New Gene Variant Discovered for ALS

dna_helixLeadArtFrom the Editors at Medical Xpress, December 3, 2013 •

Research led by King’s College London has identified a new genetic variant, located on chromosome 17, associated with sporadic amyotrophic lateral sclerosis (ALS) – the most common form of motor neurone disease (MND).

With genetic data from over 17,000 individuals, the study is the largest of its kind and provides a new insight into the genetic structure of the disease.

ALS is a neurodegenerative disease which causes progressive muscle paralysis and is fatal within 3-5 years. Around 10 per cent of cases run in families, with the remainder occurring sporadically. Previous studies have identified a number of genetic variants associated with familial ALS, but for non-familial, or sporadic, ALS, only a gene on chromosome 9 has been identified.

The new study, published in Human Molecular Genetics, is the result of a large international collaboration led by scientists at the Institute of Psychiatry at King’s, in collaboration with universities in the UK, Italy, USA, Germany, Netherlands and France, and is the largest genome wide association study (GWAS) for ALS to date.

A total of 13,225 individuals (6,100 cases and 7,125 controls) were analysed for almost 7 million genetic variants. This included 3,959 newly genotyped Italian individuals (1,982 cases of ALS and 1,977 controls) combined with published genotype data from the Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy.

The researchers identified a novel variant on chromosome 17 associated with ALS risk (17q11.2) and confirmed the association with the previously reported gene on chromosome 9 (9p21.2). The association on chromosome 17 was then confirmed in an independent set of 4,656 individuals.

The researchers estimate for the first time that the contribution of common to non-familial ALS is approximately 12%. The newly identified genetic variant on chromosome 17 is closely linked to a gene (SARM1) known to play a key role in axon, or nerve fibre death. The authors add that this new finding may lead to the discovery of new pathways involved in ALS, indicating potential new drug targets.

Dr Isabella Fogh and Dr John Powell from the Department of Neuroscience at the Institute of Psychiatry at King’s are co-authors of the study.

Dr Fogh says: “This is really exciting work. Whilst there have been a number of genes identified in familial ALS, very few have been identified in sporadic ALS, even though this form of the disease accounts for 90% of cases. Multiple genetic and environmental factors are implicated in the development of this devastating disorder. What we have here is another key part of the puzzle.”

More information: Isabella Fogh et al. ‘A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis’ Human Molecular Genetics hmg.oxfordjournals.org/content/early/2013/11/20/hmg.ddt587.full.pdf

Journal reference: Human Molecular Genetics search and more info website

Provided by King’s College London

New Device Delays Ventilator Need for Some ALS Patients (Op-Ed)

By Dr. Stephen Kolb for Live Science, December 3, 2013 •

For patients with amyotrophic lateral sclerosis (ALS), the simple act of breathing is often a tough thing to do. Now, these patients have new hope, as a device has been approved by the U.S. Food and Drug Administration (FDA) that may help patients to breathe more easily without a ventilator.

lungs-diagram-120926ALS, also known as Lou Gehrig’s disease, is a rapidly progressing, incurable and fatal neuromuscular disease characterized by progressive muscle weakness that results in paralysis. For ALS patients, diaphragm weakness contributes significantly to respiratory insufficiency, and ultimately respiratory failure, which is the most common cause of death for these patients. As the phrenic nerve to the diaphragm muscle fails, patients lose the ability to breathe without ventilator support.

Approximately 30,000 people in the United States live with ALS. More than 5,600 new cases are diagnosed each year, and about 3,300 of those patients might benefit from a diaphragmatic pacing system (DPS).

I recently worked with my colleague, Dr. Patrick Ross, a thoracic surgeon at The Ohio State University Wexner Medical Center to implant the NeuRx DPS device in Mary Pat Murry of London, Ohio. Our integrated ALS clinic and surgical center is the first to offer this new device to patients in Ohio, Kentucky and Indiana. We are one of only 30 integrated, multidisciplinary ALS clinics nationwide currently offering the device.

The device provides electrical stimulation to the nerve that innervates the diaphragm, similar to how a cardiac pacemaker works to stimulate the heart. When the device stimulates the nerve, the diaphragm contracts, and this helps condition the muscle to improve fatigue resistance during normal exertion.

Most ALS patients develop chronic hypoventilation over the course of their disease. Traditionally, we assist them with non-invasive ventilator support. The hope is that the diaphragmatic pacing system will help patients breathe for a longer period without needing a ventilator.

The DPS treatment is working well for Murry, whose respiratory function initially increased and has now plateaued, instead of continuing to decline. She tells me she feels more rested and has more energy since she has been using the DPS about 10 hours a day.

In 2014, Ohio State will participate in a national multi-center clinical trial that will try to determine if DPS treatment for patients with ALS and hypoventilation will improve survival or diaphragm function. About 20 Northeast ALS Consortium (NEALS) centers in the United States will participate in the randomized study that will enroll 180 patients. Study participants will be randomly assigned in a 2:1 ratio to DPS or standard-of-care treatment groups.

In an earlier multi-center clinical trial, the device was approved by the FDA under a Humanitarian Device Exemption marketing approval, based on demonstration of safety and probable benefit, including the likelihood that it will help ALS patients live longer and sleep better than the current standard of care. The device is controlled through a four-channel, battery-powered, external pulse generator.

The NeuRx DPS was developed over 20 years through a joint effort of physicians and engineers at several institutions.

ALS is incurable and right now physicians can’t stop its progress, but we are optimistic that this will give people with ALS a better quality of life during the course of their disease.

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Dr. Stephen Kolb, a neurologist at The Ohio State University Wexner Medical Center, contributed this article to LiveScience’s Expert Voices: Op-Ed & Insights.

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The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

Diaphragm Pacing System Benefits Patients With ALS

From the editors of Science Daily, Oct. 17, 2013 •

Respiratory failure is one of the major complications associated with amyotrophic lateral sclerosis (ALS). The quest for alternative approaches for treating respiratory failure has led to the study, and subsequent FDA approval, of diaphragm pacing for use in ALS patients. However, there are still important unanswered questions about its benefit and impact.

In a study presented at the annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), the outcomes of 28 of 34 ALS patients with diaphragm pacing systems (DPS) were analyzed for up to 14 months after implantation. All patients also used a bi-level positive airway pressure (BiPAP) portable ventilator after DPS implantation. More than 50% of the patients reduced their use of BiPAP during the first 3-4 months after implantation and had slower declines in respiratory function. Overall, the researchers found that diaphragm pacing resulted in improved quality of life, with better sleep and daytime functioning, better breathing, and less fatigue.

“This study presents important positive results at one-year of follow-up that support the use of diaphragm pacing as an additional strategy to manage respiratory failure in patients with ALS,” said Carlos Luciano, MD, AANEM News Science Editorial Board member.

“The data also confirms previously published results suggesting that diaphragm pacing improves sleep in ALS patients.”

SOURCE: The above story is based on materials provided by American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), via Newswise.

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The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

ImStar Selects Lead ALS Drug Candidate for Study by Mid-2014

VANCOUVER, November 30, 2013  ImStar Therapeutics, a private biotechnology company developing a new approach to treat patients with ALS, has selected IMS-088 as its lead drug candidate for the treatment of Amyotrophic Lateral Sclerosis (ALS). The company is preparing to initiate IND-enabling studies in the second half of 2014.

IMS-088 is a novel, small-molecule drug that stems from the discovery of a new target for ALS by ImStar co-founder Dr Jean-Pierre Julien termed TANA (i.e. TDP-43 Associated NF-kB Activation). IMS-088 is the first in a series of novel drugs derived from withaferin A, a natural compound isolated from the leaves of the winter cherry plant (Withania somnifera) that inhibits activation of a key inflammation pathway. In preclinical ALS disease models, withaferin A produced substantial improvements in function and extended survival, but lacked optimal characteristics to be developed as a drug. IMS-088 was designed by ImStar chemists to have superior drug-like properties and has been shown to be potent and safe in preclinical studies.

In conjunction with the selection of a lead compound, ImStar has filed a patent application with the United States Patent and Trademark Office covering novel withanolide therapeutics.

“We are very excited to announce the selection of IMS-088 as ImStar’s lead ALS compound. As we continue with preclinical development next year, we hope to establish IMS-088 as a safe and effective new drug candidate for ALS,” said Jean-Pierre Julien, ImStar’s chief scientific officer. “This is an important milestone for ImStar,” said Daniel Wattier, CEO of ImStar, “It reflects our commitment to transforming this important discovery into a practical treatment for patients.”

Amyotrophic Lateral Sclerosis (ALS), commonly known as “Lou Gehrig’s disease”, is a progressive neurodegenerative disease that inhibits an individual’s ability to control voluntary muscle movement. ALS leads to paralysis and death in most cases.

SOURCE: PharmaBiz.com

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The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

 

Neuraltus’ NP001 Phase 2 Results Highlighted at 24th International Symposium on ALS/MND

Findings Show Positive Trends in Slowing Advancement of Disease, as well as Enhanced Activity of NP001 in Patients with Increased Baseline Inflammation; Phase III expected in 2014

PALO ALTO, California, December 9, 2013 — Neuraltus Pharmaceuticals, Inc. announced today that promising efficacy results of the Company’s Phase 2 clinical program of NP001 for the treatment of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) were highlighted in an oral presentation at the 24th International Symposium on ALS/MND, held in Milan, Italy.  Study efficacy results demonstrated positive trends in the ability of NP001 to slow the rate of disease progression, ranging from 13 to 19% in multiple parameters of clinical benefit, although these pre-defined endpoints did not reach statistical significance.  According to a post hoc analysis, a greater percentage of patients receiving NP001 experienced a halt in disease progression which reached statistical significance when compared to the combination of concurrent and matched historical (placebo) controls.  The high dose of NP001 (2mg/kg) halted progression in 27% of patients compared to 11% of patients on placebo.  Further, NP001 was found to be safe and well-tolerated in the study.

In addition, the researchers discovered a trend in greater improvement in patients with higher baseline inflammation who received the high dose of NP001, achieving a 44% improvement compared to placebo.  These findings provide further support for the hypothesis that NP001′s primary mechanism of action is the restoration of normal function in inflammatory macrophages.  The Phase 2 data were reported in an oral presentation, titled “Additional Follow-up and Biomarker Data from a Phase II Safety and Preliminary Efficacy Trial of NP001: A Novel Immune Regulator for Slowing Progression of ALS,” delivered by Principal Investigator Robert G. Miller, MD, who serves as Director of the Forbes Norris MDA/ALS Research and Treatment Center of the California Pacific Medical Center.

NP001 is a small molecule regulator of inflammatory macrophage activity.  Aberrant macrophage activity is believed to be a significant contributor to the pathology underlying ALS and other neurodegenerative diseases.  Neuraltus’ NP001 is designed to restore the normal functioning of macrophages within the central nervous system.

According to Dr. Miller, “We are pleased to report the current, most up-to-date findings from the Phase 2 study.  Clinical effects of NP001 are consistent with what we’ve seen in earlier research, which demonstrated that NP001 is able to lower markers of abnormal inflammatory macrophages in in vitro and in vivo preclinical studies, as well as in a dose-dependent manner in earlier-stage clinical work.  In the Phase 2 study, we saw a halting of disease progression in 27% of the high-dose treatment group patients, a finding we have never seen in prior ALS trials.  In addition, we strongly believe the trial design confirmed the utility of using historical placebo controls for signal amplification and hypothesis generation and that the benefit-risk supports further development of NP001.  We look forward to the continued progress of this program.”

Neuraltus recently updated their development timeline for NP001, noting that the Company is expecting to initiate a Phase 3 study sometime in 2014.

More About the Phase 2 NP001 Study

The multi-center, double-blind, placebo-controlled, Phase 2 study enrolled 136 patients with ALS. Patients were randomized to receive either placebo, or 1mg/kg or 2mg/kg intravenous infusion of NP001 over a period of six months, followed by a six-month follow-up period. The study was designed to evaluate the change in slope of the ALS Functional Rating Score Revised (ALSFRS-R) and the safety and tolerability of NP001, as well as change from baseline in ALSFRS-R through six months, a joint rank analysis of change of ALSFRS-R adjusted for mortality and changes in readily measured peripheral inflammation biomarkers. An additional secondary endpoint agreed upon with the FDA was the inclusion of matched historical placebo control ALS patients to increase signal detection and power.

Post hoc analysis of the Phase 2 study showed a dose response to NP001 with 27% of the patients who received 2mg/kg NP001 having no progression of their disease during the six-month dosing period. This is approximately 2.5 times as many as were seen in the concurrent placebo group. When historical placebo controls were included with concurrent controls, this difference versus placebo became statistically significant. Although post hoc analysis must be considered cautiously and can be subject to bias, the magnitude of the benefit identified underscores a potentially clinically relevant and meaningful result. In addition, results from the study demonstrated trends of clinical benefit for the 2 mg/kg cohort in the primary endpoint of change in slope of the ALSFRS-R, and in the secondary endpoints of change from baseline in ALSFRS-R through six months and a joint rank analysis of change of ALSFRS-R adjusted for mortality.  Further, the benefit of NP001 related to the degree of baseline inflammation in patients.  Those patients with greater baseline inflammation and who received the high dose of NP001 experienced a 44% greater slope improvement (positive trend did not reach significance, however).

About Neuraltus Pharmaceuticals, Inc.

Neuraltus Pharmaceuticals, Inc. is a privately-held biopharmaceutical company developing novel therapeutics to treat neurological disorders. Neuraltus’ clinical-stage product candidate, NP001, has been shown to regulate the activation of select immune cells (macrophages), transforming them from an activated or inflammatory state to their normal quiescent state in order to normalize the cellular environment of critical nerve cells. Neuraltus has completed a Phase 2 clinical study of NP001 in patients with amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), results of which were reported in late 2012.

For more information on Neuraltus, please visit www.neuraltus.com.

CONTACT: 

Rich Casey, President and CEO, Neuraltus Pharmaceuticals, Inc.
Tel: (650) 424-1600 x. 300
Email: rcasey@neuraltus.com

Burns McClellan, on behalf of Neuraltus
Justin Jackson (media)
jjackson@burnsmc.com

SOURCE: Neuraltus Pharmaceuticals, Inc.

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The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

Cytokinetics to Present BENEFIT-ALS Trial Insights at International Symposium

South San Francisco, California, December 2, 2013 – Cytokinetics announced today that a presentation relating to tirasemtiv and BENEFIT-ALS, is scheduled to be presented at the 24th International Symposium on ALS/MND to be held December 6-8, 2013 at the Atahotel Quark in Milan, Italy.

The presentation will elaborate on the clinical trial design and include enrollment and baseline demographics data from BENEFIT-ALS (Blinded Evaluation of Neuromuscular Effects and Functional Improvement with Tirasemtiv in ALS), which is evaluating tirasemtiv, a novel mechanism skeletal muscle activator, as a potential treatment for patients with amyotrophic lateral sclerosis (ALS).

Platform Presentation at the 24th International Symposium on ALS/MND

Date:   Saturday, December 7, 2013
Location:  Atahotel Quark, Aquarium Room
Presentation Time:  4:00 PM – 4:15 PM (Central European Time)
Session:  8B – Clinical Trials and Trial Design
Title:  The Effect of Tirasemtiv on Functional Status in Patients with ALS
Presenter:  Jeffrey M. Shefner, M.D., Ph.D., Professor and Chair, Department of Neurology at the Upstate Medical University, State University of New York

About Tirasemtiv and BENEFIT-ALS

Tirasemtiv, a novel skeletal muscle activator, is the lead drug candidate from the company’s skeletal muscle contractility program.  Tirasemtiv selectively activates the fast skeletal muscle troponin complex by increasing its sensitivity to calcium and, in preclinical studies, demonstrated increases in skeletal muscle force in response to neuronal input and delays in the onset and reductions in the degree of muscle fatigue.  In previously conducted Phase IIa clinical trials in patients with ALS, tirasemtiv appeared generally well-tolerated, and demonstrated encouraging trends to improvement in patients’ functional abilities and increases in measures of respiratory and skeletal muscle strength and endurance.  BENEFIT-ALS is a Phase IIb, multi-national, double-blind, randomized, placebo-controlled, clinical trial designed to evaluate the safety, tolerability and potential efficacy of tirasemtiv in patients with ALS.

About Cytokinetics

Cytokinetics is a clinical-stage biopharmaceutical company focused on the discovery and development of novel small molecule therapeutics that modulate muscle function for the potential treatment of serious diseases and medical conditions. Cytokinetics’ lead drug candidate from its cardiac muscle contractility program, omecamtiv mecarbil, is in Phase II clinical development for the potential treatment of heart failure.

Amgen Inc. holds an exclusive license worldwide to develop and commercialize omecamtiv mecarbil and related compounds, subject to Cytokinetics’ specified development and commercialization participation rights. Cytokinetics is independently developing tirasemtiv, a fast skeletal muscle activator, as a potential treatment for diseases and medical conditions associated with neuromuscular dysfunction. Tirasemtiv is currently the subject of a Phase II clinical trials program and has been granted orphan drug designation and fast track status by the U.S. Food and Drug Administration and orphan medicinal product designation by the European Medicines Agency for the potential treatment of amyotrophic lateral sclerosis, a debilitating disease of neuromuscular impairment.

Cytokinetics is collaborating with Astellas Pharma Inc. to develop CK-2127107, a skeletal muscle activator structurally distinct from tirasemtiv, for non-neuromuscular indications. All of these drug candidates have arisen from Cytokinetics’ muscle biology focused research activities and are directed towards the cytoskeleton. The cytoskeleton is a complex biological infrastructure that plays a fundamental role within every human cell. Additional information about Cytokinetics can be obtained at www.cytokinetics.com.

Source: Cytokinetics, Inc. via Globenewswire

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The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

ALS TDI and Neurimmune Partner to Advance Treatments for ALS

CAMBRIDGE, Massachusetts,, December 6, 2013 – The ALS Therapy Development Institute (ALS TDI), together with its wholly-owned subsidiary, Anelixis Therapeutics, announced today that it has formed a research partnership with Neurimmune to advance potential treatments for ALS, also known as Lou Gehrig’s disease. The research partnership will explore a human monoclonal antibody that targets misfolded superoxide dismutase 1 (SOD1). Misfolded SOD1 accumulates in familial and sporadic ALS, suggesting a generalized role as a drug target for ALS treatments.

logo_neurimmune

HeaderLogo

“We are excited by the results of Neurimmune’s findings,” says Steve Perrin, Ph.D., CEO & CSO of ALS TDI. “Recent evidence would suggest that therapies targeting misfolded SOD1 could be important in both sporadic and familial forms of ALS. It is crucial that we use every tool available to us to advance potential treatments toward the clinic, and we are proud to work together with Neurimmune to attempt to do just that.”

The collaboration will explore the high-affinity human antibodies developed by Neurimmune that selectively target misfolded SOD1. In preclinical studies with transgenic mice, chronic antibody treatment significantly reduced SOD1 pathology and rescued spinal cord motor neurons, resulting in significantly reduced muscle atrophy, better motor functions and increased survival. Neurimmune will present the key findings of their approach at the International Symposium on ALS/MND Research in Milan, Italy on December 7, 2013.

“ALS is a devastating neuromuscular disease, and there is an urgent need for new and effective therapies that can slow or stop its progression,” says Jan Grimm, Ph.D., CSO of Neurimmune. “Our human antibodies are directed against pathologically misfolded SOD1 and the selected lead candidate shows marked efficacy in independent ALS animal models. We believe that there is significant potential for this therapeutic approach for ALS and are enthusiastic to jointly advancing the program towards clinical development together with ALS TDI.”

Information about ALS TDI’s subsidiary, Anelixis Therapeutics, can be found here: http://www.als.net/docs/uploads/Anelixis_updated_for_web.pdf

About ALS Therapy Development Institute (ALS TDI)
The mission of the ALS Therapy Development Institute (ALS TDI) is to discover and develop effective treatments to end ALS as soon as possible. ALS TDI is the world’s largest independent ALS/MND drug development-focused nonprofit organization. It currently has partnerships with dozens of pharmaceutical and biotechnology companies worldwide in order to advance potential treatments into the clinic. Its lead ALS therapeutic candidate, Novartis’ (Switzerland) Gilenya (TDI-132), is in Phase 2A clinical trial for ALS, and the Institute has a research agreement on a second candidate with Biogen Idec (USA) and UCB SA (Belgium) for future clinical development. For more information, visitwww.als.net.

About Anelixis Therapeutics
Anelixis Therapeutics, LLC is a mission-aligned translational medicine and drug development company created by the ALS Therapy Development Institute in 2013. It uses innovative business models as a virtual biotech to advance potential ALS treatments, licensed from the Institute and other like-minded organizations, through early stage clinical development, adding value to the most promising lead candidates and preparing them for later stage development together with larger biotechnology and pharmaceutical companies. For more information, visit www.AnelixisTherapeutics.com or contact 617-599-6514.

About Neurimmune
Neurimmune is a Swiss biotech company focusing on the development of a novel class of human antibody therapeutics for the treatment and prevention of severe diseases. Based upon its unique Reverse Translational Medicine™ technology platform, Neurimmune has created a strong and sustainable pipeline of human antibody programs targeting CNS indications. Neurimmune’s business strategy focuses on the discovery and development of therapeutic antibodies at early stages of the pharmaceutical value chain and partnering product candidates for later-stage development and marketing. Neurimmune’s lead program for Alzheimer’s disease is partnered with Biogen Idec and currently in Phase 1b clinical testing. For additional information, please visit www.neurimmune.com.

Media Contact:
Rob Goldstein, ALS TDI, 617-441-7295, rgoldstein@als.net

Source: ALS Therapy Development Institute

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The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

University of Adelaide Sheds Light on Neurodegenerative Pathway

University of Adelaide researchers have identified a likely molecular pathway that causes a group of untreatable neurodegenerative diseases, including Huntington’s disease and Lou Gehrig’s disease.

The group of about 20 diseases, which show overlapping symptoms that typically include nerve cell death, share a similar genetic mutation mechanism ? but how this form of mutation causes these diseases has remained a mystery.

“Despite the genes for some of these diseases having been identified 20 years ago, we still haven’t understood the underlying mechanisms that lead to people developing clinical symptoms,” says Professor Robert Richards, Head of Genetics in the University’s School of Molecular and Biomedical Sciences.

“By uncovering the molecular pathway for these diseases, we now expect to be able to define targets for intervention and so come up with potential therapies. Ultimately this will help sufferers to reduce the amount of nerve cell degeneration or slow its progression.”

In an article published in Frontiers in Molecular Neuroscience, Professor Richards and colleagues describe their innovative theory and new evidence for the key role of RNA in the development of the diseases. RNA is a large molecule in the cell that copies genetic code from the cell’s DNA and translates it into the proteins that drive biological functions.

People with these diseases all have expanded numbers of copies of particular sequences of the ‘nucleotide bases’ which make up DNA.

“In most cases people with these diseases have increased numbers of repeat sequences in their RNA,” says Professor Richards. “The disease develops when people have too many copies of the repeat sequence. Above a certain threshold, the more copies they have the earlier the disease develops and the more severe the symptoms. The current gap in knowledge is why having these expanded repeat sequences of genes in the RNA translates into actual symptoms.”

Professor Richards says evidence points towards a dysfunctional RNA and a pivotal role of the body’s immune system in the development of the disease.

“Rather than recognising the ‘expanded repeat RNA’ as its own RNA, we believe the ‘expanded repeat RNA’ is being seen as foreign, like the RNA in a virus, and this activates the innate immune system, resulting in loss of function and ultimately the death of the cell,” he says.

The University of Adelaide laboratory modelled and defined the expanded repeat RNA disease pathway using flies (Drosophila). Other laboratories have reported tell-tale, but previously inexplicable, signs characteristic of this pathway in studies of patients with Huntington’s disease and Myotonic Dystrophy.

“This new understanding, once proven in each of the relevant human diseases, opens the way for potential treatments, and should give cause for hope to those with these devastating diseases,” Professor Richards says.

This research has been part-funded by the National Health and Medical Research Council of Australia and the National Ataxia Foundation of the USA.

SOURCE: University of Adelaide

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The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

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RASCALS Board of Directors Welcomes Sandra Putney as New Treasurer

The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is delighted to welcome Sandra Putney to the foundation’s Board of Directors, where she will assume the duties of Treasurer. Sandra is committed to using her business acumen and leadership abilities to safeguard donor dollars while ensuring that donations are maximized for the organization’s mission.

“It was my wish going into 2013 that this would be a breakout year for this organization. The addition of Sandra to our executive committee has certainly helped to achieve that goal, said R.A.S.C.A.L.S. founder and president, Robert Stehlin. “She has been with us virtually from the beginning, volunteering for our trivia night and participating in the foundation’s 5K. We couldn’t be more happy that she has agreed to take on this critical role.”

Sandra pursued undergraduate studies in business and accounting at Webster University In Webster Groves, Missouri. She then went on to receive a Masters degree in accounting at Nova Southeastern University in Ft. Lauderdale, Florida. Following graduation, Sandra obtained her Certified Public Accountant license here in the state of Missouri.

She has spent seven years leading the finance functions for the Gateway Area Chapter of the National Multiple Sclerosis Society, before accepting a position for the organization’s home office last year as the Director of Finance, Field.

Sandra is happy to call St. Louis her hometown, where she lives with her husband of five years and their new baby boy, Jack, who was born in June of 2013.  In addition to her infant son, she is passionate about Zumba, music, and traveling, Her other charitable efforts include the United Way and Young Women’s Breast Cancer Program.

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The Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.) is an all-volunteer 501(c)(3) charity. 100% of all funds raised go to building awareness, treatment research and development, plus ALS family assistance. There are no administrative costs.

Contributions are tax-deductible.

You may also be interested in visiting the RASCALS Store.

The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.

New Therapeutic Target Identified for ALS

SAN DIEGO,  November 8, 2013 — A team of scientists led by researchers from the University of California, San Diego School of Medicine and Ludwig Institute for Cancer Research have identified a novel therapeutic approach for the most frequent genetic cause of ALS, a disorder of the regions of the brain and spinal cord that control voluntary muscle movement, and frontal temporal degeneration, the second most frequent dementia.

Published ahead of print in last week’s online edition of the journal PNAS, the study establishes using segments of genetic material called antisense oligonucleotides – ASOs – to block the buildup and selectively degrade the toxic RNA that contributes to the most common form of ALS, without affecting the normal RNA produced from the same gene.

The new approach may also have the potential to treat frontotemporal degeneration or frontotemporal dementia (FTD), a brain disorder characterized by changes in behavior and personality, language and motor skills that also causes degeneration of regions of the brain.

In 2011, scientists found that a specific gene known as C9orf72 is the most common genetic cause of ALS. It is a very specific type of mutation which, instead of changing the protein, involves a large expansion, or repeated sequence of a set of nucleotides – the basic component of RNA.

A normal C9orf72 gene contains fewer than 30 of the nucleotide repeat unit, GGGGCC. The mutant gene may contain hundreds of repeats of this unit, which generate a repeat containing RNA that the researchers show aggregate into foci.

“Remarkably, we found two distinct sets of RNA foci, one containing RNAs transcribed in the sense direction and the other containing anti-sense RNAs,” said first author Clotilde Lagier-Tourenne, MD, PhD, UC San Diego Department of Neurosciences and Ludwig Institute for Cancer Research.

The researchers also discovered a signature of changes in expression of other genes that accompanies expression of the repeat-containing RNAs. Since they found that reducing the level of expression of the C9orf72 gene in a normal adult nervous system did not produce this signature of changes, the evidence demonstrated a toxicity of the repeat-containing RNAs that could be relieved by reducing the levels of those toxic RNAs.

“This led to our use of the ASOs to target the sense strand. We reduced the accumulation of expanded RNA foci and corrected the sense strand of the gene. Importantly, we showed that we could remove the toxic RNA without affecting the normal RNA that encodes the C9orf72 protein. This selective silencing of a toxic RNA is the holy grail of gene silencing approaches, and we showed we had accomplished it,” Lagier-Tourenne added.

Targeting the sense strand RNAs with a specific ASO did not, however, affect the antisense strand foci nor did it correct the signature of gene expression changes. “Doing that will require separate targeting of the antisense strand – or both – and has now become a critical question,“ Lagier-Tourenne said.

“This approach is exciting as it links two neurodegenerative diseases, ALS and FTD, to the field of expansion, which has gained broadened interest from investigators,” said co-principal investigator John Ravits, MD, UC San Diego Department of Neurosciences. “At the same time, our study also demonstrates the – to now – unrecognized role of anti-sense RNA and its potential as a therapeutic target.”

Contributors to the study included lead authors Ravits and Don W. Cleveland, PhD, chair of Cellular and Molecular Medicine, professor of Medicine and Neuroscience, and Ludwig Institute for Cancer Research investigator; co-first author Michael Baughn, UC San Diego, along with researchers from Isis Pharmaceuticals of Carlsbad, CA and Cedars-Sinai Medical Center, Los Angeles, and Washington University School of Medicine, St. Louis.

The research was supported by grants from the National Institutes of Health K99NS075216; by research project funding from Target ALS and the Amyotrophic Lateral Sclerosis Association; from the Packard Center for ALS Research at Johns Hopkins University; and support from the Ludwig Institute for Cancer Research.

SOURCE: University of California, San Diego Health Sciences

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