SBIR-STTR Award

Platelet Bioreactor for Treatment of Radiation-Induced Thrombocytopenia
Award last edited on: 2/17/2022

Sponsored Program
SBIR
Awarding Agency
NIH : NIAID
Total Award Amount
$600,000
Award Phase
2
Solicitation Topic Code
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Principal Investigator
Lea M Beaulieu

Company Information

Platelet Biogenesis Inc

65 Grove Street Suite 303
Watertown, MA 02472
Location: Single
Congr. District: 05
County: Middlesex

Phase I

Contract Number: 1R43AI125134-01A1
Start Date: 1/5/2017    Completed: 12/31/2018
Phase I year
2017
Phase I Amount
$300,000
Platelet Biogenesis is developing a microfluidic bioreactor that reproduces key features of adult bone marrow (physiological microenvironment) to produce human platelets (PLTs). PLTs are the 'band- aids' of the bloodstream, responsible for clot formation and blood vessel repair. Low PLT count is a significant consequence of a radiation accident or deliberate nuclear attack, for which PLTs are a critical first-line therapy to prevent mortality due to uncontrolled bleeding. PLT units comprising ~1.5x109 PLTs/mL (3x1011 PLTs total) are currently derived exclusively from human volunteer donors, and must be stored at or above 22oC to avoid irreversible temperature-related activation/aggregation. Risk of bacterial/viral growth during room temperature storage results in short shelf life (5 days). Blood centers typically do not have more than a 1.5-day PLT inventory available for transfusion under non-emergency situations (1, 2), and there are currently no licensed PLT therapeutics for thrombocytopenia to treat radiation exposures(3). To address this major unmet need we will validate our bioreactor to generate functional PLTs from megakaryocyte progenitors at clinical scale to treat radiation-induced thrombocytopenia (RIT). To date we have shown that: (1) It is feasible to generate functional megakaryocytes and PLTs from human induced pluripotent stem cells (iPSCs, a potentially unlimited source of progenitor cells which can be stored frozen for years)(4) and (2) we can improve the rate and extent of PLT production from human iPSC-derived megakaryocytes above established static culture approaches(5). In our current bioreactor time to initiation of PLT production is reduced from 6 hours to immediately, the percent of PLT-producing progenitors is increased from 10% to more than 90%, the time to completion of PLT production (~1.5x106 PLTs per 300 µL transfusion unit) is reduced from 18 hours to 8 hours, and PLT morphology, ultrastructure and in vitro function is comparable to and consistent with blood PLTs(6). Aim 1. Apply our existing bioreactor to produce 1x108 murine PLTs per 300 µL transfusion unit from primary megakaryocytes, and assess PLT function in vitro. Morphology, cytoskeletal organization, granule content, ultrastructure, biomarker expression, aggregation, and clot retraction of bioreactor-derived PLTs will be compared to blood PLTs under resting and activated conditions. Aim 2. Infuse bdPLTs into sub-lethally irradiated mice to measure bdPLT immunogenicity, clearance, circulation time, hemostatic activity, and determine bdPLT function in vivo. To determine whether bdPLTs are functional in vivo, we will assess bdPLT clearance and circulation time (relative to blood PLT controls), and test their immunogenicity in genetically-distinct and isogenic mouse strains. Aim 3. Determine bdPLT hemostatic activity and thrombus formation in an isogenic adult mouse model of RIT. (non-GLP pilot study) To determine whether bdPLTs can be applied to treat RIT, we will assess bdPLT function in adult mice following sub-lethal ?-irradiation (~6.25 Gy).

Public Health Relevance Statement:
Human platelets are presently derived exclusively from volunteer donors and have a shelf life of 5 days, making platelet unit inventory especially vulnerable to depletion during public emergencies such as a major radiation accident or deliberate attack. There are currently no licensed platelet therapeutics and insufficient platelet supply in the Strategic National Stockpile(3) to meet projected demand in such situations. Platelet BioGenesis is developing a microfluidic bioreactor that mimics key physiological triggers of the bone marrow microenvironment to rapidly produce platelets in order to meet high volume platelet transfusion needs for use in radiation-related emergencies.

Project Terms:
Achievement; Address; Adult; Agreement; American; Animals; Biogenesis; Biological; Biological Markers; Bioreactors; Bleeding time procedure; Blood; Blood Circulation; Blood Platelets; blood vessel development; Blood Vessels; Bone Marrow; cancer therapy; Clinical; Clot retraction; Coagulation Process; Collection; Cytoplasmic Granules; Cytoskeletal Modeling; Data; Drug Kinetics; Embryo; Emergency Situation; Engineering; Equipment and supply inventories; Fetal Liver; Freezing; Grant; Growth; Half-Life; Hemorrhage; Hemostatic Agents; Hour; Human; Human Volunteers; Immunocompromised Host; immunogenicity; improved; In Vitro; in vivo; induced pluripotent stem cell; Infusion procedures; Investigational Drugs; irradiation; Label; Letters; Licensing; Life; Measures; Mediation; Medical; meetings; Megakaryocytes; Microfluidics; Morphology; mortality; mouse model; Mouse Strains; Mus; New Drug Approvals; Nuclear; Operative Surgical Procedures; Perfusion; Phase; Physiological; Pilot Projects; Platelet Count measurement; Platelet Transfusion; prevent; Production; progenitor; Radiation; Radiation Accidents; Radiation exposure; Radiation therapy; Recovery; repaired; Research; Rest; Risk; Safety; shear stress; Small Business Innovation Research Grant; Source; standard of care; Stem cells; Survival Rate; Tail; Temperature; Testing; Therapeutic; Thrombocytopenia; Thrombus; Time; Transfusion; Transplantation; Vendor; Viral; volunteer

Phase II

Contract Number: 5R43AI125134-02
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
2018
Phase II Amount
$300,000
Platelet Biogenesis is developing a microfluidic bioreactor that reproduces key features of adult bone marrow (physiological microenvironment) to produce human platelets (PLTs). PLTs are the 'band- aids' of the bloodstream, responsible for clot formation and blood vessel repair. Low PLT count is a significant consequence of a radiation accident or deliberate nuclear attack, for which PLTs are a critical first-line therapy to prevent mortality due to uncontrolled bleeding. PLT units comprising ~1.5x109 PLTs/mL (3x1011 PLTs total) are currently derived exclusively from human volunteer donors, and must be stored at or above 22oC to avoid irreversible temperature-related activation/aggregation. Risk of bacterial/viral growth during room temperature storage results in short shelf life (5 days). Blood centers typically do not have more than a 1.5-day PLT inventory available for transfusion under non-emergency situations (1, 2), and there are currently no licensed PLT therapeutics for thrombocytopenia to treat radiation exposures(3). To address this major unmet need we will validate our bioreactor to generate functional PLTs from megakaryocyte progenitors at clinical scale to treat radiation-induced thrombocytopenia (RIT). To date we have shown that: (1) It is feasible to generate functional megakaryocytes and PLTs from human induced pluripotent stem cells (iPSCs, a potentially unlimited source of progenitor cells which can be stored frozen for years)(4) and (2) we can improve the rate and extent of PLT production from human iPSC-derived megakaryocytes above established static culture approaches(5). In our current bioreactor time to initiation of PLT production is reduced from 6 hours to immediately, the percent of PLT-producing progenitors is increased from 10% to more than 90%, the time to completion of PLT production (~1.5x106 PLTs per 300 µL transfusion unit) is reduced from 18 hours to 8 hours, and PLT morphology, ultrastructure and in vitro function is comparable to and consistent with blood PLTs(6). Aim 1. Apply our existing bioreactor to produce 1x108 murine PLTs per 300 µL transfusion unit from primary megakaryocytes, and assess PLT function in vitro. Morphology, cytoskeletal organization, granule content, ultrastructure, biomarker expression, aggregation, and clot retraction of bioreactor-derived PLTs will be compared to blood PLTs under resting and activated conditions. Aim 2. Infuse bdPLTs into sub-lethally irradiated mice to measure bdPLT immunogenicity, clearance, circulation time, hemostatic activity, and determine bdPLT function in vivo. To determine whether bdPLTs are functional in vivo, we will assess bdPLT clearance and circulation time (relative to blood PLT controls), and test their immunogenicity in genetically-distinct and isogenic mouse strains. Aim 3. Determine bdPLT hemostatic activity and thrombus formation in an isogenic adult mouse model of RIT. (non-GLP pilot study) To determine whether bdPLTs can be applied to treat RIT, we will assess bdPLT function in adult mice following sub-lethal ?-irradiation (~6.25 Gy).

Public Health Relevance Statement:
Human platelets are presently derived exclusively from volunteer donors and have a shelf life of 5 days, making platelet unit inventory especially vulnerable to depletion during public emergencies such as a major radiation accident or deliberate attack. There are currently no licensed platelet therapeutics and insufficient platelet supply in the Strategic National Stockpile(3) to meet projected demand in such situations. Platelet BioGenesis is developing a microfluidic bioreactor that mimics key physiological triggers of the bone marrow microenvironment to rapidly produce platelets in order to meet high volume platelet transfusion needs for use in radiation-related emergencies.

Project Terms:
Achievement; Address; Adult; Agreement; American; Animals; Biogenesis; Biological; Biological Markers; Bioreactors; Bleeding time procedure; Blood; Blood Circulation; Blood Platelets; Blood Vessels; Bone Marrow; cancer therapy; Clinical; Clot retraction; Coagulation Process; Collection; Cytoplasmic Granules; Cytoskeletal Modeling; Data; Drug Kinetics; Embryo; Emergency Situation; Engineering; Equipment and supply inventories; Fetal Liver; Freezing; Grant; Growth; Half-Life; Hemorrhage; Hemostatic Agents; Hour; Human; Human Volunteers; Immunocompromised Host; immunogenicity; Immunologics; improved; In Vitro; in vivo; induced pluripotent stem cell; Infusion procedures; Investigational Drugs; irradiation; Label; Letters; Licensing; Life; Measures; Mediation; Medical; Megakaryocytes; Microfluidics; Morphology; mortality; mouse model; Mouse Strains; Mus; New Drug Approvals; Nuclear; Operative Surgical Procedures; Perfusion; Phase; Physiological; Pilot Projects; Platelet Count measurement; Platelet Transfusion; prevent; Production; progenitor; Radiation; Radiation Accidents; Radiation exposure; Radiation therapy; Recovery; repaired; Research; Rest; Risk; Safety; shear stress; Small Business Innovation Research Grant; Source; standard of care; Stem cells; Survival Rate; Tail; Temperature; Testing; Therapeutic; Thrombocytopenia; Thrombus; Time; Transfusion; Transplantation; Vendor; Viral; volunteer