm scientists have shown that the cells are capable of giving all the neuron cell types: neurons themselves but also glial cells (oligodendrocytes and astrocytes). Less known but just as important as the neurons, the glial cells provide nourishment and help to control neuronal activity. These precursor cells discovered in the spinal cord are of great therapeutic interest since they could compensate, via its use in gene therapy, for the neuronal and/or glial losses in traumatic lesions, neurodegenerative pathologies or those affecting the myelin sheath surrounding the neurons. Before therapeutic use can be envisaged, there is a need to explore the diversity of these cells and the details of their differentiation. "The therapeutic interest of so-called adult stem cells is now generally acknowledged by the scientific community. Although there is still a long way to go, this work constitutes a major step forward for all the pathologies affecting the motoneurons for which no treatment exists at the present time," says Alain Privat.
This research project on stem cells is being conducted within the framework of the European RESCUE consortium ("Research Endeavor for Spinal Cord in United Europe"), which seeks to indicate treatments for repairing spinal injuries responsible for paraplegia and tetraplegia.
Coordinated by Alain Privat, this project brings together 10 partners including the NEUREVA start-up in Montpellier and 6 European countries (Belgium, the Czech Republic, France, Germany, Spain and the United Kingdom). It is funded to the tune of EUR2.7 million as part of the 6th European Framework Programme for Research and Technological Development.
Adult human spinal cord harbours neural precursor cells that generate neurons and glial cells in vitro. C. Dromard (1), H. Guillon (1), V. Rigau (2), C. Ripoll (1), JC Sabourin (1), F Perrin (1), F Scamps (1),S Bozza (1), P. Sabatier (5), N Lonjon (1,5), H Duffau5, F. Vachiery-Lahaye (3), M. Prieto (1), C Tran Van Ba (1), L. Deleyrolle (1), A. Boularan (4), K. Langley (1), M. Gaviria (1), A. Privat (1), J.P. Hugnot (1), L.Bauchet (1,5,6) (1) Inserm U583, Physiopathologie et Thérapie des déficits sensoriels et moteurs, Institut des Neurosciences de Montpellier, Hôpital St ELOI, BP 74103 80, av Augustin Fliche 34091 Montpellier Cedex 05, France. (2) Service d'Anatomopathologie, CHU Montpellier, France. (3) Coordination hospitalière de prélèvement et Etablissement Français des Greffes, CHU Montpellier, France. (4) Département Anesthésie Réanimation C, CHU Montpellier, France. (5) Département de Neurochirurgie, CHU Montpellier, France. (6) Centre Propara Languedoc-Mutualité Montpellier, France J. Neurosc Res 2008 March 2008
Alain Privat Directeur de recherche Unité Inserm 583 email@example.com JP Hugnot Neural stem cell group Institut of Neuroscience of Montpellier Unité Inserm U583 firstname.lastname@example.org Tel: 04 99 63 60 08
Saturday, May 10, 2008
Thursday, May 8, 2008
May 7th, 2008
Test of maturity for stem cellsStem cells can differentiate into 220 different types of body cell. The development of these cells can now be systematically observed and investigated with the aid of two new machines that imitate the conditions in the human body with unprecedented accuracy.Stem cells are extremely versatile: They can develop in 220 different ways, transforming themselves into a correspondingly diverse range of specialized body cells. Biologists and medical scientists plan to make use of this differentiation ability to selectively harvest cardiac, skin or nerve cells for the treatment of different diseases. However, the stem cell culture techniques practiced today are not very efficient. What proportion of a mass of stem cells is transformed into which body cells? And in what conditions? "We need devices that keep doing the same thing and thus deliver statistically reliable data," says Professor Günter Fuhr, director of the Fraunhofer Institute for Biomedical Engineering IBMT in St. Ingbert.Two prototypes of laboratory devices for stem cell differentiation enable the complex careers of stem cells to be systematically examined for the first time ever. These devices are the result of the international project ‘CellPROM' - ‘Cell Programming by Nanoscaled Devices' - which was funded by the European Union to the tune of 16.7 million euros and coordinated by the IBMT. "The type of cell culture used until now is too far removed from the natural situation," says CellPROM project coordinator Daniel Schmitt - for in the body, the stem cells come into contact with solute nutrients, messenger RNAs and a large number of different cells. Millions of proteins rest in or on the cell membranes and excite the stem cells to transform themselves into specialized cells. "We want to provide the stem cells in the laboratory with a surface that is as similar as possible to the cell membranes," explains Daniel Schmitt. "To this end, the consortium developed a variety of methods by which different biomolecules can be efficiently applied to cell-compatible surfaces."In the two machines - MagnaLab and NazcaLab - the stem cells are brought into contact with the signal factors in a pre-defined manner. In MagnaLab, several hundred cells grow on culture substrates that are coated with biomolecules. In NazcaLab, large numbers of individual cells, washed around by a nutrient solution, float along parallel channels where they encounter micro-particles that are charged with signal factors. "We use a microscope and a camera to document in fast motion how individual cells divide and differentiate," says Schmitt. The researchers demonstrated on about 20 different cell models that the multi-talents can be stimulated by surface signals to transform themselves into specialized cells.
Wednesday, May 7, 2008
Monday, May 5, 2008