110% Gratitude to All Our Volunteers

April marks National Volunteer Month. This observance holds very special meaning for all of us here at the Robert A. Stehlin Campaign for ALS (R.A.S.C.A.L.S.). That’s because we are a 100% all-volunteer 501(c)(3) non-profit charity. There are no administrative costs.

That means no salaries, payments, or perks for anyone. Out-of-pocket expenses truly means out of our own pockets. There are no fancy cars or credits for gas or mileage. No big offices to write off. In fact, we don’t even have an office. Everyone works from home—and from the heart.

As a result, 100% of all funds raised by the R.A.S.C.A.L.S. Foundation go directly to fighting ALS. The money goes to things like maintaining this informative Web site to educate and build awareness. It helps fund promising treatment research and development. And it goes to ALS family assistance, such as our annual Higher Education Scholarship program.

Together with our generous donors, it is our volunteers who make all of this possible, selflessly giving it 110% whenever called upon, through their time, energy, and compassion.  I couldn’t be more proud—or grateful.

On behalf of ALS survivors and families everywhere, I thank you from the bottom my heart. Your efforts are top of mind each and every day.

                                                                            — Bob Stehlin

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For more information on volunteer opportunities, contact the RASCALS founder and president, Bob Stehlin, at 636-464-6704.

You may also send him an email at stl.rascals@yahoo.com.

(Bob is an ALS survivor, diagnosed September 11, 2009.)

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NEALS SOD1 Research is First Antisense Oligonucleotide Trial for a Central Nervous System Disorder

Antisense Oligonucleotides May be Feasible ALS Therapeutic Strategy

BOSTON, Massachusetts, March 29, 2013 — Published online today in Lancet Neurology, an SOD1-related familial ALS trial under the direction of NEALS researchers Timothy Miller, MD, PhD (Washington University School of Medicine) and Merit Cudkowicz (Massachusetts General Hospital) indicates that antisense oligonucleotide delivery to the central nervous system may be a feasible therapeutic strategy in treating ALS.  Mutations in SOD-1 cause 13% of familial ALS cases.

The placebo controlled, double-blind, randomized, dose escalation Phase I clinical trial sought to evaluate safety, tolerability, and pharmacokinetics of ISIS 333611, an antisense oligonucleotide against SOD1.  Participants with ALS caused by mutations in SOD1 were enrolled. ISIS 333611 was well-tolerated.  There were no safety concerns.  ISIS 333611 was delivered by intrathecal infusion using an external pump over 11.5 hours at increasing doses to four cohorts of eight subjects with SOD1 mutation (randomized 6 drug: 2 placebo/cohort).  Participants could enroll in more than one cohort.  The four consecutive dose cohorts were 0.15 mg, 0.5 mg, 1.5 mg, and 3 mg.  Pharmacokinetic levels were consistent with levels predicted from preclinical studies.

Supported by Isis Pharmaceuticals, the Muscular Dystrophy Association, and the ALS Association, the Isis trial is the first time antisense oligonucleotides were delivered directly to the cerebrospinal fluid (CSF) of patients with SOD1 ALS.  It was also the first antisense oligonucleotide trial for a central nervous system disorder. The concept of “turning off” SOD1 in patients with this mutation led to the groundbreaking Phase I trial.  “What we developed is a way to turn off harmful genes, erase them essentially by deleting a small part of the RNA which then no longer makes this abnormal protein,” Miller states.  This approach will also likely be applicable to other diseases of the central nervous system.

The Phase I trial took place at four NEALS clinical research sites: Washington University in St. Louis, Massachusetts General Hospital, Johns Hopkins University, and Methodist Neurological Institute.  Study Coordination and Data Management was led by the MGH Neurological Clinical Research Institute (NCRI). A total of 21 participants were enrolled in the trial.  Further development of SOD1 antisense oligos for SOD1 familial ALS is ongoing.

About the Northeast ALS Consortium (NEALS)
The Northeast ALS Consortium (NEALS) is an international, independent, non-profit group of researchers who collaboratively conduct clinical research in Amyotrophic Lateral Sclerosis (ALS) and other motor neuron diseases. Their mission is to translate scientific advances into new treatments for people with ALS and motor neuron disease as rapidly as possible.  NEALS has over 100 member sites in the United States, Canada, Ireland, and Israel.
www.alsconsortium.org

About the Neurological Clinical Research Insitute (NCRI) at Massachusetts General Hospital
The Neurological Clinical Research Institute (NCRI) at Massachusetts General Hospital accelerates translational research in neurological disorders through initiating and testing novel therapies.  The NCRI has an extensive history in leading clinical research to find new treatments for neurological diseases including Amyotrophic Lateral Sclerosis (ALS), myasthenia gravis, diabetic neuropathy, stroke, multiple sclerosis, Parkinson’s disease, and Huntington’s disease.
www.NCRInstitute.org

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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.

 

‘RNA Sponge’ Mechanism May Cause ALS/FTD Neurodegeneration

The most common genetic cause of both ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) was recently identified as an alteration in the gene C9orf72. But how the mutation causes neurodegenerative disease appeared mysterious.

Researchers at Emory University School of Medicine have demonstrated that this ALS/FTD mutation may be harmful because it creates an “RNA sponge,” soaking up an important regulatory protein that binds RNA.

The results were published online Monday in the Proceedings of the National Academy of Sciences, Early Edition.

“We think that the RNA itself is part of the disease mechanism,” says co-author Thomas Wingo, MD, assistant professor of neurology at Emory University School of Medicine. “In both cell culture and fruit flies, we’ve been able to show that we can add back the protein depleted by the RNA and ameliorate the problem.”

The finding provides insight into the mechanism of disease in ALS and FTD, both in cases where C9orf72 is altered and in other cases. It suggests some forms of ALS/FTD may have common elements with other neurodegenerative disorders caused by noncoding repeats, such as myotonic dystrophy, spinocerebellar ataxia and fragile X-associated tremor/ataxia syndrome.

The senior author is Peng Jin, PhD, professor of human genetics at Emory University School of Medicine. The first authors are a former graduate student, Zihui Xu, PhD, now at Huazhong University of Science and Technology in China, and research specialist Mickael Poidevin.

ALS is a fatal disease in which motor neurons in the brain and spinal cord degenerate. As the illness progresses, patients lose the ability to walk, talk and breathe. FTD is a form of dementia in which the patients primarily experience deterioration in behavior, personality or language.

Many neurologists and researchers consider these conditions as sharing clinical and pathological features. Mutations in several genes have been linked to both ALS and FTD, which suggests that they have a common mechanism. However, most cases are considered sporadic, meaning that they don’t have a clear family history.

In 2011, a mutation was identified within C9orf72 as the most common genetic cause of ALS and FTD, accounting for 5 to 7 percent of cases of each disease. The mutation doesn’t seem to affect the protein encoded by C9orf72. Instead, it expands a block of repetitive DNA, so that the sequence “GGGGCC” is repeated hundreds of times outside the parts of the gene that encode protein.

This looks similar to “noncoding repeat” expansions responsible for other neurodegenerative disorders such as myotonic dystrophy, spinocerebellar ataxia and fragile X-associated tremor/ataxia syndrome.

Some researchers have reported that the GGGGCC repeat produces RNA that is translated into an unusual protein that aggregates in cells. These protein aggregates are thought to be toxic to neurons. Emory researchers have an alternative explanation: the GGGGCC repeat RNA itself is toxic.

The Emory team tested the effects of producing the GGGGCC repeat RNA, which proved toxic to cultured mammalian neuronal cells and caused neurodegeneration in fruit flies. When the repeat RNA was produced in flies’ motor neurons, the flies had reduced motor activity.

The repeat RNA appears to be harmful because, when overproduced, it sequesters a protein called Pur alpha, which sticks to the GGGGCC repeats. Scientists had previously found that Pur alpha is necessary for neuronal development and is involved in the transport of RNA within neurons. Making neuronal cells or flies produce more Pur alpha to compensate reverses the toxicity caused by the RNA, the Emory scientists found.

“For ALS and FTD, this suggests a disease-fighting strategy of targeting either the toxic RNA itself or its interaction with Pur alpha,” Jin says. “It also hints that there is a common RNA-based mechanism contributing to several neurodegenerative diseases.”

Sequestering Pur alpha appears to cause its redistribution within the neurons of patients affected by ALS/FTD. The Emory team was able to detect clumpy “inclusions” containing Pur alpha in samples of brain tissue from individuals with C9orf72 mutations – and also in other individuals with FTD but without C9orf72 mutations.

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The research was supported by the National Institute for Neurological Disorders and Stroke (R01 NS051630 and R21NS067461) and the Atlanta Veterans Administration Medical Center.

Reference:

Z. Xu, M. Poidevin, X. Li, Y. Li, L. Shu, D.L. Nelson, H. Li, M. Gearing, T.S. Wingo and P. Jin. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes

SOURCE: Emory Health Sciences

Contact: Quinn Eastman
404-727-7829
qeastma@emory.edu

 

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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.

Johns Hopkins Researchers Discover New Clues About How ALS Develops

Role of cells other than motor neurons much larger than anticipated

BALTIMORE, Maryland, March 31, 2013 — Johns Hopkins scientists say they have evidence from animal studies that a type of central nervous system cell other than motor neurons plays a fundamental role in the development of amyotrophic lateral sclerosis (ALS), a fatal degenerative disease. The discovery holds promise, they say, for identifying new targets for interrupting the disease’s progress.

In a study described online in Nature Neuroscience, the researchers found that, in mice bred with a gene mutation that causes human ALS, dramatic changes occurred in oligodendrocytes—cells that create insulation for the nerves of the central nervous system—long before the first physical symptoms of the disease appeared. Oligodendrocytes located near motor neurons—cells that govern movement—died off at very high rates, and new ones regenerated in their place were inferior and unhealthy.

The researchers also found, to their surprise, that suppressing an ALS-causing gene in oligodendrocytes of mice bred with the disease—while still allowing the gene to remain in the motor neurons—profoundly delayed the onset of ALS. It also prolonged survival of these mice by more than three months, a long time in the life span of a mouse. These observations suggest that oligodendrocytes play a very significant role in the early stage of the disease.

johns_hopkins_medicine

“The abnormalities in oligodendrocytes appear to be having a negative impact on the survival of motor neurons,” says Dwight E. Bergles, Ph.D., a co-author and a professor of neuroscience at the Johns Hopkins University School of Medicine. “The motor neurons seem to be dependent on healthy oligodendrocytes for survival, something we didn’t appreciate before.”

“These findings teach us that cells we never thought had a role in ALS not only are involved but also clearly contribute to the onset of the disease,” says co-author Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology at Johns Hopkins and director of the Johns Hopkins Medicine Brain Science Institute.

Scientists have long believed that oligodendrocytes functioned only as structural elements of the central nervous system. They wrap around nerves, making up the myelin sheath that provides the “insulation” that allows nerve signals to be transmitted rapidly and efficiently. However, Rothstein and others recently discovered that oligodendrocytes also deliver essential nutrients to neurons, and that most neurons need this support to survive.

The Johns Hopkins team of Bergles and Rothstein published a paper in 2010 that described in mice with ALS an unexpected massive proliferation of oligodendrocyte progenitor cells in the spinal cord’s motor neurons, and that these progenitors were being mobilized to make new oligodendrocytes. The researchers believed that these cells were multiplying because of an injury to oligodendrocytes, but they weren’t sure what was happening. Using a genetic method of tracking the fate of oligodendrocytes, in the new study, the researchers found that cells present in young mice with ALS were dying off at an increasing rate in concert with advancing disease. Moreover, the development of the newly formed oligodendrocytes was stalled and they were not able to provide motor neurons with a needed source of cell nutrients.

To determine whether the changes to the oligodendrocytes were just a side effect of the death of motor neurons, the scientists used a poison to kill motor neurons in the ALS mice and found no response from the progenitors, suggesting, says Rothstein, that it is the mutant ALS gene that is damaging oligodendrocytes directly.

Meanwhile, in separate experiments, the researchers found similar changes in samples of tissues from the brains of 35 people who died of ALS. Rothstein says it may be possible to see those changes early on in the disease and use MRI technology to follow progression.

“If our research is confirmed, perhaps we can start looking at ALS patients in a different way, looking for damage to oligodendrocytes as a marker for disease progression,” Rothstein says. “This could not only lead to new treatment targets but also help us to monitor whether the treatments we offer are actually working.”

ALS, also known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, affects nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary.

There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival.

Even though myelin loss has not previously been thought to occur in the gray matter, a region in the brain where neurons process information, the researchers in the new study found in ALS patients a significant loss of myelin in one of every three samples of human tissue taken from the brain’s gray matter, suggesting that the oligodendrocytes were abnormal. It isn’t clear if the oligodendrocytes that form this myelin in the gray matter play a different role than in white matter—the region in the brain where signals are relayed.

The findings further suggest that clues to the treatment of other diseases long believed to be focused in the brain’s gray matter—such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease—may be informed by studies of diseases of the white matter, such as multiple sclerosis (MS). Bergles says ALS and MS researchers never really thought their diseases had much in common before.

Oligodendrocytes have been under intense scrutiny in MS, Bergles says. In MS, the disease over time can transform from a remitting-relapsing form—in which myelin is attacked but then is regenerated when existing progenitors create new oligodendrocytes to re-form myelin—to a more chronic stage in which oligodendrocytes are no longer regenerated. MS researchers are working to identify new ways to induce the creation of new oligodendrocytes and improve their survival. “It’s possible that we may be able to dovetail with some of the same therapeutics to slow the progression of ALS,” Bergles says.

Other Johns Hopkins researchers involved in the study include Shin H. Kang, Ph.D.; Ying Li, Ph.D.; Ileana Lorenzini, M.S.; and Lyle Ostrow, M.D., Ph.D.

This research was supported by grants from the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NS 051509), the ALS Association, P2ALS, the Robert Packard Center for ALS Research at Johns Hopkins and the Brain Science Institute.

SOURCE: John Hopkins Medicine

Media Contact:

Stephanie Desmon
410-955-8665
sdesmon1@jhmi.edu

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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 Inc. Announces Initiation of First-Time-in-Humans, Phase I Clinical Trial of CK-2127107

SAN FRANSCISCO, California, April 1, 2013 – Cytokinetics, Incorporated announced today the initiation of a first-time-in-humans, Phase I clinical trial of CK-2127107 in healthy male volunteers. Cytokinetics is developing CK-2127107, a novel small molecule activator of the fast skeletal muscle troponin complex, for the potential improvement of skeletal muscle function in diseases and medical conditions associated with neuromuscular dysfunction, muscular weakness, and/or muscle fatigue. Like tirasemtiv, the lead drug candidate from the company’s skeletal muscle activator program, CK-2127107 slows the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers, which sensitizes the sarcomere to calcium.

CK-2127107 was discovered in connection with Cytokinetics’ optimization of a different chemical series than that which produced tirasemtiv, which is currently being evaluated in BENEFIT-ALS (Blinded Evaluation of Neuromuscular Effects and Functional Improvement with Tirasemtiv in ALS). BENEFIT-ALS is an international, double-blind, randomized, placebo-controlled, Phase IIb clinical trial designed to evaluate the safety, tolerability and potential efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis (ALS). Advancing CK-2127107 to Phase I evaluation in healthy subjects is consistent with Cytokinetics’ corporate strategy to characterize a potential back-up compound to tirasemtiv in humans and to enable the evaluation of fast skeletal muscle troponin activation in a potentially broader set of clinical indications.

The Phase I clinical trial of CK-2127107 is a double-blind, randomized, placebo-controlled study designed to assess the safety, tolerability, and pharmacokinetics of single ascending oral doses of CK-2127107 administered to healthy adult males in a three period, escalating dose, crossover design. The primary objective of this study is to determine the safety and tolerability of single doses of CK-2127107 administered orally to healthy male volunteers. The secondary objective is to evaluate the pharmacokinetic profile of single doses of CK-2127107.

“This first-time-in-humans clinical trial of CK-2127107 builds on our expertise in the biology of skeletal muscle function,” stated Fady Malik, MD, PhD, Cytokinetics’ Senior Vice President, Research and Early Development. “Advancing CK-2127107 provides us an opportunity to develop a pipeline of drug candidates focused on skeletal muscle weakness resulting from an array of diseases associated with muscle wasting or primary neuromuscular dysfunction.”

“The initiation of this Phase I clinical trial is further demonstration of Cytokinetics’ commitment to build a portfolio of drug candidates with novel mechanisms that leverage our expertise in the biology of the cytoskeleton and our pioneering pharmacology associated with muscle contractility,” stated Robert I. Blum, Cytokinetics’ President and CEO. “CK-2127107 is the sixth novel chemical entity that has arisen from our research and development activities to proceed to human clinical testing.”

Background on Fast Skeletal Muscle Activators

Skeletal muscle contractility is driven by the sarcomere, the fundamental unit of skeletal muscle contraction. It is a highly ordered cytoskeletal structure composed of several key proteins. The first, skeletal muscle myosin, is the cytoskeletal motor protein that converts chemical energy into mechanical force through its interaction with a second protein, actin. A set of regulatory proteins, which includes tropomyosin and several types of troponin, make the actin-myosin interaction dependent on changes in intracellular calcium levels. Cytokinetics’ skeletal muscle contractility program is focused to the discovery and development of small molecule skeletal sarcomere activators and leverages Cytokinetics’ expertise gained from its ongoing discovery and development of cardiac sarcomere activators, including the cardiac myosin activator omecamtiv mecarbil, now in Phase IIb clinical development as a potential treatment for heart failure. In non-clinical models, skeletal sarcomere activators have demonstrated pharmacological activity that may lead to new therapeutic options for diseases associated with aging, muscle wasting, and neuromuscular dysfunction. The clinical effects of muscle wasting, fatigue and loss of mobility can range from decreased quality of life to, in some instances, life-threatening complications. By directly improving skeletal muscle function, a small molecule activator of the skeletal sarcomere may potentially enhance physical performance and quality of life in patients with conditions marked by muscle weakness, including neuromuscular diseases such as ALS, myasthenia gravis, cachexia, sarcopenia and general frailty associated with aging.

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 (excluding Japan) to develop and commercialize omecamtiv mecarbil and related compounds, subject to Cytokinetics’ specified development and commercialization participation rights. Cytokinetics is independently developing tirasemtiv and CK-2127107, both fast skeletal muscle activators, as potential treatments for diseases and medical conditions associated with aging, muscle wasting or 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 in which treatment with tirasemtiv produced potentially clinically relevant pharmacodynamic effects in Phase II trials. 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.

This press release contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the “Act”). Cytokinetics disclaims any intent or obligation to update these forward-looking statements, and claims the protection of the Act’s Safe Harbor for forward-looking statements. Examples of such statements include, but are not limited to, statements relating to Cytokinetics’ research and development activities, including the conduct, design and results of clinical trials, the significance and utility of clinical trial results, and the properties and potential benefits of Cytokinetics’ skeletal muscle activators, including tirasemtiv and CK-2127107, and other drug candidates. Such statements are based on management’s current expectations, but actual results may differ materially due to various risks and uncertainties, including, but not limited to, Cytokinetics anticipates that it will be required to conduct at least one confirmatory Phase III clinical trial of tirasemtiv in ALS patients which will require significant additional funding, and it may be unable to obtain such additional funding on acceptable terms, if at all; potential difficulties or delays in the development, testing, regulatory approvals for trial commencement, progression or product sale or manufacturing, or production of Cytokinetics’ drug candidates that could slow or prevent clinical development or product approval, including risks that current and past results of clinical trials or preclinical studies may not be indicative of future clinical trials results, patient enrollment for or conduct of clinical trials may be difficult or delayed, Cytokinetics’ drug candidates may have adverse side effects or inadequate therapeutic efficacy, the U.S. Food and Drug Administration or foreign regulatory agencies may delay or limit Cytokinetics’ or its partners’ ability to conduct clinical trials, and Cytokinetics may be unable to obtain or maintain patent or trade secret protection for its intellectual property; Amgen’s decisions with respect to the design, initiation, conduct, timing and continuation of development activities for omecamtiv mecarbil; Cytokinetics may incur unanticipated research and development and other costs or be unable to obtain additional financing necessary to conduct development of its products; Cytokinetics may be unable to enter into future collaboration agreements for its drug candidates and programs on acceptable terms, if at all; standards of care may change, rendering Cytokinetics’ drug candidates obsolete; competitive products or alternative therapies may be developed by others for the treatment of indications Cytokinetics’ drug candidates and potential drug candidates may target; and risks and uncertainties relating to the timing and receipt of payments from its partners, including milestones and royalties on future potential product sales under Cytokinetics’ collaboration agreements with such partners. For further information regarding these and other risks related to Cytokinetics’ business, investors should consult Cytokinetics’ filings with the Securities and Exchange Commission.

Contact:

Joanna L. Goldstein

Manager, Corporate Communications & Marketing

(650) 624-3000

Source: Cytokinetics, Inc. via Thomson Reuters ONE

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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.