Amyotrophic lateral sclerosis (ALS) patients develop fatal paralysis as a result of progressive motor neuron loss in the brain and spinal cord. There are more than 5, 000 new cases of ALS per year in the United States, with typical age of onset between 40 and 70 years of age. While SOD1 is a cytoplasmic protein, misfolded SOD1 can be secreted and form extracellular oligomers and aggregates. Mutations in superoxide dismutase-1 (mSOD1) result in misfolding and aggregation of SOD1 and are found in a subset of familial ALS cases. However, misfolded SOD1 has also been identified in spinal cord samples from many sporadic cases of ALS. Regulatory T cells (Tregs) have tolerogenic and anti-inflammatory functions and are being pursued as cell-based therapeutics to block auto-inflammatory immune cells. Higher numbers of Tregs (CD4+CD25hiCD127lo) in ALS patients are associated with a slower disease progression. We have developed novel chimeric antigen receptors (CARs) that recognize aggregated SOD1 and trigger Treg function. In this manner, we aim to provide a large number of Tregs that are specific for a disease-associated protein and will become activated at the site of misfolded, aggregated SOD1. We have further enhanced the activity of CAR Tregs by engineering them to produce BNDF, a key neuronal survival factor. We have developed a novel mouse model for ALS by breeding the G93A SOD1 transgene onto the NSG mouse background to create mSOD1-NSG mice. These mice allow the engraftment of human cells and they develop a progressive disease resulting in inflammation in the spinal cord and limb paralysis that mimic findings in ALS. The aim of this project is to perform IND-enabling studies required for translation of this therapy into the clinic.
Public Health Relevance Statement: PROJECT NARRATIVE Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that affects nerve cells in the brain and spinal cord causing loss of muscle control; ALS currently lacks effective options of treatment. Increased neuroinflammation is an important contributor to the progression of ALS which makes it an attractive therapeutic target. Our goal in this Fast Track application is to develop our novel CAR Treg therapeutic, CM-CS1, to reduce inflammation and damage to neurons in ALS, thus preventing disease progression and protecting neuronal survival and function.
Project Terms: Affect; AD dementia; Alzheimer Type Dementia; Alzheimer disease dementia; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimers Dementia; Primary Senile Degenerative Dementia; primary degenerative dementia; senile dementia of the Alzheimer type; Alzheimer's Disease; Amyotrophic Lateral Sclerosis Motor Neuron Disease; Gehrig's Disease; Lou Gehrig Disease; Amyotrophic Lateral Sclerosis; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anti-Inflammatory Agents; immunogen; Antigens; Blood - brain barrier anatomy; Blood-Brain Barrier; Hemato-Encephalic Barrier; bloodbrain barrier; Brain; Brain Nervous System; Encephalon; Breeding; Cell physiology; Cell Function; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Subcellular Process; Cells; Cell Body; Communities; Diagnosis; Disease; Disorder; Engineering; Limb structure; Extremities; Limbs; Non-Trunk; Genetic Engineering; Genetic Engineering Biotechnology; Genetic Engineering Molecular Biology; Recombinant DNA Technology; genetically engineered; Goals; Heredity; Homeostasis; Autoregulation; Physiological Homeostasis; Human; Modern Man; Incidence; Inflammation; Macrophage; MÏ; Motor Neurons; Motor Cell; motoneuron; Mus; Mice; Mice Mammals; Murine; Muscular Atrophy; Muscle Atrophy; muscle breakdown; muscle degradation; muscle deterioration; muscle loss; muscle wasting; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Nerve Degeneration; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; nervous system disorder; Nervous System Diseases; Neurologic Disorders; Neurological Disorders; neurological disease; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Parkinson Disease; Paralysis Agitans; Parkinson; Primary Parkinsonism; Patients; Play; Proteins; Risk; Role; social role; Spinal Cord; Medulla Spinalis; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Regulatory T-Lymphocyte; Treg; regulatory T-cells; CD4 Positive T Lymphocytes; CD4 Cells; CD4 T cells; CD4 helper T cell; CD4 lymphocyte; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; T4 Cells; T4 Lymphocytes; Tissues; Body Tissues; Toxicology; United States; CSIF; CSIF-10; Cytokine Synthesis Inhibitory Factor; IL-10; IL10; IL10A; Interleukin 10 Precursor; Interleukin-10; Mediating; BDNF; Brain-Derived Neurotrophic Factor; Site; Clinical; Phase; Hortega cell; gitter cell; mesoglia; microglial cell; microgliocyte; perivascular glial cell; Microglia; Age of Onset; Individual; Oxidative Stress; Disease Progression; Oncology Cancer; Oncology; transgene; Transgenes; Engraftment; cell mediated therapies; cell-based therapeutic; cell-based therapy; cellular therapeutic; cellular therapy; Cell Therapy; Therapeutic; Attenuated; attenuate; attenuates; Life; Immune; Immunes; Clinic; Route; extracellular; Paralysed; Palsy; Plegia; paralysis; paralytic; Neurodegenerative Disorders; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; mutant; neuron loss; nerve cell death; nerve cell loss; neuron cell death; neuron cell loss; neuron death; neuronal cell death; neuronal cell loss; neuronal death; neuronal loss; neuroprotection; neuroprotective; superoxide dismutase 1; SOD-1; SOD-1 protein; SOD1; SOD1 gene; SOD1 gene product; novel; Exclusion; Disease model; disorder model; Pathogenesis; Reporting; Therapeutic Intervention; intervention therapy; Modeling; Sampling; Molecular Interaction; Binding; preventing; prevent; Cytoplasmic Protein; Progressive Disease; Age Years; Data; in vivo; Development; developmental; neural inflammation; neuroinflammatory; neuroinflammation; designing; design; fALS; familial ALS; familial amyotrophic lateral sclerosis; insoluble aggregate; protein aggregate; protein aggregation; motor neuron degeneration; innovate; innovative; innovation; murine model; mouse model; therapeutic target; neuronal survival; chimeric antigen T cell receptor; chimeric antigen receptor; glial cell activation; glial activation; autoinflammatory; Amyotrophic Lateral Sclerosis patients; ALS patients; Injections; Teff cell; effector T cell; engineered T cells; therapeutically effective; translational therapeutics; translational therapy; manufacture
