ALS Gene C9orf72 Study Published in Journal “Neuron”

Pictured above: Dr. Gao’s laboratory team

A new disease pathway for C9orf72-related ALS was revealed in journal Neuron in a study led by principle investigator Dr. Fen-Biao Gao from the University of Massachusetts Medical School in Worcester, Mass. The research team found that the C9orf72 expansion leads to DNA damage, signifying another potential ALS therapeutic target. The ALS Association supported this encouraging study that also included current and past Milton Safenowitz Postdoctoral Fellows Dr. Dejun Yang (2015 recipient) and Dr. Helene Tran (2012 recipient).

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ALS Gene C9orf72 Damages DNA Revealing a New Disease Pathway

The most commonly inherited gene in familial ALS, C9orf72, points to DNA damage causing oxidative stress, according to a new study funded by The ALS Association. The study was published in the journal Neuron and led by principle investigator Fen-Biao Gao, Ph.D. and first author Rodrigo Lopez-Gonzalez, Ph.D. from the Department of Neurology at University of Massachusetts Medical School in Worcester, Mass. Findings from this paper point to DNA damage as a disease pathway of C9orf72-related ALS.

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New Protein Target Emerges for C9orf72 the Most Common Genetic Form of ALS

research news banner 2015Targeting a single protein, called SUPT4H1, reduces the levels of the three toxic entities created by the C9orf72 gene expansion, the most common genetic cause of ALS, according to a study published in the journal Science. The finding suggests that SUPT4H1 may be a promising candidate for therapy development for people whose disease is caused by expansion of the C9orf72 gene. The study was supported by The ALS Association and led by senior investigators Leonard Petrucelli, Ph.D., of the Mayo Clinic in Jacksonville, Fla and Aaron Gitler, Ph.D., of Stanford University in Stanford, Calif., along with co-lead investigators Nicholas Kramer, Ph.D., Yari Carlomagno, Ph.D., Fen-Biao Gao, Ph.D., and Yong-Jie Zhang, Ph.D.

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New ALS Research from the American Academy of Neurology Meeting

Some important advances in understanding and treatment of ALS were reported at the Annual Meeting of the American Academy of Neurology, held in Vancouver, BC, in April. Among the highlights were studies conducted by Drs. Lindsey Hayes, Sara van Mossevelde, Adriano Chio, Teresa Jacobs, Jeremy Shefner and Wendy Kaye.

Lindsey Hayes, M.D., Ph.D., from Johns Hopkins University in Baltimore, presented evidence that tracking one of the unusual proteins made by the C9orf72 mutation may provide a good biomarker for response to therapy against the mutation. Among other effects, the mutation causes the production of so-called dipeptide repeat proteins (DPRs), small proteins composed of two repeating amino acids. Dr. Hayes found that the level of one DPR, made of glycine and proline, fell in step with a dose increase of an antisense treatment against the C9orf72 mutation, suggesting that measurement of this DPR may be useful in clinical trials of antisense treatment. The work was done in cell culture and will need to be validated in other models before relying on it for clinical trials.

Sara van Mossevelde, M.D., of University of Antwerp in Antwerpen, Belgium, presented evidence that the C9orf72 gene mutation, the most common genetic cause of ALS, exhibits a phenomenon known as “anticipation,” meaning that the disease begins earlier in each succeeding generation, often due to expansion of a repeat mutation over time. She and her colleagues studied the clinical characteristics of 29 multi-generational families with the mutation and showed that those in the youngest generation had disease onset about 7 years earlier than their grandparents. Perhaps surprisingly, the duration of disease did not differ between the generations, unlike the common pattern of more severe disease in successive generations seen in other diseases that show anticipation. The explanation for this difference is not yet clear.

Dr. van Mossevelde provided important new clinical features of people living with ALS due to mutations in the TBK1 gene. The mutation also causes frontotemporal dementia (FTD). Onset was about age 62 and the average disease duration was 4.7 years. Behavioral changes and memory loss were important features of those with FTD.

Adriano Chio, M.D., of University of Torino in Turin, Italy, presented data on the influence of the APOE gene on the cognitive features of people with ALS. The same gene figures prominently in Alzheimer’s disease, where possession of the APOE2 allele (form of the gene) is associated with a reduced risk of dementia. Surprisingly, Dr. Chio found the opposite in ALS. People with ALS carrying the APOE2 allele had a 2.5-fold increase in their risk for dementia, compared to those not carrying the allele. The reason for this difference between ALS and Alzheimer’s disease is unclear, but investigation of the reason may provide some insight into the factors that determine whether a person with ALS will develop dementia.

Commencing non-invasive ventilation (NIV) before it is needed may provide some additional benefits compared to waiting, according to a pilot study from Teresa Jacobs, M.D., and colleagues at the University of Michigan in Ann Arbor, Mich. Using a novel trial design, in which people with ALS whose forced vital capacity (FVC), a standard measure of respiratory function, was above 50% of predicted, were randomized to either active NIV or sham NIV, in which the settings on the ventilator were too low to deliver the appropriate force for ventilatory assistance. The FVC of those receiving active treatment declined more slowly than it did in those receiving sham treatment. “This trend toward improved respiratory function seen in this pilot trial warrants further study of early NIV therapy in ALS,” Dr. Jacobs concluded.

Jeremy Shefner, M.D., Ph.D., of Barrow Neurologic Institute in Phoenix, Ariz. and colleagues presented data showing that changes in a respiratory measure called slow vital capacity (SVC) predicted changes in other measures of ALS decline, including need for invasive ventilation and risk of death. The results are important for interpreting clinical trial results for tirasemtiv, a drug shown to slow the decline in SVC in people with ALS. A Phase III clinical trial to test tirasemtiv, called VITALITY-ALS (Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year-ALS) began in July 2015, in which change in SVC will be a primary outcome measure to determine the drug’s symptomatic effect in ALS.

Wendy Kaye, Ph.D., and colleagues from the National ALS Registry showed the feasibility of a national biorepository of ALS biospecimens, including tissue and body fluids. Based on the success of this pilot study, the Registry will launch a nationwide biorepository in the fall of 2016.

New C9orf72 Mouse Models Show Neurodegeneration from Most Common Genetic Cause of ALS

research news banner 2015Two independent research studies both funded by The ALS Association, including principal investigator Laura Ranum, Ph.D., of the University of Florida in Gainesville and the other study led by Don Cleveland, Ph.D., of University of California San Diego in San Diego and Clotilde Lagier-Tourenne, M.D., Ph.D., of Massachusetts General Hospital in Boston, have developed new mouse models of the C9orf72 mutation that show neurodegeneration and motor and cognitive deficits reminiscent of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition, one group showed that these effects could be ameliorated in mice by antisense therapy against the mutant gene.

“These studies represent significant progress in understanding the consequences of the C9orf72 gene mutation and in developing a therapy against it,” said Lucie Bruijn, Ph.D., M.B.A., Chief Scientist for The ALS Association.

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New Disease Mechanism Revealed for C9orf72 Gene Mutations

research news banner 2015In a new study funded by The ALS Association, Yong-Jie Zhang, Ph.D., Leonard Petrucelli, Ph.D., and their research team from the Mayo Clinic in Jacksonville, Fla. have uncovered a new and potentially important disease mechanism that occurs in the C9orf72 gene, the most common genetic form of ALS. This study was published today in top-tiered scientific journal Nature Neuroscience.

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New Discovery of Normal Function of ALS Gene Will Aid Drug Development to Slow or Stop Disease

ALS research news banner 2015Mutations in the C9orf72 gene are known to be the most common genetic cause of ALS. According to new research, C9orf72 is important for immune system function in its normal form, an important discovery made by scientists Jacqueline O’Rourke, Ph.D., and Robert Baloh, M.D., of Cedars-Sinai Medical Center in Los Angeles, that is likely to influence the development of treatments aimed at silencing the C9orf72 mutant gene. The findings were published today in the journal Science.

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New ALS Model Argues for Early Treatment

ALS Research BannerWashington, D.C. (December 2, 2015) — Results from two independent research groups on an important new mouse model of inherited ALS gene C9orf72 indicate that development of disease pathology precedes neurodegeneration, and can be reversed by therapies targeting the mutant gene responsible for the pathology. The studies were funded in part by The ALS Association.

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New Study Points to Protein, not RNA, as Culprit in C9orf72 ALS

research news banner 2015Abnormal protein production, not RNA aggregation, damages neurons in the most common genetic form of ALS, according to new ALS Association-funded research. The study was published in the journal Neuron.

Mutation in the C9orf72 gene is the most common genetic cause of ALS, accounting for up to 40% of all familial disease and six percent of sporadic disease. The mutation is an expansion of a six-nucleotide repeat, GGGGCC, from as few as two units in the normal gene to hundreds or even thousands in the mutated form. Production of RNA from the mutation leads to two potentially harmful consequences: accumulation of this RNA in the cell nucleus and production of unusual “dipeptide repeat” proteins. Researchers are actively investigating which of these two consequences may contribute to neuron death in ALS.

In the new study, Helene Tran, Ph.D., and Fen-Biao Gao, Ph.D., both of the University of Massachusetts Medical School in Worcester, and colleagues, showed that abundant accumulation of RNA in the nucleus did not affect neuronal survival. In contrast, damage to neurons from dipeptide repeat proteins was significant, and a temperature-related increase in toxicity was proportional to the increased production of the proteins, not the accumulation of RNA. Based on their results, they suggest that treatments aimed at reducing the effects of the proteins might be therapeutic.

The research was performed in fruit flies, which were also used in several other recent studies investigating the pathogenic mechanism of the C9orf72 mutation. Those studies showed that the mutation impaired transport out of the nucleus; one of the studies demonstrated that the expanded RNA contributed directly to the disease.

“This important paper adds to the growing understanding of the pathogenesis of the C9orf72 gene,” said Lucie Bruijn, Ph.D., M.B.A., Chief Scientist for The ALS Association. “It will be important to understand whether the differences in mechanism suggested by this group of new studies are due to differences in the models used in each or are pointing toward multiple toxic effects at work at the same time in the disease. As we learn more about the consequences of the gene mutation, we will be able to better target our efforts toward the most effective avenues for reversing those consequences.”

Dr. Tran is a 2012 recipient of the Milton Safenowitz Post-Doctoral Research Fellow Award from The ALS Association, funded through the generosity of the Safenowitz family through the Greater New York Chapter and are in memory of Mr. Safenowitz, who died of ALS in 1998. “It is extremely encouraging as a young scientist to feel supported by The ALS Association,” Dr. Tran said.

ALS (amyotrophic lateral sclerosis) is a progressive neurodegenerative disease that affects neurons (nerve cells) in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. There is no cure and no life-prolonging treatments for the disease.

Two New Studies Supported by The ALS Association Highlight Discovery Around Most Common ALS Gene Mutation

research news banner 2015In today’s issue of Nature, two new studies funded in part by The ALS Association both highlight an important new discovery around the C9orf72 mutation, the most common genetic defect associated with amyotrophic lateral sclerosis (ALS). Both studies emphasize that a key driver of the development of ALS due to this mutation is an export-import imbalance between the cell’s nucleus and its non-nuclear portion, or cytoplasm.

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. For unknown reasons, veterans are twice as likely to develop ALS as the general population. There is no cure, and only one drug approved by the U.S. Food and Drug Administration (FDA) modestly extends survival.

“These new studies help us further understand a significant pathway in the ALS disease process and strengthens the evidence that RNA mishandling is a major contributor to ALS even beyond the genetic cases of ALS believed to be caused by the C9orf72 mutation,” said Lucie Bruijn, Ph.D., M.B.A., and Chief Scientist for the Association. “Importantly, this discovery may provide us with strong candidates for future drug development,” she continued.

In the first study, scientists have discovered that one major consequence of the C9orf72 gene mutation is disruption of RNA export from the cell nucleus. Working in fruit flies carrying various forms of the mutation, the researchers discovered 18 genes that worked to either worsen or mitigate the effects of the mutation. All 18 encoded either components of the nuclear pore or other proteins involved in regulating traffic of RNA and proteins in and out of the cell nucleus. One consequence was an increase in the amount of RNA retained in the nucleus, a change that was also seen in cells derived from people with disease due to the C9orf72 mutation.

The work was performed by first authors Brian Freibaum, Ph.D., of St. Jude’s Children’s Research Hospital in Memphis, Tennessee, and Yubing Lu, Ph.D., of University of Massachusetts Medical Center in Worcester; and led by J. Paul Taylor, M.D., Ph.D., of St. Jude’s, and Fen-Biao Gao, Ph.D. of University of Mass. Dr. Gao was supported by The ALS Association’s Greater Chicago Chapter State of Illinois Grant.

“C9ORF72 mutations are by far the most common genetic defect associated with both ALS and FTD, so understanding how the mutation causes disease is tremendously important for efforts to develop therapies to stop or reverse the death of neurons in the brain and spinal cord of patients,” said co-corresponding author Dr. Taylor.

In the second study, researchers at Johns Hopkins University showed that the expanded RNA of the C9orf72 mutation interacts directly with a protein called RanGAP1, which controls traffic of materials across the membrane separating the nucleus from the cytoplasm in all cells, including the motor neurons affected in ALS. That interaction appears to interrupt the normal regulation of cross-membrane flow of materials. The trafficking defect was seen in both a fly model of the disease and in cells from people with ALS. The defect could be mitigated with treatments that targeted the extra RNA produced by the mutation.

The work was performed by co-first authors Ke Zhang, Ph.D., a recipient of the Milton Safenowitz Post-doctoral in 2014, and Christopher Donnelly, Ph.D., and senior authors and Association-supported scientists Rita Sattler, Ph.D., Thomas Lloyd, M.D., Ph.D., and Jeffrey Rothstein, M.D., Ph.D., all of Johns Hopkins University in Baltimore, Maryland. Dr. Ke Zhang-supported by Greater Philadelphia Chapter of The ALS Association.

“These exciting results focus our attention more strongly on the role of cross-membrane trafficking in understanding how the C9orf72 gene causes ALS,” according to Lucie Bruijn, Ph.D., M.B.A., Chief Scientist for The ALS Association. “The ability of experimental treatments to reverse these effects in this model also gives us more reason to hope that a similar approach may offer benefits in people with ALS. This study and the recent report by a second group also showing defects in nuclear transport provide a stronger basis for developing therapy to target this important pathway.”

As referenced above, Dr. Donnelly is a recipient of The ALS Association’s Milton Safenowitz Post-Doctoral Fellowships for ALS Research, which encourages and facilitates promising young scientists to enter the ALS field. Funding for this two-year research award is made possible by the generosity of the Safenowitz family through the Greater New York Chapter of The ALS Association and is in memory of Mr. Safenowitz, who died of ALS in 1998.