A promising drug treatment could revolutionize the treatment of patients suffering from ALS

Biologists identify promising drug for ALS treatment

University of Alberta scientists find a new application for an existing drug, with potential to slow progression of the devastating degenerative disease.

A new drug could significantly slow the progression of ALS, also known as Lou Gehrig’s disease, according to new research by University of Alberta biologists. Current treatments slow progression of the degenerative disease by only a few months, and these findings could revolutionize the treatment of patients suffering from ALS, extending and improving quality of life.

The drug, called telbivudine, targets a protein that misfolds and does not function correctly in patients with ALS. “SOD1 is a protein that is known to misfold and misbehave in most cases of patients with ALS,” explained Ted Allison, associate professor in the Department of Biological Sciences and co-author on the study. “We showed that telbivudine can greatly reduce the toxic properties of SOD1, including improving the health of the subject’s motor neurons and improving movement.”

The research team used computer simulations to identify drugs with the potential for targeting the SOD1 protein. From this shortlist, the scientists identified and tested the most likely candidates—including telbivudine—using animal models.

“ALS is not well-understood,” said lead author Michele DuVal, who recently completed the PhD portion of the Faculty of Medicine & Dentistry’sMD/PhD program under the supervision of Allison. “We don’t yet know exactly what goes wrong first in the motor neurons or how the misbehaving SOD1 causes toxicity. Because there is still much to learn about the disease, the ALS research community focuses on both understanding ALS and on developing promising therapies.”

The discovery of telbivudine as a potential treatment is particularly exciting because the drug is already in use for treating patients with hepatitis. “It is already proven safe to use in patients, and it has very good potential for repurposing to use in a new clinical setting against ALS,” said Allison.

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New Therapy Delays Muscle Atrophy in Lou Gehrig’s Disease Mouse Model

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Mouse study could provide foundation for future human therapeutics

Supplementing a single protein found in the spinal cord could help prevent symptoms of Lou Gehrig’s disease, according to a new study out of Case Western Reserve University School of Medicine. Researchers found high levels of the protein—called mitofusion 2 or Mfn2—prevented nerve degeneration, muscle atrophy, and paralysis in a mouse model of the disease. Since Mfn2 is often depleted during Lou Gehrig’s, the new study suggests supplementing it could be a novel therapeutic approach for the disease.

Lou Gehrig’s disease, or amyloid lateral sclerosis (ALS), is a progressive disorder that devastates motor nerve cells. People with ALS slowly lose the ability to control muscle movement, and are ultimately unable to speak, eat, move, or breathe. The cellular mechanisms behind ALS are also found in certain types of dementia. For the estimated 15,000 Americans living with ALS, the findings offer new hope for ways to delay symptoms.

“We found a way to alleviate age and ALS-related muscular atrophy in our mouse models,” said Xinglong Wang, PhD, associate professor of pathology at Case Western Reserve University School of Medicine. “Amazingly, we could delay ALS symptom onset by 67 days.”

Wang led the study, recently published in Cell Metabolism, in which researchers successfully staved off muscle atrophy and paralysis simply by increasing Mfn2 levels in mouse spinal cords.

Wang and colleagues tested the most widely used ALS mouse model. They genetically engineered the diseased mice to have increased Mfn2 levels—but only in nerve cells that extend from the spinal cord and connect to muscle fibers. In late stages of the disease, mice with high Mfn2 levels in these nerves were a healthy weight, and did not have any of the muscle atrophy, gait abnormalities, or reduced grip strength that mice in control groups developed. Even mice who underwent heavy sciatic nerve damage benefited from elevated Mfn2 levels.

Said Wang, “Upregulation of Mfn2 specifically in nerve cells is sufficient to abolish skeletal muscle loss in ALS and aged mice, despite ALS-causing protein being found in all organs and tissues.”

By studying nerve cells collected from the mice, Wang’s team uncovered how Mfn2 offers its protective effects. The researchers found Mfn2 coexists with nutrients in cell structures called mitochondria. Their experiments showed mitochondria travel along nerve cell extensions—axons—and deliver the nutrients to the point where nerve cells and muscle fibers meet. This preserves sensitive connections—synapses—between nerve and muscle cells and prevents muscle atrophy. “We found mitochondria function as miniature ‘trucks’ to transport protein along axons to prevent synaptic degeneration,” explained Wang.

Cellular transport is not typically in the job description for mitochondria. The ancient cellular structures are well-known to be “powerhouses of the cell”—producing energy that keeps cells running. According to Wang, “this is a novel, previously unrecognized role for mitochondria.”

Specifically, Wang’s team found mitochondria use Mfn2 on their surfaces to carry a nutrient called calpstatin. Calpstatin inhibits harmful enzymes that break down nerves and muscle fibers. With the help of Mfn2, mitochondria carry calpstatin along nerve cells axons to meet muscle cells. There, calpstatin prevents enzymes from destroying delicate synapse connections. But without Mfn2, mitochondria can’t carry the nutrient.

According to Wang, the findings have broad implications. “Mfn2 deficiency or mutations are commonly observed in patients with ALS, peripheral neuropathy, Alzheimer’s disease, and other neurodegenerative diseases in which synaptic loss has long been recognized as a prominent early feature,” he says. “Supplementing Mfn2 may be a common and effective therapeutic approach to treat a wide range of diseases including but not limited muscular disorders, patients with nerve injury and various major neurodegenerative diseases associated with synaptic loss.”

Learn more: Novel Therapy Delays Muscle Atrophy in Lou Gehrig’s Disease Model

 

 

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New therapy copper-ATSM halts progression of Lou Gehrig’s disease in mice

Copper, zinc superoxide dismutase SOURCE: Joseph Beckman, 541-737-8867

Copper, zinc superoxide dismutase
SOURCE:
Joseph Beckman, 541-737-8867

Researchers at Oregon State University announced today that they have essentially stopped the progression of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, for nearly two years in one type of mouse model used to study the disease – allowing the mice to approach their normal lifespan.

The findings, scientists indicate, are some of the most compelling ever produced in the search for a therapy for ALS, a debilitating and fatal disease, and were just published in Neurobiology of Disease.

“We are shocked at how well this treatment can stop the progression of ALS,” said Joseph Beckman, lead author on this study, a distinguished professor of biochemistry and biophysics in the College of Science at Oregon State University, and principal investigator and holder of the Burgess and Elizabeth Jamieson Chair in OSU’s Linus Pauling Institute.

In decades of work, no treatment has been discovered for ALS that can do anything but prolong human survival less than a month. The mouse model used in this study is one that scientists believe may more closely resemble the human reaction to this treatment, which consists of a compound called copper-ATSM.

It’s not yet known if humans will have the same response, but researchers are moving as quickly as possible toward human clinical trials, testing first for safety and then efficacy of the new approach.

ALS was identified as a progressive and fatal neurodegenerative disease in the late 1800s, and gained international recognition in 1939 when it was diagnosed in American baseball legend Lou Gehrig. It’s known to be caused by the death and deterioration of motor neurons in the spinal cord, which in turn has been linked to mutations in copper, zinc superoxide dismutase.

Copper-ATSM is a known compound that helps deliver copper specifically to cells with damaged mitochondria, and reaches the spinal cord where it’s needed to treat ALS. This compound has low toxicity, easily penetrates the blood-brain barrier, is already used in human medicine at much lower doses for some purposes, and is well tolerated in laboratory animals at far higher levels. Any copper not needed after use of copper-ATSM is quickly flushed out of the body.

Experts caution, however, that this approach is not as simple as taking a nutritional supplement of copper, which can be toxic at even moderate doses. Such supplements would be of no value to people with ALS, they said.

The new findings were reported by scientists from OSU; the University of Melbourne in Australia; University of Texas Southwestern; University of Central Florida; and the Pasteur Institute of Montevideo in Uruguay. The study is available as open access in Neurobiology of Disease.

Using the new treatment, researchers were able to stop the progression of ALS in one type of transgenic mouse model, which ordinarily would die within two weeks without treatment. Some of these mice have survived for more than 650 days, 500 days longer than any previous research has been able to achieve.

In some experiments, the treatment was begun, and then withheld. In this circumstance the mice began to show ALS symptoms within two months after treatment was stopped, and would die within another month. But if treatment was resumed, the mice gained weight, progression of the disease once again was stopped, and the mice lived another 6-12 months.

In 2012, Beckman was recognized as the leading medical researcher in Oregon, with the Discovery Award from the Medical Research Foundation of Oregon. He is also director of OSU’s Environmental Health Sciences Center, funded by the National Institutes of Health to support research on the role of the environment in causing disease.

“We have a solid understanding of why the treatment works in the mice, and we predict it should work in both familial and possibly sporadic human patients,” Beckman said. “But we won’t know until we try.”

Familial ALS patients are those with more of a family history of the disease, while sporadic patients reflect the larger general population.

“We want people to understand that we are moving to human trials as quickly as we can,” Beckman said. “In humans who develop ALS, the average time from onset to death is only three to four years.”

The advances are based on substantial scientific progress in understanding the disease processes of ALS and basic research in biochemistry. The transgenic mice used in these studies have been engineered to carry the human gene for “copper chaperone for superoxide dismutase,” or CCS gene. CCS inserts copper into superoxide dismustase, or SOD, and transgenic mice carrying these human genes die rapidly without treatment.

After years of research, scientists have developed an approach to treating ALS that’s based on bringing copper into specific cells in the spinal cord and mitochondria weakened by copper deficiency. Copper is a metal that helps to stabilize SOD, an antioxidant protein whose proper function is essential to life. But when it lacks its metal co-factors, SOD can “unfold” and become toxic, leading to the death of motor neurons.

There’s some evidence that this approach, which works in part by improving mitochondrial function, may also have value in Parkinson’s disease and other conditions, researchers said. Research is progressing on those topics as well.

The treatment is unlikely to allow significant recovery from neuronal loss already caused by ALS, the scientists said, but could slow further disease progression when started after diagnosis. It could also potentially treat carriers of SOD mutant genes that cause ALS.

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Findings point toward one of first therapies for Lou Gehrig’s disease

English: Amyotrophic lateral sclerosis MRI (axial FLAIR) demonstrates increased T2 signal within the posterior part of the internal capsule, consistent with the clinical diagnosis of ALS source:Radiopedia.org (Photo credit: Wikipedia)

Researchers have determined that a copper compound known for decades may form the basis for a therapy for amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.

In a new study just published in the Journal of Neuroscience, scientists from Australia, the United States (Oregon), and the United Kingdom showed in laboratory animal tests that oral intake of this compound significantly extended the lifespan and improved the locomotor function of transgenic mice that are genetically engineered to develop this debilitating and terminal disease.

In humans, no therapy for ALS has ever been discovered that could extend lifespan more than a few additional months. Researchers in the Linus Pauling Institute at Oregon State University say this approach has the potential to change that, and may have value against Parkinson’s disease as well.

“We believe that with further improvements, and following necessary human clinical trials for safety and efficacy, this could provide a valuable new therapy for ALS and perhaps Parkinson’s disease,” said Joseph Beckman, a distinguished professor of biochemistry and biophysics in the OSU College of Science.

“I’m very optimistic,” said Beckman, who received the 2012 Discovery Award from the OHSU Medical Research Foundation as the leading medical researcher in Oregon.

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Lou Gehrig’s Disease: From Patient Stem Cells to Potential Treatment Strategy in One Study

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Translational Research Goes Seamless: After Creating Neurons From Patients’ Skin Cells, Cedars-Sinai-led Researchers ‘Treat’ Gene Defect in a Dish, Indicating the Therapy May Work

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.

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