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Principal Investigator: Elizabeth Ottinger
Organization: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
Fiscal Year: 2024
Award: $1,066,904
Funding agency: National Center for Advancing Translational Sciences
We have engaged in productive partnerships across various therapeutic areas in collaboration with NIH and external academic researchers and companies. During the current fiscal year, progress was made in meeting the objectives of these various collaborations. The team is further refining the high-content ASO screening assays utilizing organoids. Complementing this work, algorithms to analyze the data from these assays are under active development in collaboration with the informatics team and confirm the ability of these data to predict toxicity accurately. Animal toxicity experiments of the ASOs are in progress to benchmark the high-content screening assays. In collaboration with clinical groups at the NIH Clinical Center, the design of the clinical trial is underway and will shortly be submitted for consideration.
ASO Toxicity Assay Development: We continue refining the high-content screening assays using cell-based platforms that will substitute for low-throughput animal toxicity experiments. These screening platforms rely on organoids to predict the toxic side effects of ASOs and improve the safety pharmacology of this drug class. In parallel, we are constructing and benchmarking algorithms that predict toxicity, allowing bad ASOs to be eliminated early in the design phase. In this way, we are speeding up the process of ASO development and making it cheaper and faster to produce disease-modifying therapies for rare diseases. We collaborate with pharmaceutical companies and academic researchers to achieve these ambitious targets.
We continue to work with Ionis Pharmaceuticals and Roche, two of the leaders in the ASO field, on our in vitro and in vivo screening platform development. Recent progress was made in developing and validating 2D and 3D human cell-based ASO toxicity assays using in vitro and nonclinical in vivo toxicity and safety data. We have incorporated iPSC-derived human neuronal cells into the development of these assays. The approach supports using a patient's cells in future IND-directed safety and toxicity studies for N=1 or a few diseases.
Development of a Predictive Model of Safety and Toxicity of Candidate ASO Therapies: We continue to develop a platform to evaluate the safety and acute toxicity of ASOs in mice. These animal data have been compared to the results of cell-based screening assays and have validated the ability of the in vitro assays to predict the toxicity properties of ASOs in animals and to rely on the in vitro cell-based studies for future safety readouts.
Our screening assay can reduce the need for future animal experimental testing and predict the safety of prospective candidate ASOs intended for clinical use. This project aims to provide sufficient and confirmatory in vivo data to the point that the FDA accepts cell-based in vitro data instead of conventional animal toxicology studies currently required for advancing new ASOs to clinical trials.
N=1 Gene Identification in Neurodegenerative and Systemic Rare Diseases: Individualized N=1 therapies target a minimal number of people, even as few as one. We continue to work with the N=1 Collaborative, academia, foundations, and biotech companies to bring customizable treatments targeting the underlying genetic defect as safely and quickly as possible in rare diseases.
We are focused on using antisense oligonucleotides (ASOs), as they are rapidly customizable, cost-efficient to manufacture, straightforward to administer and have a growing safety and efficacy record. Through these efforts, we are establishing a standardized framework for individualized medicine that will extend to other customizable platform technologies such as siRNAs, RNA therapeutics, and CRISPR.
To test our drug development pipeline, we have worked on candidate ASOs related to genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as demonstration projects. ALS is a rare neurodegenerative disease characterized by progressive loss of motor neurons leading to respiratory failure and death. Approximately 7,000 Americans die of ALS yearly, which will increase dramatically in the future because of population aging. In collaboration with Dr. Derek Narendra (NINDS) and Dr. Justin Kwan, the director of the NINDS ALS clinic at the NIH Clinical Center, we work on developing ASOs and screening assays to identify lead ASOs suitable for IND-enabling studies toward clinical trials
ASO Delivery Development: Most rare diseases affect the central nervous system, meaning gene therapies such as ASOs must be delivered intrathecally. While manageable, this route of administration adds to the complexity when scaling up treatments within the general rare disease population. We explore advanced delivery approaches, such as lipid nanoparticles, chemical structure, and conjugation with targeting moieties. Each system shows promise, but the goal of oral delivery of gene therapy agents requires considerable ongoing effort.
The resources at NCATS bring key competencies to speed up research on delivery approaches. We continue to collaborate with Optimeos Life Sciences to apply their tunable nanoparticle technology to deliver ASOs. We are working on in vitro and in vivo experiments to explore additional aspects of this innovative delivery system to neurons and other tissues. Together, we are exploring this payload delivery method to decrease the dose and mitigate the toxicity of ASOs. If successful, this novel modality will empower the ASO field to find a safe way to distribute this new class of therapeutics to target tissues. Initial experiments demonstrate the uptake of the nanoparticles into neurons and other cell types, highlighting the potential value of this new delivery approach.
Terms: <3-D><3-Dimensional><3D><ASO therapeutics><ASO therapy><ASO treatment><Academia><Affect><Airway failure><Algorithms><American><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Amyotrophic lateral sclerosis and frontotemporal degeneration><Amyotrophic lateral sclerosis and frontotemporal dementia><Animal Experiments><Animal Testing><Animals><Antisense Agent><Antisense Oligonucleotide Therapy><Antisense Oligonucleotides><Area><Assay><Benchmarking><Best Practice Analysis><Bioassay><Biologic Sciences><Biological Assay><Biological Sciences><Bioscience><Biotech><Biotechnology><Body Tissues><CNS Nervous System><CRISPR><CRISPR/Cas system><Cell Body><Cells><Central Nervous System><Cessation of life><Chemical Structure><Clinic><Clinical><Clinical Trials><Clinical Trials Design><Clustered Regularly Interspaced Short Palindromic Repeats><Collaborations><Competence><DNA Therapy><Data><Death><Degenerative Neurologic Disorders><Development><Diagnosis><Disease><Disorder><Dose><Drug Industry><Drugs><FTD/ALS><FTLD/ALS><Foundations><Frontotemporal Lobar Degeneration/Amyotrophic lateral sclerosis><Future><Gehrig's Disease><Gene Delivery><Gene Therapy Agent><Gene Transfer Clinical><Genes><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic defect><Goals><Human><In Vitro><Induced pluripotent stem cell derived human neuron><Informatics><Investigators><Laboratories><Lead><Life Sciences><Lou Gehrig Disease><Medication><Methods><Mice><Mice Mammals><Modality><Modern Man><Motor Cell><Motor Neurons><Murine><Mus><Mutation><NCATS><NIH><NINDS><National Center for Advancing Translational Sciences><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><National Institutes of Health><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Non-Polyadenylated RNA><Oral><Organoids><Orphan Disease><Patients><Pb element><Persons><Pharmaceutic Industry><Pharmaceutical Agent><Pharmaceutical Industry><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Pharmacology><Phase><Population><Process><Productivity><Property><RNA><RNA Gene Products><RNA based therapeutics><RNA based therapy><RNA therapy><Rare Diseases><Rare Disorder><Research><Research Personnel><Research Resources><Researchers><Resources><Respiratory Failure><Ribonucleic Acid><Route><Safety><Short interfering RNA><Small Interfering RNA><Speed><Standardization><System><Technology><Testing><Therapeutic><Time><Tissues><Toxic effect><Toxicities><Toxicology><United States National Institutes of Health><Universities><Work><acute toxicity><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aging population><amyotrophic lateral sclerosis with frontotemporal dementia><amyotrophic lateral sclerosis/FTLD><amyotrophic lateral sclerosis/frontotemporal dementia><amyotrophic lateral sclerosis/ftd><animal data><animal experiment><anti-sense oligonucleotide drug><anti-sense oligonucleotide therapy><anti-sense oligonucleotide treatment><anti-sense therapy><antisense drug><antisense oligo><antisense oligonucleotide therapeutic><antisense therapeutics><antisense therapy><assay development><benchmark><bio-printing><bioprinting><cell type><clinical center><computer based prediction><cost><cost efficient><customized therapy><customized treatment><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design><designing><developmental><drug development><drug discovery><drug/agent><effective therapy><effective treatment><empowerment><experiment><experimental animal><experimental animals><experimental research><experimental study><experiments><first in man><first-in-human><frontotemporal dementia-amyotrophic lateral sclerosis><frontotemporal lobar dementia amyotrophic lateral sclerosis><gene repair therapy><gene therapy><gene-based therapy><gene-based treatment><gene-directed therapy><gene-targeted therapy><gene-targeted treatment><genetic therapy><genome mutation><genomic therapy><heavy metal Pb><heavy metal lead><hiPSC-derived neurons><human iPSC-derived sensory neuron><iPSC-derived human neuron><improved><in vitro Assay><in vivo><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><innovate><innovation><innovative><lipid based nanoparticle><lipid nanoparticle><manufacture><manufacturing facility><manufacturing plants><meeting><meetings><motoneuron><nano particle><nano-sized particle><nanoparticle><nanosized particle><neglect><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal><neuronal degeneration><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new technology><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel technologies><novel therapeutics><novel therapy><oligonucleotide delivery><orphan disorder><patient specific therapies><patient specific treatment><pharmaceutical><population aging><prediction algorithm><predictive modeling><production plants><prospective><scale up><screening><screenings><siRNA><side effect><tailored medical treatment><tailored therapy><tailored treatment><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><technology platform><technology system><therapeutic RNA><three dimensional><timeline><unique treatment><uptake>