Clinical Research in ALS: CRiALS

There is an enormous need for a better understanding of the clinical, demographic, and  genetic features that underlie the phenotypic variability of ALS. Indeed, it may be more  accurate to define ALS as a “syndrome” defined by the commonality of clinical features  and progression. The syndrome of ALS may encompass a number disease mechanisms  that will require different approaches for therapeutic intervention, and one could hypothesize  that our failures in clinical trials for ALS are due to the inclusion of multiple disease types,  some of which are not responsive to the experimental drug under investigation. Thus, we  need to better understand whether multiple mechanisms of ALS truly exist, and to do that we  need to better define the disease by documenting phenotypes along with genetic, serologic,  and physiological features of disease. This improved categorization of disease will result in  the definition of specific disease features that will allow for clinical trials targeting specific  disease mechanisms. The CRiALS project, supported by MDA funding, has generated a  world-class clinical database and biobank for use locally, nationally, and internationally for  discovery research focused on better defining the mechanisms of ALS, which will lead to  drug targets and directed therapeutics.

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Grantee: Jonathan Glass M.D.

Grant type: Restricted Research Grant

Award total: $130,966

Institution: Emory University

Country: USA

Silence ALS: a platform for the development of individualized ASOs

ALS is a fatal neurodegenerative disease that affects tens of thousands of Americans. Therapeutic options for ALS patients remain severely limited, but for the ~15% of ALS patients with a disease-causing mutation, gene-based approaches – including gene silencing with antisense oligonucleotides (ASOs) – offer a promising strategy to target the primary mechanisms responsible for neurodegeneration.  Industry-sponsored efforts focused on ALS caused by C9orf72, SOD1 and FUS mutations are ongoing, offering hope to the majority of ALS patients and families with genetic forms of the disease.  Silence ALS is a partnership between Columbia University and the n-Lorem Foundation that aims to extend these gene-based therapeutic strategies to ALS patients with ultra-rare mutations, expanding access to this powerful technology through a non-profit, precision medicine initiative. Initial efforts have focused on symptomatic individuals, however, through the ALS Families Project at Columbia – a longitudinal study of pre-symptomatic carriers of ALS gene mutations - we will design and develop personalized ASO therapeutics for individuals at risk, with the goal of initiating treatment as early as possible after disease onset, and ideally, before the first signs or symptoms of the disease appear to delay if not prevent disease onset and progression.

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Grantee: Neil Shneider M.D., Ph.D.

Grant type: Restricted Research Grant

Award total: $119,757.00

Institution: The Trustees of Columbia University in the City of New York

Country: USA

Development of next-generation therapies for Duchenne muscular dystrophy

Duchenne muscular dystrophy is a severe muscle disorder caused by genetic abnormalities which affect the normal production of a functional molecule, called dystrophin. One way to remediate this situation is to introduce correct copies of dystrophin into the affected muscles using a biological carrier. This technique is named gene replacement. Among the numerous agents developed in medical research, Adeno-associated viral vectors (AAV) are found to be the most efficient gene carriers. However, these vectors present a limited cargo capacity and are unable to transport large genes like dystrophin. Here, we present a new method in which we split the dystrophin gene into multiple fragments transportable by AAV. Once in the cell, these fragments are reassembled into a functional protein using molecules called inteins. This method can be used to replace any gene larger than what an AAV vector can accommodate and could have a broad application.

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Grantee: Hichem Tasfaout, PhD

Grant type: Development Grant

Award total: $210,000.00

Institution: University of Washington

Country: USA

Stem Cell Targeting in Duchenne Muscular Dystrophy

Correcting genetic defects within the endogenous muscle SCs could provide a long-term therapy for muscle disorders with potential to repair a patient’s muscles over his/her lifetime. Although a number of studies have now shown muscle SC targeting is feasible using AAV, the efficiency is low, and it is still not known if these studies efficiently targeted quiescent muscle SCs and if there are any associated toxicities after transduction that prevent their ability to continuously restore dystrophin after multiple rounds of injury. This work will perform a careful evaluation of AAV toxicities in stem cells (Aim 1) and functionality after targeting (Aim 2) using conventional (AAV9) and novel AAV stem cell targeting variants.

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Grantee: April Pyle, PhD

Grant type: Research Grant

Award total: $300,000.00

Institution: The Regents of the University of California, Los Angeles

Country: USA

microRNA as biomarkers for phenoconversion in pre familial ALS

Amyotrophic lateral sclerosis (ALS) is severe neurodegenerative condition of the human motor neuron system. Some cases of ALS are associated with genetic mutations, but it is not known whether, or at what age, individuals carrying these mutations will manifest the symptoms of the disease, as they remain without symptoms for many years. If there were blood tests of patient condition, they could have been tremendously helpful in answering these questions. However, today there are no such blood tests.The Hornstein lab at Weizmann Institute of Science innovate blood tests for ALS. We use groundbreaking technologies for measuring RNA in the bloodstream, as new means to predict disease severity. The RNA markers that we offer to develop in this program will take our technology one step further and may provide a new panel of non-invasive tools for disease characterization, enhance basic research of disease and facilitate drug development.

Partial funding for this grant comes from AFM Telethon.

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Grantee: Eran Hornstein MD, PhD

Grant type: Research Grant

Award total: $300,000

Institution: Weizmann Institute of Science

Country: Israel

Single-cell Multiomic analysis of cellular and epigenetic dynamics in EDMD

Laminopathies are a large group of human degenerative disease, of which the most common involve heart and muscles. Despite varying in terms of symptoms these disorders are caused by defects in two closely related protein called Lamin A and C that are normally associated with nuclear membrane of cells. How the loss of these proteins leads to the development of muscular degeneration or affects the heart is not completely understood. It is known however that affected cells display different degrees of abnormalities in their nuclear shape. Overall, destabilization of nuclear membrane could impact how DNA is packed and accessed which, in turn, influences which genes are expressed. These proteins are found in most cell types in the human body and so, in principle, each of these cell types could be impacted. Here we focus on their potential role in muscle loss and on how the mutual interaction of different cell types are altered in this context. To do so we propose to use a new strategy that combines different layers of information: gene expression, imaging and DNA accessibility and is capable of study all the different cell type simultaneously. This new approach will enable us to and correlate the different nuclear abnormalities with their potential correlation with gene expression to better understand the steps that leads from the genetic mutation to the outcome of the disease.

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Grantee: Lorenzo Giordani, PhD

Grant type: Research Grant

Award total: $299,573.00

Institution: Sorbonne Université-Inserm UMRS974

Country: France

HEALEY ALS Platform Trial

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease for which there is no cure yet. Recent discoveries in ALS research are generating a rich pipeline of promising drugs that await testing in clinical trials, and new hope that effective treatments may be within reach.

The Healey & AMG Center at Massachusetts General Hospital, in partnership with the Northeast ALS Consortium, launched the HEALEY ALS Platform Trial in 2020. The study team focused on developing a patient-centric trial to 1) support and empower the ALS community; 2) accelerate drug development by testing multiple drugs simultaneously; and 3) advance scientific knowledge through testing of novel biomarkers that can provide answers more rapidly than traditional endpoints.

Now that we have established an efficient and robust platform trial for people living with ALS, we are at a turning point to capitalize upon what we have learned from the trial so far, share our data and resources with the ALS and other disease communities, and adapt the trial for even greater efficiency.

With MDA’s continued support, we propose to 1) accelerate ALS scientific knowledge and drug development through biomarker research; 2) enhance patient outreach and recruitment through collaboration with MDA Care Centers and MOVR; and 3) engage with the FDA to adapt the trial based on previous experience and share our learnings with the community. Robust collaboration with MDA will be critical to achieve such goals.

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Grantee: Sabrina Paganoni MD, PhD

Grant type: Clinical Research Grant

Award total: $500,000.00

Institution: Massachusetts General Hospital (Mass General)

Country: USA

Novel type of monogenic diabetes in patients with Welander distal myopathy

Hitherto unknown clinical findings show that patients with Welander distal myopathy (WDM), a dominantly inherited muscular disease, may be at increased risk of getting diabetes of an atypical form. WDM is caused by a mutation in TIA1, a key link to failure of insulin-producing cells in diabetes. AIM We will determine whether WDM patients have increased risk of diabetes and explore the causes and possibilities for treatment and prevention. METHODOLOGY Patients will drink a concentrated sugar solution on a single occasion. Blood samples are then collected on different time points over 2 hours for analyses of blood sugar and hormones. The results will be compared to relatives without WDM. Our PRELIMINARY RESULTS show that >30% of WDM patients have diagnosed diabetes, which is far more than expected and previously unknown. This overrepresentation of diabetes suggests that WDM and diabetes may have similar causes. The WDM TIA1 mutation causes loss of insulin production, promoting diabetes, an event prevented by the diabetes drug liraglutide. SIGNIFICANCE The diabetes in WDM patients may be a novel form of diabetes caused by their TIA1 mutation. The events causing diabetes in WDM patients may be possible to treat or prevent by already approved antidiabetic drugs (liraglutide). Beneficial effects of such drugs against muscular disease in humans have been recently reported. Additionally, the FDA has approved use of such a drug against muscular dystrophy.

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Grantee: Ake Sjoholm MD, PhD

Grant type: Research Grant

Award total: $94,414.00

Institution: Region Gavleborg

Country: Sweden

The role of cholesterol metabolism abnormalities in Coenzyme Q deficiency

Coenzyme Q is a lipid present in all cell membranes and involved in many biological functions, including energy production in the mitochondria. Defects in the making of CoQ cause Primary CoQ deficiencies, which often manifest in infancy or childhood with involvement of several organs, including kidney, brain, and heart. We studied CoQ-deficient kidney disease for many years and showed that defect in energy production is not the only mechanism responsible for kidney failure. In this application, we propose a novel mechanism of disease responsible for brain and heart diseases in CoQ deficiency. Since CoQ is produced through the same pathway that produces cholesterol and the two branches are co-regulated, we aim to establish the role of alterations in cholesterol metabolism in the demise of brain and heart in the contest of CoQ deficiency, using a novel mouse model that partially reproduces the human disease, and heart and brain cells derived from patients skin fibroblasts. The ultimate goal is to discover potential therapeutic targets for CoQ deficiency and other diseases where low CoQ has been found. In fact, patients often do not respond to CoQ supplementation because CoQ does not accumulate effectvely in tissues.

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Grantee: Catarina Quinzii, MD

Grant type: Research Grant

Award total: $300,000.00

Institution: Columbia University Irving Medical Center

Country: USA

Investigating mechanistic drivers of MuSK autoimmunity

Myasthenia gravis (MG) is a rare neurological disease characterized by muscle weakness. This disease is caused by antibodies that bind to specific proteins expressed on muscle cells, blocking the communication between nerves and muscles. In a subset of patients, such antibodies recognize a protein called muscle-specific tyrosine kinase (MuSK). In MuSK MG, muscle weakness is typically severe, and most patients experience difficulty breathing, swallowing, and talking. Importantly, these symptoms respond well to rituximab, a medication that reduces the number of white blood cells producing anti-MuSK antibodies. Following rituximab, most patients show no symptoms for several months. But despite such striking improvements, the disease eventually reappears, requiring hospitalization and additional treatments. Researchers have discovered the precise mechanism through which anti-MuSK antibodies cause muscle weakness. These advances notwithstanding, there remain unknowns about the cause and persistence of the disease, hindering a definitive cure. Our project will investigate which factors contribute to the chronic course of MuSK MG. First, we will study the cells that cause the disease and how they mature to produce the antibodies. Second, we will examine whether gut bacteria can mimic MuSK and increase the production of anti-MuSK antibodies, a process known as “molecular mimicry”. Our research is designed to provide new insights that could lead to better treatments for MuSK MG.

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Grantee: Gianvito Masi, MD

Grant type: Development Grant

Award total: $207,815.00

Institution: Yale University

Country: USA

Novel approaches for understanding and preventing AAV non-muscle toxicity

Gene therapy is an exciting therapeutic approach that holds great promise for the treatment of a number of neuromuscular conditions. The success of the spinal muscular atrophy gene therapy program demonstrates the potential for this treatment. However, in the SMA program, as well as in several gene therapy programs currently in clinical trial, liver related toxicity has been a serious occurrence. In fact, two patients have died of liver failure after receiving SMA gene therapy, and 4 patients have died in the X-linked myotubular myopathy trial. This speaks to the severity and importance of the problem of gene therapy related liver toxicity. At present, there is an incomplete understanding of how and why AAV mediated gene therapy causes liver problems, and there are no adequate treatments. A critical barrier to studying this has been the fact that mouse models have not shown any significant liver injury after AAV exposure. We have overcome this barrier by developing a novel diet paradigm, wherein exposure of mice to a more human like diet sensitizes them to developing liver toxicity after AAV exposure. Using this approach, we can now study liver injury in response to gene therapy, and identify strategies to prevent it. The goals of this proposal are to: (1) define the changes that occur over time in the liver after exposure to AAV; (2) determine if these changes are the same for all AAVs and transgenes; and (3) test strategies to prevent liver inflammation or AAV liver entry.

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Grantee: James Dowling MD, PhD

Grant type: Research Grant

Award total: $300,000

Institution: The Hospital for Sick Children

Country: Canada

Aberrant mt-mRNA folding as mediator of mitochondrial encephalomyopaties

Mitochondrial diseases are disorders that affect how our cells produce energy. They are most common in children and frequently lead to problems in the brain and heart. We want to study two specific genes that are linked to these diseases: ATP6 and ATP8. Such genes provide the instructions for making the energetic system of the cell. However, the exact way these genes work is not fully understood. We want to use new techniques to study how the genes are used to make proteins. We believe that a special process might be responsible for making sure the proteins are produced in the right amount. We also believe that understanding such process would explain the disease. Knowing how the disease works will help us find new ways to treat these conditions in the future.

Partial funding for this grant comes from AFM Telethon.

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Grantee: Michele Brischigliaro, PhD

Grant type: Development Grant

Award total: $210,000

Institution: Miller School of Medicine of the University of Miami

Country: USA