Innovations in Science
Paired Prime Editors to treat Friedreich’s Ataxia
Prime editing (PE), a novel type of gene editing, represents a promising therapeutic approach for FA because it addresses its root cause, the removal of the GAA expansions in the FXN gene. The advantage of gene editing approaches over gene therapy for FA is that, upon removal of the GAA repeats, the edited FXN gene will still be under the control of its natural regulator, thus alleviating concerns about the overexpression of frataxin and associated toxicity. This multi-disciplinary team of investigators will test several novel PE tools, comparing their efficacy and specificity. The aim is to demonstrate robust and specific GAA repeat removal from the FXN gene in human FA cells. One approach, PRIME–Del, uses an editing tool in which only one strand of the DNA is cut. This may reduce efficiency but will also reduce unwanted edits in the DNA (off targets). PE-Cas9-based deletion and repair (PEDAR) uses an editing tool that cuts both strands of the DNA, which may prove to be more efficient but has the safety liability of inversions and deletions in the DNA. One liability of PE is that it requires a machinery that is very large and doesn’t fit in AAV, the viral system used to deliver genetic medicines to tissues. Therefore, the investigators have devised a system in which two halves (split editors) of the gene editing machinery are delivered separately. By comparing efficiency and specificity of these different approaches the team will be able to identify an editing tool with the optimal combination of high efficiency of editing and reduced rate of off-targets in the genome.
Co-funded with Friedreich's Ataxia Research Alliance.
Grantee: Jonathan Watts, PhD
Grant type: Research Grant
Award total: $125,000.00
Institution: University of Massachusetts Chan Medical School
Country: USA
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.
Digital Object Identifier (DOI)
Grantee: Jonathan Glass, MD
Grant type: Restricted Research Grant
Award total: $105,515.00
Institution: Emory University
Country: USA
A Comprehensive Database for RYR1-Related Disorders
The RYR1 gene encodes the largest ion channel in humans, RyR1. Pathogenic RYR1 variants cause a wide spectrum of rare, slowly progressive, neuromuscular disorders with different pathologic mechanisms that result in intracellular calcium dysregulation. A subset of RYR1 variants are also linked to malignant hyperthermia susceptibility. There is no approved treatment for RYR1-RD. Over 2000 RYR1 variants have been reported yet most are classified as "variants of uncertain significance". We therefore developed two datasets as the foundation for a dedicated RYR1 database: (1) Clinical dataset comprising published genotype-phenotype data on over 2500 patients. Key data elements: clinical diagnosis, mode of inheritance, ClinVar and gnomAD entries, a detailed multi-system profile of clinical manifestations, histopathology, demographics, contracture test results, and ACMG pathogenicity classifications. (2) Nonclinical dataset comprising analyses on more than 250 unique RYR1 variants published over the past 30 years across 16 model systems. Key data elements: variant mapping to the 3D RyR1 structure, predictive bioinformatic analyses, and functional analyses from model systems. Overall goal: To launch a comprehensive publicly available online database to support clinical trial readiness, facilitate collaboration, and enhance understanding of RYR1-RD for patients, researchers, and medical professionals.
Partial funding for this grant comes from the RYR-1 Foundation.
Digital Object Identifier (DOI)
Grantee: Joshua Todd, PhD
Grant type: Infrastructure Grant
Award total: $294,670.00
Institution: National Institute of Neurological Disorders and Stroke, NIH NINDS
Country: USA
Quantifying Gait Velocity with the ActiMyo Wearable Devices in ALS
ALS trials depend on quantifiable measures of function to detect if an experimental therapy is working. Current ALS outcomes, like the ALS Functional Rating Scale – Revised (ALSFRS-R) and vital capacity, are collected in clinic and thus are recorded infrequently and yield small trial datasets. Advances in machine learning and artificial intelligence are revolutionizing medicine but require large datasets. Mobile apps and wearable sensors can collect large datasets about daily function while participants do very little except wear a device or answer questions on a mobile app. The ActiMyo device is a wearable sensor for the ankle and wrist that collects information regarding movement of the limbs. Algorithms calculate activity and walking metrics – specifically the 95th percentile stride velocity (SV95C), which regulators have accepted as a trial endpoint in muscular dystrophy. The Beiwe smartphone app obtains activity data and delivers questionnaires to evaluate the effect of ALS on people’s daily life. We will conduct a 12-month study of 30 participants with ALS wearing the ActiMyo device and using the Beiwe smartphone app to compare the SV95C and other digital outcome measures to traditional in-clinic ALS trial outcome measures, including the ALSFRS-R. Our goal is to collect more data, more rapidly and more easily to hasten ALS drug development. Specifically, we will confirm the utility of the SV95C and other digital features of movement as trial endpoints in ALS.
Digital Object Identifier (DOI)
Grantee: James Berry, M.D.
Grant type: Research Grant
Award total: $200,000.00
Institution: Massachusetts General Hospital (Mass General)
Country: United States
Mechanisms of fatty liver disease and impaired drug metabolism in DM1
Myotonic Dystrophy type 1 (DM1) is a multi-systemic neuromuscular disorder affecting 1 in 3000 people. Much of the focus in DM1 research has been on the effects within the muscle and neurological tissues. However, DM1 patients also suffer from increased levels of various metabolic and liver-specific symptoms, such as non-alcoholic fatty liver disease, metabolic syndrome, and liver damage. Additionally, DM1 patients are abnormally sensitive to a wide range of analgesics and muscle relaxants, resulting in prolonged anesthesia recovery, heightened pulmonary dysfunction, and in some cases, death. So far, these symptoms have been attributed to the disruption of neurological and muscular functions associated with DM1 but could also be explained by the malfunctioning of the liver, a major site for nutrient and drug metabolism. This proposal aims to understand the precise effects of DM1 on the liver; determine to what extent DM1 diseased livers exhibit susceptibility to risks from lifestyle choices such as diet and drugs; and investigate how the interference with MBNL activity causes metabolic and drug clearance pathologies which can jeopardize the health of DM1 patients and complicate their treatment.
Digital Object Identifier (DOI)
Grantee: Auinash Kalsotra PhD
Grant type: Research Grant
Award total: $300,000.00
Institution: The Board of Trustees of the University of Illinois Urbana-Champaign
Country: United States
Clinical Research in ALS (CRiALS): A comprehensive resource for human research
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.
Grantee: Jonathan Glass, MD
Grant type: Restricted Research Grant
Award total: $154,797.00
Institution: Emory University
Country: United States
Clinical Study of Anti-AAV Antibody Depletion using Efgartigimod alfa-fcab in Boys with DMD Prior to and Following AAV Gene Therapy
Study objectives:
Assessment of the safety and efficacy of intravenous administration of VYVGART in a two-arm study to lower anti-adeno associated virus (AAV) antibody titers in boys with Duchenne muscular dystrophy (DMD) with both pre-existing antibody and previous exposure to AAV in another therapeutic study.
Primary: Explore the ability of VYVGART? to lower anti-AAV capsid antibody pre and post exposure to AAV.
Secondary: Determine the safety and tolerability of VYVGART? in boys with Duchenne muscular dystrophy.
Digital Object Identifier (DOI)
Grantee: Barry Byrne M.D., Ph.D.
Grant type: Clinical Research Grant
Award total: $100,000.00
Institution: University of Florida
Country: United States
Astrocyte-microglia crosstalk in C9orf72 ALS/FTD
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now recognized as a spectrum disease with approximately 50% of ALS patients exhibiting cognitive impairments and about 15% of FTD patients developing motor deficits. Most studies aimed at elucidating mechanisms of cognitive impairments in this spectrum disease focused on disease mechanisms of neuronal cells in the brain, while non-neuronal cells, so called glial cells, have been largely ignored and overlooked. The development of induced pluripotent stem cell (iPSC) technologies has facilitated the generation of disease models for ALS/FTD. This technology allows us to create a ‘brain in a dish’, which consists of patient-derived iPSCs converted into brain-like cells. To better understand how patients with C9orf72 ALS/FTD, the most prevalent genetic mutation leading to this disease spectrum, develop cognitive impairments and most importantly, how we can provide specific treatments for these patients, we propose to focus our studies on glial cell-to-cell communication and regulation using iPSCs derived from C9orf72 ALS-FTD patients. In specific, we aim to study how astrocytes and microglia, two distinct glial cell types in the brain, co-regulate each other using molecular and cellular techniques. We will also test how this regulation impacts neuronal function, but most importantly, how this glia-glia co-regulation goes rouge during disease and contributes to neuronal dysfunction in C9orf72 ALS/FTD.
Digital Object Identifier (DOI)
Grantee: Rita Sattler, Ph.D.
Grant type: Research Grant
Award total: $300,000.00
Institution: Dignity Health dba St. Joseph's Hospital & Medical Center, Phoenix, AZ
Country: United States
Seizure susceptibility in congenital muscular dystrophies
Dystroglycanopathy is a form of congenital muscular dystrophy that occurs due to defective function of the protein Dystroglycan. Most cases of dystroglycanopathy arise from mutations in one of 19 genes that are required for the synthesis of sugar chains present on Dystroglycan. These sugar chains are required for Dystroglycan's function, and mediate its binding to other proteins. In addition to muscular dystrophy, patients with dystroglycanopathy can also present with a wide range of neurological symptoms, depending on the nature of the specific genetic mutation. On the severe end, this can manifest as widespread brain abnormalities that can be easily detected by MRI, whereas patients with milder dystroglycanopathy may present with cognitive deficits even when brain scans are normal. Dystroglycanopathy patients also have an elevated risk of seizures. Recent studies using mouse models of dystroglycanopathy have identified a new role for Dystroglycan in regulating the formation and function of inhibitory synapses in the brain. Similar to human patients, these mouse models are more susceptible to seizures, and this scales with the severity of the loss of Dystroglycan function. We propose to use whole brain activity mapping to determine how these seizures progress in two of these mouse models, and test whether gene therapy approaches can correct synaptic defects and reduce seizure susceptibility.
Digital Object Identifier (DOI)
Grantee: Kevin Wright, Ph.D.
Grant type: Research Grant
Award total: $299,974.00
Institution: Oregon Health & Science University - OHSU
Country: United States
A novel RNA treatment for Amyotrophic lateral sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a progressive condition affecting the nerves supplying muscles (motor neurons), resulting in weakness, paralysis, and death. ALS is surprisingly common, occurring in ~1:400 individuals, with no effective treatment options existing. One of the first pathological processes occurring in ALS is the disruption of the meeting point of the neuron and the muscle— the neuromuscular junction (NMJ). Based on previous data from our laboratory, we propose that a small RNA molecule called miR126-5P can regulate several biochemical pathways that are essential to maintain the NMJ. This novel target is usually highly expressed in motor neurons and muscles, protecting against toxic signals. In ALS models, it is decreased. We suggest that elevation of miR126 levels will restore motor neuron axons, muscle contraction and prevent paralysis in ALS. To test this hypothesis, we will over-express miR126 both in ALS mice and unique patients NMJ cellular models and track neuron function and survival. We will also evaluate the specific effects of miR126 on ALS-related gene expression. If successful, these studies will not only deepen our understanding of ALS; they will also greatly facilitate the development of RNA-based therapies for ALS and related conditions.
Grantee: Eran Perlson, Ph.D
Grant type: Research Grant
Award total: $299,000.00
Institution: Tel Aviv University
Country: Israel
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