R42NS098918
Project Grant
Overview
Grant Description
Epigenetic Markers and Sustained Cytoprotection for Stroke Treatment - Project Summary/Abstract
Stroke injury occurs over a long duration through pathologic changes leading to long-term neurologic dysfunction. There is an urgent need of therapeutic strategies that can provide safe and efficacious therapeutic effects to the hypoperfused brain with long-lasting endogenous neuroprotection for prevention of long-term neurologic dysfunction.
Sufficient evidence has pointed out that XENON (XE), a bioactive gas, has profound neuroprotective effects with advantages of rapid diffusion across the blood-brain barrier (BBB) with minimal side effects. Researchers at the University of Texas Health Science Center at Houston (UTSCH-H) have been able to incorporate XE into liposomes and demonstrated that XE-liposomal treatment post-stroke resulted in activation of endogenous brain protection following ischemic stroke.
Corroborated mechanisms of XE cytoprotection include the activation of endogenous cytoprotective molecules. In a NIH Phase I STTR, UTHSC-H collaborated with Zymo Research Corporation (Zymo), an experienced epigenetics company. We have shown proof of concept that intermittent XENON(XE)-liposomal treatment after stroke extends endogenous neuroprotection and induces epigenetic changes. Such sustained endogenous neuroprotection can be distinguished by a panel of differentially methylated biomarkers indicative of activation of specific signal transduction pathways.
As brain pathological changes/progression post stroke last for months, to be clinically useful, to extend the window for neuroprotection duration. We hypothesize that endogenous neuroprotection seen via epigenetic markers can be enhanced and consolidated and into the chronic recovery phase, meanwhile, translate to clinical relevant model. We do this with a three-phase xenon administration strategy. Two XE formulations, XE- liposomes and oral XE formulation, will be used to extend the treatment window. We will establish maximal therapeutic efficacy and then translate into aged rat to increase rigor.
The epigenetic biomarker panel identified in the Phase I STTR will be used to assess and validate XE long term neuroprotective effects via the 3-phased administration regime in our Phase 2 STTR. Our goal is to optimize, validate, and translate the XE liposomal formulation from Phase I and evaluate a new complementary xenon cyclodextrin (XE-CD) formulation for oral administration for the chronic stroke recovery phase, whilst commercializing both XE intravenous and oral formulations. We will continue epigenetic biomarker development as a diagnostic tool for evaluating stroke progression and treatment effects.
Our aims are:
1) To develop final formulations of XE-liposomes and XE-enriched solution, and to evaluate parameters for product reproducibility and analyze pharmacokinetics of both formulations;
2) To maintain neuroprotection over a longer duration by adding an oral XE-CD formulation following the IV acute XE-liposomal agent administration (acute to chronic recovery strokes) in both adult and aged animals; and
3) To finalize, and scale the XE-liposomal and XE-CD-oral formulations for an IND application.
Our long-term goal is to bring this strategy and these two formulations into clinical trials to stabilize and treat stroke from the acute to the long-term recovery phase.
Stroke injury occurs over a long duration through pathologic changes leading to long-term neurologic dysfunction. There is an urgent need of therapeutic strategies that can provide safe and efficacious therapeutic effects to the hypoperfused brain with long-lasting endogenous neuroprotection for prevention of long-term neurologic dysfunction.
Sufficient evidence has pointed out that XENON (XE), a bioactive gas, has profound neuroprotective effects with advantages of rapid diffusion across the blood-brain barrier (BBB) with minimal side effects. Researchers at the University of Texas Health Science Center at Houston (UTSCH-H) have been able to incorporate XE into liposomes and demonstrated that XE-liposomal treatment post-stroke resulted in activation of endogenous brain protection following ischemic stroke.
Corroborated mechanisms of XE cytoprotection include the activation of endogenous cytoprotective molecules. In a NIH Phase I STTR, UTHSC-H collaborated with Zymo Research Corporation (Zymo), an experienced epigenetics company. We have shown proof of concept that intermittent XENON(XE)-liposomal treatment after stroke extends endogenous neuroprotection and induces epigenetic changes. Such sustained endogenous neuroprotection can be distinguished by a panel of differentially methylated biomarkers indicative of activation of specific signal transduction pathways.
As brain pathological changes/progression post stroke last for months, to be clinically useful, to extend the window for neuroprotection duration. We hypothesize that endogenous neuroprotection seen via epigenetic markers can be enhanced and consolidated and into the chronic recovery phase, meanwhile, translate to clinical relevant model. We do this with a three-phase xenon administration strategy. Two XE formulations, XE- liposomes and oral XE formulation, will be used to extend the treatment window. We will establish maximal therapeutic efficacy and then translate into aged rat to increase rigor.
The epigenetic biomarker panel identified in the Phase I STTR will be used to assess and validate XE long term neuroprotective effects via the 3-phased administration regime in our Phase 2 STTR. Our goal is to optimize, validate, and translate the XE liposomal formulation from Phase I and evaluate a new complementary xenon cyclodextrin (XE-CD) formulation for oral administration for the chronic stroke recovery phase, whilst commercializing both XE intravenous and oral formulations. We will continue epigenetic biomarker development as a diagnostic tool for evaluating stroke progression and treatment effects.
Our aims are:
1) To develop final formulations of XE-liposomes and XE-enriched solution, and to evaluate parameters for product reproducibility and analyze pharmacokinetics of both formulations;
2) To maintain neuroprotection over a longer duration by adding an oral XE-CD formulation following the IV acute XE-liposomal agent administration (acute to chronic recovery strokes) in both adult and aged animals; and
3) To finalize, and scale the XE-liposomal and XE-CD-oral formulations for an IND application.
Our long-term goal is to bring this strategy and these two formulations into clinical trials to stabilize and treat stroke from the acute to the long-term recovery phase.
Awardee
Funding Goals
(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Irvine,
California
926145914
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the End Date has been extended from 08/31/22 to 08/31/27 and the total obligations have increased 227% from $1,082,714 to $3,536,579.
Zymo Research Corporation was awarded
Epigenetic Markers Sustained Stroke Cytoprotection: XE-Liposomal & XE-
Project Grant R42NS098918
worth $3,536,579
from the National Institute of Neurological Disorders and Stroke in May 2017 with work to be completed primarily in Irvine California United States.
The grant
has a duration of 10 years 3 months and
was awarded through assistance program 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders.
The Project Grant was awarded through grant opportunity PHS 2023-2 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42] Clinical Trial Not Allowed).
SBIR Details
Research Type
STTR Phase II
Title
Epigenetic Markers and Sustained Cytoprotection for Stroke Treatment
Abstract
PROJECT SUMMARY/ABSTRACT Stroke injury occurs over a long duration through pathologic changes leading to long-term neurologic dysfunction. There is an urgent need of therapeutic strategies that can provide safe and efficacious therapeutic effects to the hypoperfused brain with long-lasting endogenous neuroprotection for prevention of long-term neurologic dysfunction. Sufficient evidence has pointed out that xenon (Xe), a bioactive gas, has profound neuroprotective effects with advantages of rapid diffusion across the blood-brain barrier (BBB) with minimal side effects. Researchers at The University of Texas Health Science Center at Houston (UTSCH-H) have been able to incorporate Xe into liposomes and demonstrated that Xe-liposomal treatment post-stroke resulted in activation of endogenous brain protection following ischemic stroke. Corroborated mechanisms of Xe cytoprotection include the activation of endogenous cytoprotective molecules. In a NIH Phase I STTR, UTHSC-H collaborated with Zymo Research Corporation (Zymo), an experienced epigenetics company. We have shown proof of concept that intermittent Xenon(Xe)-liposomal treatment after stroke extends endogenous neuroprotection and induces epigenetic changes. Such sustained endogenous neuroprotection can be distinguished by a panel of differentially methylated biomarkers indicative of activation of specific signal transduction pathways. As brain pathological changes/progression post stroke last for months, to be clinically useful, to extend the window for neuroprotection duration. We hypothesize that endogenous neuroprotection seen via epigenetic markers can be enhanced and consolidated and into the chronic recovery phase, meanwhile, translate to clinical relevant model. We do this with a three-phase Xenon administration strategy. Two Xe formulations, Xe- liposomes and oral Xe formulation, will be used to extend the treatment window. We will establish maximal therapeutic efficacy and then translate into aged rat to increase rigor. The epigenetic biomarker panel identified in the Phase I STTR will be used to assess and validate Xe long term neuroprotective effects via the 3-phased administration regime in our Phase 2 STTR. Our goal is to optimize, validate, and translate the Xe liposomal formulation from phase I and evaluate a new complementary Xenon cyclodextrin (Xe-CD) formulation for oral administration for the chronic stroke recovery phase, whilst commercializing both Xe intravenous and oral formulations. We will continue epigenetic biomarker development as a diagnostic tool for evaluating stroke progression and treatment effects. Our aims are: 1) to develop final formulations of Xe-liposomes and Xe-enriched solution, and to evaluate parameters for product reproducibility and analysis pharmacokinetics of both formulations; 2) to maintain neuroprotection over a longer duration by adding an oral Xe-CD formulation following the IV acute Xe-liposomal agent administration (Acute to Chronic Recovery Strokes) in both adult and aged animals; and 3) to finalize, and scale the Xe-Liposomal and Xe-CD-Oral formulations for an IND application. Our long-term goal is to bring this strategy and these two formulations into clinical trials to stabilize and treat stroke from the acute to the long term recovery phase.PROJECT NARRATIVE Stroke injury occurs over a long duration through pathologic changes leading to long-term neurologic dysfunction. Neuroprotection for a long period post stroke could prevent or slow neurovascular deterioration. We aim to establish and translate two therapeutic agents (Xenon liposomes and Xe oral formulations) along with a novel delivery strategy to stimulate and consolidate long-term endogenous cytoprotection and tolerance to provide new opportunities for more complete stroke treatment. Identification of reliable biomarkers to guide determination of best frequency and duration of xenon-containing formulations and a translatable therapeutic administration protocol that allows consistent, long-lasting protection post stroke.
Topic Code
NINDS
Solicitation Number
PA19-270
Status
(Ongoing)
Last Modified 8/20/25
Period of Performance
5/1/17
Start Date
8/31/27
End Date
Funding Split
$3.5M
Federal Obligation
$0.0
Non-Federal Obligation
$3.5M
Total Obligated
Activity Timeline
Transaction History
Modifications to R42NS098918
Additional Detail
Award ID FAIN
R42NS098918
SAI Number
R42NS098918-3932194335
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Small Business
Awarding Office
75NQ00 NIH National Institute of Neurological Disorders and Stroke
Funding Office
75NQ00 NIH National Institute of Neurological Disorders and Stroke
Awardee UEI
MNUYHHMKG8N9
Awardee CAGE
3JZV6
Performance District
CA-47
Senators
Dianne Feinstein
Alejandro Padilla
Alejandro Padilla
Budget Funding
Federal Account | Budget Subfunction | Object Class | Total | Percentage |
---|---|---|---|---|
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Health and Human Services (075-0886) | Health research and training | Grants, subsidies, and contributions (41.0) | $841,419 | 100% |
Modified: 8/20/25