Lou Gehrig's disease: From patient stem cells to potential treatment strategy in one studyOctober 25, 2013
Although the technology has existed for just a few years, scientists increasingly use "disease in a dish" models to study genetic, molecular and cellular defects. But a team of doctors and scientists led by researchers at the Cedars-Sinai Regenerative Medicine Institute went further in a study of Lou Gehrig's disease, a fatal disorder that attacks muscle-controlling nerve cells in the brain and spinal cord.
After using an innovative stem cell technique to create neurons in a lab dish from skin scrapings of patients who have the disorder, the researchers inserted molecules made of small stretches of genetic material, blocking the damaging effects of a defective gene and, in the process, providing "proof of concept" for a new therapeutic strategy - an important step in moving research findings into clinical trials.
The study, published Oct. 23 in Science Translational Medicine, is believed to be one of the first in which a specific form of Lou Gehrig's disease, or amyotrophic lateral sclerosis, was replicated in a dish, analyzed and "treated," suggesting a potential future therapy all in a single study.
"In a sense, this represents the full spectrum of what we are trying to accomplish with patient-based stem cell modeling. It gives researchers the opportunity to conduct extensive studies of a disease's genetic and molecular makeup and develop potential treatments in the laboratory before translating them into patient trials," said Robert H. Baloh, MD, PhD, director of Cedars-Sinai's Neuromuscular Division in the Department of Neurology and director of the multidisciplinary ALS Program. He is the lead researcher and the article's senior author.
Laboratory models of diseases have been made possible by a recently invented process using induced pluripotent stem cells - cells derived from a patient's own skin samples and "sent back in time" through genetic manipulation to an embryonic state. From there, they can be made into any cell of the human body.
The cells used in the study were produced by the Induced Pluripotent Stem Cell Core Facility of Cedars-Sinai's Regenerative Medicine Institute. Dhruv Sareen, PhD, director of the iPSC facility and a faculty research scientist with the Department of Biomedical Sciences, is the article's first author and one of several institute researchers who participated in the study.
"In these studies, we turned skin cells of patients who have ALS into motor neurons that retained the genetic defects of the disease," Baloh said. "We focused on a gene, C9ORF72, that two years ago was found to be the most common cause of familial ALS and frontotemporal lobar degeneration, and even causes some cases of Alzheimer's and Parkinson's disease. What we needed to know, however, was how the defect triggered the disease so we could find a way to treat it."
Frontotemporal lobar degeneration is a brain disorder that typically leads to dementia and sometimes occurs in tandem with ALS.
The researchers found that the genetic defect of C9ORF72 may cause disease because it changes the structure of RNA coming from the gene, creating an abnormal buildup of a repeated set of nucleotides, the basic components of RNA.
"We think this buildup of thousands of copies of the repeated sequence GGGGCC in the nucleus of patients' cells may become "toxic" by altering the normal behavior of other genes in motor neurons," Baloh said. "Because our studies supported the toxic RNA mechanism theory, we used two small segments of genetic material called antisense oligonucleotides - ASOs - to block the buildup and degrade the toxic RNA. One ASO knocked down overall C9ORF72 levels. The other knocked down the toxic RNA coming from the gene without suppressing overall gene expression levels. The absence of such potentially toxic RNA, and no evidence of detrimental effect on the motor neurons, provides a strong basis for using this strategy to treat patients suffering from these diseases."
Researchers from another institution recently led a phase one trial of a similar ASO strategy to treat ALS caused by a different genetic mutation and reportedly uncovered no safety issues.
Clive Svendsen, PhD, director of the Regenerative Medicine Institute and one of the article's authors, has studied ALS for more than a decade. "ALS may be the cruelest, most severe neurological disease, but I believe the stem cell approach used in this collaborative effort holds the key to unlocking the mysteries of this and other devastating disorders. Within the Regenerative Medicine Institute, we are exploring several other stem cell-based strategies in search of treatments and cures," he said, adding that ALS affects 30,000 to 50,000 people in the U.S., but unlike other neurodegenerative diseases, it is almost always fatal, usually within three to five years.
Svendsen recently received a $17.8 million grant from the California Institute for Regenerative Medicine. In collaboration with Baloh and the ALS clinical team at Cedars-Sinai, this study will support a novel stem cell and growth factor therapy for ALS.
Researchers from UCLA; the Mayo Clinic in Jacksonville, Fla.; the University of California, San Diego; Washington University School of Medicine in St. Louis, Mo.; and Isis Pharmaceuticals contributed to the C9ORF72 study.
The research was supported by National Institutes of Health grants NS055980, NS069669, NIH-U24NS07837; and California Institute of Regenerative Medicine grant RT2-02040. Baloh holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. Analytical work was partially supported by the UCLA Muscular Dystrophy Core Center funded by the National Institute of Arthritis, Musculoskeletal and Skin Disorders (P30 AR057230) within the Center for Duchenne Muscular Dystrophy at UCLA.
Citation: Science Translational Medicine, "Targeting RNA foci reduces pathology in iPSC-derived motor neurons from C9ORF72 repeat patients."
Cedars-Sinai Medical Center
Related Stem Cells Current Events and Stem Cells News Articles
Amid terror threats, new hope for radiation antidote
University of Virginia School of Medicine researchers have identified promising drugs that could lead to the first antidote for radiation exposure that might result from a dirty bomb terror attack or a nuclear accident such as Chernobyl.
Zika virus infects human placental macrophages
One of Zika's mysteries is how the virus passes from an infected mother, through the placenta, to a developing fetus.
Faster, more efficient CRISPR editing in mice
University of California, Berkeley scientists have developed a quicker and more efficient method to alter the genes of mice with CRISPR-Cas9, simplifying a procedure growing in popularity because of the ease of using the new gene-editing tool.
Recent progress in tracking the viability of transplanted stem cells in vivo
Noninvasive cell-tracking methods are indispensable for assessing the safety and efficacy of stem-cell based therapy. Thus, the research of noninvasive cell-tracking methods for determining in vivo the translocation and long-term viability of the transplanted stem cells have received considerable attention.
Carnegie Mellon develops bio-mimicry method for preparing and labeling stem cells
Researchers led by Carnegie Mellon University Professor of Biological Sciences Chien Ho have developed a new method for preparing mesenchymal stem cells (MSCs) that not only leads to the production of more native stem cells, but also labels them with a FDA approved iron-oxide nanoparticle (Ferumoxytol).
Harnessing engineered slippery surfaces for tissue repair
Transplanting a preformed dense and coherent sheet of regenerative stem cells directly onto damaged heart, cartilage or bone tissue of ailing patients often is a more promising route to recovery than transplanting the cells just loosely mixed together.
Review finds fathers' age, lifestyle associated with birth defects
A growing body of research is revealing associations between birth defects and a father's age, alcohol use and environmental factors, say researchers at Georgetown University Medical Center. They say these defects result from epigenetic alterations that can potentially affect multiple generations.
Scientists identify protein which could improve treatments for recurrent miscarriages
Scientists at the University of Sheffield have identified a protein, involved in the development of the human placenta, may also help embryos implant in the womb - something which could improve treatments for recurrent miscarriages and pre-eclampsia.
Brazilian Zika virus strain causes birth defects in experimental models
Researchers at University of California San Diego School of Medicine, with colleagues in Brazil and Senegal, have described the first "direct experimental proof" that the Brazilian strain of Zika virus can actually cause severe birth defects.
Stem cells from diabetic patients coaxed to become insulin-secreting cells
Signaling a potential new approach to treating diabetes, researchers at Washington University School of Medicine in St. Louis and Harvard University have produced insulin-secreting cells from stem cells derived from patients with type 1 diabetes.
More Stem Cells Current Events and Stem Cells News Articles