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At least 181 records · Page 10
All sourcesNASA NTRSDOE OSTI
NASA NTRS2000

Nutritional Biochemistry of Space Flight

Adequate nutrition is critical for maintenance of crew health during and after extended-duration space flight. The impact of weightlessness on human physiology is profound, with effects on many systems related to nutrition, including bone, muscle, hematology, fluid and electrolyte regulation. Additionally, we have much to learn regarding the impact of weightlessness on absorption, m~tabolism , and excretion of nutrients, and this will ultimately determine the nutrient requirements for extended-duration space flight. Existing nutritional requirements for extended-duration space flight have been formulated based on limited flight research, and extrapolation from ground-based research. NASA's Nutritional Biochemistry Laboratory is charged with defining the nutritional requirements for space flight. This is accomplished through both operational and research projects. A nutritional status assessment program is included operationally for all International Space Station astronauts. This medical requirement includes biochemical and dietary assessments, and is completed before, during, and after the missions. This program will provide information about crew health and nutritional status, and will also provide assessments of countermeasure efficacy. Ongoing research projects include studies of calcium and bone metabolism, and iron absorption and metabolism. The calcium studies include measurements of endocrine regulation of calcium homeostasis, biochemical marker~ of bone metabolism, and tracer kinetic studies of calcium movement in the body. These calcium kinetic studies allow for estimation of intestinal absorption, urinary excretion, and perhaps most importantly - deposition and resorption of calcium from bone. The Calcium Kinetics experiment is currently being prepared for flight on the Space Shuttle in 2001, and potentially for subsequent Shuttle and International Space Station missions. The iron study is intended to assess whether iron absorption is down-regulated dUl1ng space flight. This is critical due to the red blood cell changes which occur, and the increase in iron storage that has been observed after space flight. The Iron Absorption and Metabolism experiment is currently planned for long-term flights on the International Space Station.

Smith, Scott M.↗
NASA NTRS2010

A Biomathematical Model of Lymphopoiesis and Its Application to Acute and Chronic Irradiation Assessment

After the events of September 11, 2001, there is an increasing concern of the occurrence of radiological terrorism that may result in significant casualties in densely populated areas. Much effort has been made to establish various biomarkers to rapidly assess radiation dose in mass-casualty and population-monitoring scenarios, which are demanded for effective medical management and treatment of the exposed victims. Among these the count of lymphocytes in peripheral blood and their depletion kinetics are the most important early indicators of the severity of the radiation injury. In this study, we examine a biomathematical model of lymphopoiesis which has been successfully utilized to simulate and interpret experimental data of acute and chronic irradiations on rodents [1]. With revised parameters for humans, we find this model can reproduce several sets of clinical lymphocyte data of accident victims over a wide range of absorbed doses. In addition, the absolute lymphocyte counts and the depletion rate constants calculated by this model also show good correlation with the Guskova formula and the Goans model, the two empirical tools which have been widely recognized for early estimation of the exposed dose after radiation accidents [2]. We also use the model to analyze the hematological data of the Techa River residents which were exposed to chronic low-dose irradiation during 1950-1956 [3]. This model can serve as a computational tool in radiation accident management, military operations involving nuclear warfare, radiation therapy, and space radiation risk assessment.

Hu, Shaowen↗
NASA NTRS2000

Nutritional Biochemistry of Spaceflight

Adequate nutrition is critical for crew health and safety during spaceflight. To ensure adequate nutrition, the nutrient requirements need to be both accurate and available from the spaceflight food system. The existing nutritional requirements for extended-duration spaceflight have been defined largely by extrapolation from ground-based research. However, nutritional requirements are influenced by most of the physiological consequences of spaceflight, including loss of lean, adipose, and bone tissue; changes in blood composition; and increased risk of renal stone formation. This review focuses on key areas where information has been gained in recent years: dietary intake and energy metabolism, bone health, fluid and electrolyte homeostasis, and hematological changes. Areas in which specific nutrients have the potential to serve as countermeasures to the negative effects of spaceflight are also reviewed. Dietary Intake

Smith, Scott M.↗
NASA NTRS2014

Ames Life Science Data Archive: Translational Rodent Research at Ames

The Life Science Data Archive (LSDA) office at Ames is responsible for collecting, curating, distributing and maintaining information pertaining to animal and plant experiments conducted in low earth orbit aboard various space vehicles from 1965 to present. The LSDA will soon be archiving data and tissues samples collected on the next generation of commercial vehicles; e.g., SpaceX & Cygnus Commercial Cargo Craft. To date over 375 rodent flight experiments with translational application have been archived by the Ames LSDA office. This knowledge base of fundamental research can be used to understand mechanisms that affect higher organisms in microgravity and help define additional research whose results could lead the way to closing gaps identified by the Human Research Program (HRP). This poster will highlight Ames contribution to the existing knowledge base and how the LSDA can be a resource to help answer the questions surrounding human health in long duration space exploration. In addition, it will illustrate how this body of knowledge was utilized to further our understanding of how space flight affects the human system and the ability to develop countermeasures that negate the deleterious effects of space flight. The Ames Life Sciences Data Archive (ALSDA) includes current descriptions of over 700 experiments conducted aboard the Shuttle, International Space Station (ISS), NASA/MIR, Bion/Cosmos, Gemini, Biosatellites, Apollo, Skylab, Russian Foton, and ground bed rest studies. Research areas cover Behavior and Performance, Bone and Calcium Physiology, Cardiovascular Physiology, Cell and Molecular Biology, Chronobiology, Developmental Biology, Endocrinology, Environmental Monitoring, Gastrointestinal Physiology, Hematology, Immunology, Life Support System, Metabolism and Nutrition, Microbiology, Muscle Physiology, Neurophysiology, Pharmacology, Plant Biology, Pulmonary Physiology, Radiation Biology, Renal, Fluid and Electrolyte Physiology, and Toxicology. These experiment descriptions and data can be accessed online via the public LSDA website (http://lsda.jsc.nasa.gov) and information can be requested via the Data Request form at http://lsda.jsc.nasa.gov/common/dataRequest/dataRequest.aspx or by contacting the ALSDA Office at: Alison.J.French@nasa.gov

Life Sciences↗
NASA NTRS2015

The Reusable Handheld Electrolyte and Lab Technology for Humans (rHEALTH) Sensor

The DNA Medicine Institute has produced a reusable microfluidic device that performs rapid, low-cost cell counts and measurements of electrolytes, proteins, and other biomarkers. The rHEALTH sensor is compact and portable, and it employs cutting-edge fluorescence detection optics, innovative microfluidics, and nanostrip reagents to perform a suite of hematology, chemistry, and biomarker assays from a single drop of blood. A handful of current portable POC devices provide generalized blood analysis, but they perform only a few tests at a time. These devices also rely on disposable components and depend on diverse detection technologies to complete routine tests-all ill-suited for space travelers on extended missions. In contrast, the rHEALTH sensor integrates sample introduction, processing, and detection with a compact, resource-conscious, and efficient design. Developed to monitor astronaut health on the International Space Station and during long-term space flight, this microscale lab analysis tool also has terrestrial applications that include POC diagnostics conducted at a patient's bedside, in a doctor's office, and in a hospital.

Chan, Eugene↗
NASA NTRSDate not supplied

Development of A Directed Acyclic Graph for Venous Thromboembolism During Spaceflight

Introduction: Recent studies have reported the development of venous blood flow stasis in astronauts and an occlusive venous thrombosis during spaceflight. Subsequent investigations revealed approximately one quarter of surveilled crew members had some degree of blood flow stasis in the left internal jugular vein. Therefore, NASA’s Human System Risk Board now formally tracks venous thromboembolism (VTE) as a “concern” for human spaceflight. To investigate potential mechanisms by which exposures concomitant with spaceflight (e.g., microgravity, radiation) may contribute to VTE, we developed a causal diagram in the form of a directed acyclic graph (DAG). Methods: The mechanisms by which spaceflight exposures may elevate the risk of VTE and the downstream effects on mission outcomes were critically analyzed, taking into account scientific literature and subject matter expertise consultation, and a DAG was generated. A Level-of-Evidence score for each causal relationship was assigned based on assessing the literature against a set of criteria derived from the A. Bradford Hill Causal Guidelines. Results: The set of three main factors that predispose people to VTE (hypercoagulability, endothelial damage, and blood stasis) is known as Virchow’s Triad. In constructing the DAG for VTE we articulated various mechanisms by which the principal spaceflight hazards (microgravity, radiation, closed hostile environment, isolation and confinement, distance from Earth) are thought to interact with or cause the components in Virchow’s triad. We found sufficient evidence to at least speculate that fluid shifts from microgravity, compensatory alterations in hematologic indices, spaceflight atmospheric conditions, and oxidative stress/inflammation from radiation may be potential contributors to VTE development. Discussion: Developing the DAG entailed a systematic and repeatable approach for visualizing relationships between contributing factors that may lead to VTE in spaceflight. Articulating pathways linking spaceflight exposures to VTE risk factors and possible VTE development enables subject matter experts from different domains to construct a shared mental model. Assignment of levels of evidence scores to the relationships helps identify knowledge and capability gaps that should be considered for further investigation. Furthermore, the DAG highlights modifiable variables and may therefore facilitate the development of new VTE risk mitigation strategies.

Alexander Svoronos↗
NASA NTRSDate not supplied

rHealth One Demonstration Aboard ISS: A Microfluidic Bioanalyzer Based on Sheath/Hydrodynamic Focusing Flow Cytometry

The Exploration Medical Capability (ExMC) element aims to provide astronauts with the means for their own health monitoring, diagnosis, and treatment during exploration missions. As space flight ventures further from earth, the need for autonomous medical care increases under greater constraints on size, mass, and resources. One pillar for diagnosis that crew would be separated from is laboratory analysis. Even now on ISS, blood samples must be collected and returned to earth for testing. In response, ExMC is assessing how assays for hematology, bone health, radiation exposure etc. could be addressed through commercial-off-the-shelf (COTS) and Small Business Innovation Research (SBIR) funded bioanalyzers that are miniaturizing lab technology. Since missions will reach distances where there are no timely replacements, validation on the International Space Station (ISS) is a necessary part of that assessment. In partnership with NASA Johnson Space Center (JSC) Immunology Lab and the Research Operations and Integration (ROI) element, ExMC conducted a technology demonstration on ISS of the rHEALTH ONE, a flow cytometry based bioanalyzer, to assess future devices based on this design. In flow cytometry, there are predominantly three ways to focus the cells (or particles) into a single file stream: hydrodynamic focusing, microcapillary, and acoustic focusing. The rHEALTH ONE utilizes the commercial standard, sheath-based hydrodynamic focusing. rHEALTH itself represents both a company and a suite of medical tools NASA has funded through SBIR grants towards the development of a promising diagnosis instrument for exploration missions. rHEALTH ONE is the interim version of the technology, functional as a benchtop analyzer and test bed for the next generation of rHEALTH in development. Several modifications were made to the rHEALTH ONE analyzer for operation in microgravity. For function, fluid management was key. A sheath-based analyzer uses sheath fluid to flow the sample, cleaning fluid to prevent biological contamination, and a reservoir to collect the liquid waste. The rHEALTH ONE analyzer uses bottles dependent on gravity to separate the air and liquid pathways and keep the liquids contained. It uses only 1 psig of air pressure to directly push the liquid through the device, requiring little-to-no resistance at inlet and outlet. A microtubing assembly with self-sealing luer connectors was designed – featuring 0.014 mm thick durable medical balloons to hold water inside the supply bottles – to create safe containment and easy access for the crew while maintaining the analyzer’s function. For safety, copper tape was added to the interior of the plastic housing to reduce electromagnetic interference, fluid and electrical connections were secured against vibration and leaks, and gaps were further sealed to ensure containment of the optical block and lasers. Water as the sheath and cleaning fluid and TOX 0 samples were used to reduce the biohazard risk to the crew. In May 2022, European Space Agency astronaut Samantha Cristoforetti demonstrated the rHEALTH ONE aboard ISS for its sample loading, flow cytometry, and data collection capability in microgravity. The JSC Immunology Lab provided flow cytometry expertise, designed the sample test protocol, and manufactured and benchmarked the flight samples on a ‘gold-standard’ flow cytometer. The analyzer was primed with water, purged of air, and four calibration solutions of polystyrene microparticles were tested to characterize its performance. Tightly controlled procedures and excellent execution prevented air bubble interference during air/water separation, fluid transfer, sample mixing and loading. Data showed a slight increase in signal noise on 3 of 5 channels and an anomaly of fluorophores migrating in one sample (confirmed by JSC post-flight). Flight results correctly detected the change in sample, matched the analyzer’s ground performance, and were consistent with the gold-standard’s ground results. Although areas were noted for improvement, these outcomes signified complete mission success.

R. S. Miller↗
NASA NTRSDate not supplied

Assessing Long-Term Health (LTH) Outcomes in Astronauts

NASA has linked potential Long-Term Health (LTH) risks of astronauts to their spaceflight experience, including the effects of space radiation, microgravity, and stressors such as isolation, sleep deprivation, and stress. Therefore, assessing the LTH outcomes for astronauts exposed to these hazards becomes a critical investigation in ensuring any deleterious effects are minimal. Prior research conducted into LTH outcomes of astronauts has not revealed increases in non-accidental mortality rates when compared to the U.S. general population, analog healthy cohorts, and professional athletes. One study did report an increased incidence of non-fatal cardiovascular disease events (Hazard Ratio=2.41, 95% Confidence Interval 1.26 to 4.63). Additional evidence indicates that astronauts may have increases in incidences of melanoma, prostate, and hematologic cancers, though the former is consistent with rates observed among aircraft pilots and the latter two are likely caused by detection bias due to increased screening on former astronauts.

long term health↗
NASA NTRS2024

ISS Technology Demonstrations for Future Spaceflight Medical Systems

Throughout the history of human spaceflight, crewmembers have experienced various in-flight medical conditions including illness and injury. Planned missions to the Moon and Mars will require capabilities to maintain the health of future space travelers. Mass, power, and volume available in the vehicles and habitats for these missions will be severely constrained; resupply of resources will be limited or non-existent, as will opportunities for evacuation to Earth. Furthermore, ground-based support will be hampered by communication latencies and blackouts. These vehicle and mission constraints will necessitate a medical system that has been efficiently planned, providing on-board procedural guidance in addition to a variety of medical devices and consumable resources. Medical capabilities required for the diagnosis and treatment of potential medical conditions during future spaceflight missions may include real-time health monitoring, medical imaging, and biomarker analyses ( e.g., blood or urine). Terrestrial medicine shares these needs, thus many of these medical capabilities could likely be satisfied by Commercial-Off-The-Shelf (COTS) devices and methodologies; however, in some cases the unique space environment and increased mission duration will drive the need to modify technologies and the way care is provided. NASA’s Human Research Program (HRP) Exploration Medical Capability (ExMC) Element and Mars Campaign Office’s Exploration Medical Integrated Product Team (XMIPT) are working together to decrease medical risk during exploration missions. Flight-tested medical diagnostic and treatment technologies are necessary to effectively manage medical conditions relevant to exploration missions while meeting vehicle constraints, integrating with medical decision-support tools, and enabling increasingly Earth-independent operations. Several projects have leveraged the ISS as a testbed for exploration, including 1) i n- situ blood analysis, 2) medical inventory, 3) intravenous fluid generation, and 4) autonomous medical procedure guidance. Management of several in-flight medical conditions, such as bacterial and viral infections and acute radiation syndrome, is dramatically improved with ability to assess blood cell populations, electrolytes, and metabolites. I n December 2020 and January 2021 ExMC performed an ISS technology demonstration (Tech Demo) of the HemoCue® WBC DIFF analyzer (HemoCue, Brea, CA), a COTS device that was modified to enable functionality in a spaceflight environment. This Tech Demo marked the first time that hematology measurements were successfully performed real-time in microgravity. Also modified and demonstrated was the reusable Handheld Electrolytes and Lab Technology for Humans (rHEALTH) ONE analyzer (rHEALTH, Bedford, MA), which uses flow cytometry and sheath-based hydrodynamic focusing methodologies. The rHEALTH ONE ISS Tech Demo in May 2022 demonstrated test results obtained in-flight matched those on the ground. NASA currently relies on crew self-reporting to manage and maintain medical inventory on ISS.The ability to maintain an accurate inventory becomes more critical during long duration missions since the crew will need to be increasingly autonomous in finding and utilizing medical items, including those scenarios when alternative treatments need to be considered due to limited or no resupply. HRP’s Medical Consumables Tracking (MCT) project was developed by ZIN Technologies, Inc. (Cleveland, OH), and demonstrated real-time tracking of medical supplies aboard the ISS between December 2016 and July 2018. The MCT system design utilized Radio Frequency Identification Device (RFID) technology to perform automated inventory and was installed in the Crew Health Care System (CHeCS) Resupply Stowage Rack (RSR). The challenge of limited shelf life, exacerbated by the lack of resupply opportunities, affects a plethora of medical system components including consumables, pharmaceuticals, and intravenous (IV) fluid. In 2010, ExMC funded ZIN Technologies, Inc. (Cleveland, OH), to develop the Intravenous Fluid Generation (IVGEN) system. IV fluids were successfully generated with IVGEN using the potable water supply on ISS during ISS Expedition 23. The XMIPT is in the process of developing a miniaturized version of the original IVGEN hardware for a future Tech Demo aboard the ISS. Current ISS medical operations rely heavily on preflight training and real-time remote guidance, both of which become impractical or impossible for exploration missions. The primary goal of the Autonomous Medical Officer Support (AMOS) Software Tech Demos on ISS was to confirm telemedical proof-of-concept for autonomous medical imaging in an operational setting. This novel software tool shifts emphasis from preflight training and real-time remote guidance to in-flight just-in-time instruction, a new and necessary paradigm for crew medical autonomy. AMOS introduces a novel, streamlined skill management concept for exploration missions featuring comprehensive training and guidance modules for ultrasound examinations using the ISS Ultrasound 2 (a modified GE Vivid-q™; General Electric HealthCare, Chicago, IL). With no prior crew training or remote guidance, two Tech Demos on the ISS (April 2020 and June 2022) resulted in high quality, clinically useful image sets. We will provide a review of historical, current, and planned medical devices and technologies considered for inclusion within future spaceflight medical systems and summarize hardware development activities and medical device tech demos conducted on the ISS.

Astronaut health and performance↗
DOE OSTI2022

Effect of wavelength and filter set choices on fluorogenic thrombin generation assay: Considerations for interlaboratory differences

Insufficient agreement between results of various in–house and commercial thrombin generation (TG) assays complicates TG adoption and use. can be caused by different assay variables, for example, volumes and concentrations of reagents. Although most modern assays employ the same fluorogenic thrombin substrate Z–Gly–Gly–Arg 7–amino–4–methylcoumarin (ZGGR–AMC), the excitation (Ex) and emission (Em) wavelengths used for fluorescence signal measurements can be different.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

SAXS analysis of the intrinsic tenase complex bound to a lipid nanodisc highlights intermolecular contacts between factors VIIIa/IXa

Abstract The intrinsic tenase (Xase) complex, formed by factors (f) VIIIa and fIXa, forms on activated platelet surfaces and catalyzes the activation of factor X to Xa, stimulating thrombin production in the blood coagulation cascade. The structural organization of the membrane-bound Xase complex remains largely unknown, hindering our understanding of the structural underpinnings that guide Xase complex assembly. Here, we aimed to characterize the Xase complex bound to a lipid nanodisc with biolayer interferometry (BLI), Michaelis–Menten kinetics, and small-angle X-ray scattering (SAXS). Using immobilized lipid nanodiscs, we measured binding rates and nanomolar affinities for fVIIIa, fIXa, and the Xase complex. Enzyme kinetic measurements demonstrated the assembly of an active enzyme complex in the presence of lipid nanodiscs. An ab initio molecular envelope of the nanodisc-bound Xase complex allowed us to computationally model fVIIIa and fIXa docked onto a flexible lipid membrane and identify protein–protein interactions. Our results highlight multiple points of contact between fVIIIa and fIXa, including a novel interaction with fIXa at the fVIIIa A1–A3 domain interface. Lastly, we identified hemophilia A/B-related mutations with varying severities at the fVIIIa/fIXa interface that may regulate Xase complex assembly. Together, our results support the use of SAXS as an emergent tool to investigate the membrane-bound Xase complex and illustrate how mutations at the fVIIIa/fIXa dimer interface may disrupt or stabilize the activated enzyme complex.

Hematology↗
DOE OSTI2023

Circulating SARS-CoV-2 + megakaryocytes are associated with severe viral infection in COVID-19

Several independent lines of evidence suggest that megakaryocytes are dysfunctional in severe COVID-19. Herein, we characterized peripheral circulating megakaryocytes in a large cohort of inpatients with COVID-19 and correlated the subpopulation frequencies with clinical outcomes. Using peripheral blood, we show that megakaryocytes are increased in the systemic circulation in COVID-19, and we identify and validate S100A8/A9 as a defining marker of megakaryocyte dysfunction. We further reveal a subpopulation of S100A8/A9 + megakaryocytes that contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein and RNA. Using flow cytometry of peripheral blood and in vitro studies on SARS-CoV-2–infected primary human megakaryocytes, we demonstrate that megakaryocytes can transfer viral antigens to emerging platelets. Mechanistically, we show that SARS-CoV-2–containing megakaryocytes are nuclear factor κB (NF-κB)-activated, via p65 and p52; express the NF-κB–mediated cytokines interleukin-6 (IL-6) and IL-1β; and display high surface expression of Toll-like receptor 2 (TLR2) and TLR4, canonical drivers of NF-κB. In a cohort of 218 inpatients with COVID-19, we correlate frequencies of megakaryocyte subpopulations with clinical outcomes and show that SARS-CoV-2–containing megakaryocytes are a strong risk factor for mortality and multiorgan injury, including respiratory failure, mechanical ventilation, acute kidney injury, thrombotic events, and intensive care unit admission. Furthermore, we show that SARS-CoV-2 + megakaryocytes are present in lung and brain autopsy tissues from deceased donors who had COVID-19. To our knowledge, this study offers the first evidence implicating SARS-CoV-2 + peripheral megakaryocytes in severe disease and suggests that circulating megakaryocytes warrant investigation in inflammatory disorders beyond COVID-19.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Structural analysis of platelet fragments and extracellular vesicles produced by apheresis platelets during storage

Platelets (PLTs) for transfusion can be stored for up to 7 days at room temperature (RT). The quality of apheresis PLTs decreases over storage time, which affects PLT hemostatic functions. Here, we characterized the membranous particles produced by PLT storage lesion (PSLPs), including degranulated PLTs, PLT ghosts, membrane fragments, and extracellular membrane vesicles (PEVs). The PSLPs generated in apheresis platelet units were analyzed on days 1, 3, 5, and 7 of RT storage. A differential centrifugation and a sucrose density gradient were used to separate PSLP populations. PSLPs were characterized using scanning and transmission electron microscopy (EM), flow cytometry (FC), and nanoparticle tracking analysis (NTA). PSLPs have different morphologies and a broad size distribution; FC and NTA showed that the concentration of small and large PSLPs increases with storage time. The density gradient separated 3 PSLP populations: (1) degranulated PLTs, PLT ghosts, and large PLT fragments; (2) PEVs originated from PLT activation and organelles released by necrotic PLTs; and (3) PEV ghosts. Most PSLPs expressed phosphatidyl serine and induced thrombin generation in the plasma. PSLPs contained extracellular mitochondria and some had the autophagosome marker LC3. PSLPs encompass degranulated PLTs, PLT ghosts, large PLT fragments, large and dense PEVs, and low-density PEV ghosts. The activation-related PSLPs are released, particularly during early stage of storage (days 1-3), and the release of apoptosis- and necrosis-related PSLPs prevails after that. No elevation of LC3- and TOM20-positive PSLPs indicates that the increase of extracellular mitochondria during later-stage storage is not associated with PLT mitophagy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

In vivo stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia

Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.

60 APPLIED LIFE SCIENCES↗