First‐in‐human clinical trial of allogeneic, platelet‐derived extracellular vesicles as a potential therapeutic for delayed wound healing
Abstract The release of growth factors, cytokines and extracellular matrix modifiers by activated platelets is an important step in the process of healthy wound healing. Extracellular vesicles (EVs) released by activated platelets carry this bioactive cargo in an enriched form, and may therefore rep...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-07-01
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| Series: | Journal of Extracellular Vesicles |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jev2.12332 |
| _version_ | 1797772399762997248 |
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| author | Jancy Johnson Sam Q. K. Law Mozhgan Shojaee Alex S. Hall Sadman Bhuiyan Melissa B. L. Lim Anabel Silva Karmen J. W. Kong Melanie Schoppet Chantelle Blyth Hansi N. Ranasinghe Nenad Sejic Mun Joo Chuei Owen C. Tatford Anna Cifuentes‐Rius Patrick F. James Angus Tester Ian Dixon Gregor Lichtfuss |
| author_facet | Jancy Johnson Sam Q. K. Law Mozhgan Shojaee Alex S. Hall Sadman Bhuiyan Melissa B. L. Lim Anabel Silva Karmen J. W. Kong Melanie Schoppet Chantelle Blyth Hansi N. Ranasinghe Nenad Sejic Mun Joo Chuei Owen C. Tatford Anna Cifuentes‐Rius Patrick F. James Angus Tester Ian Dixon Gregor Lichtfuss |
| author_sort | Jancy Johnson |
| collection | DOAJ |
| description | Abstract The release of growth factors, cytokines and extracellular matrix modifiers by activated platelets is an important step in the process of healthy wound healing. Extracellular vesicles (EVs) released by activated platelets carry this bioactive cargo in an enriched form, and may therefore represent a potential therapeutic for the treatment of delayed wound healing, such as chronic wounds. While EVs show great promise in regenerative medicine, their production at clinical scale remains a critical challenge and their tolerability in humans is still to be fully established. In this work, we demonstrate that Ligand‐based Exosome Affinity Purification (LEAP) chromatography can successfully isolate platelet EVs (pEVs) of clinical grade from activated platelets, which retain the regenerative properties of the parent cell. LEAP‐isolated pEVs display the expected biophysical features of EV populations and transport essential proteins in wound healing processes, including insulin growth factor (IGF) and transforming growth factor beta (TGF‐ß). In vitro studies show that pEVs induce proliferation and migration of dermal fibroblasts and increase dermal endothelial cells' angiogenic potential, demonstrating their wound healing potential. pEV treatment activates the ERK and Akt signalling pathways within recipient cells. In a first‐in‐human, double‐blind, placebo‐controlled, phase I clinical trial of healthy volunteer adults, designed primarily to assess safety in the context of wound healing, we demonstrate that injections of LEAP‐purified pEVs in formulation buffer are safe and well tolerated (Plexoval II study, ACTRN12620000944932). As a secondary objective, biological activity in the context of wound healing rate was assessed. In this cohort of healthy participants, in which the wound bed would not be expected to be deficient in the bioactive cargo that pEVs carry, all wounds healed rapidly and completely and no difference in time to wound closure of the treated and untreated wounds was observed at the single dose tested. The outcomes of this study evidence that pEVs manufactured through the LEAP process can be injected safely in humans as a potential wound healing treatment, and warrant further study in clinical trials designed expressly to assess therapeutic efficacy in patients with delayed or disrupted wound healing. |
| first_indexed | 2024-03-12T21:51:16Z |
| format | Article |
| id | doaj.art-8653f009c3a74859a8d7430f53faabab |
| institution | Directory Open Access Journal |
| issn | 2001-3078 |
| language | English |
| last_indexed | 2024-03-12T21:51:16Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Extracellular Vesicles |
| spelling | doaj.art-8653f009c3a74859a8d7430f53faabab2023-07-26T04:04:27ZengWileyJournal of Extracellular Vesicles2001-30782023-07-01127n/an/a10.1002/jev2.12332First‐in‐human clinical trial of allogeneic, platelet‐derived extracellular vesicles as a potential therapeutic for delayed wound healingJancy Johnson0Sam Q. K. Law1Mozhgan Shojaee2Alex S. Hall3Sadman Bhuiyan4Melissa B. L. Lim5Anabel Silva6Karmen J. W. Kong7Melanie Schoppet8Chantelle Blyth9Hansi N. Ranasinghe10Nenad Sejic11Mun Joo Chuei12Owen C. Tatford13Anna Cifuentes‐Rius14Patrick F. James15Angus Tester16Ian Dixon17Gregor Lichtfuss18Exopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaExopharm Ltd Melbourne VIC AustraliaAbstract The release of growth factors, cytokines and extracellular matrix modifiers by activated platelets is an important step in the process of healthy wound healing. Extracellular vesicles (EVs) released by activated platelets carry this bioactive cargo in an enriched form, and may therefore represent a potential therapeutic for the treatment of delayed wound healing, such as chronic wounds. While EVs show great promise in regenerative medicine, their production at clinical scale remains a critical challenge and their tolerability in humans is still to be fully established. In this work, we demonstrate that Ligand‐based Exosome Affinity Purification (LEAP) chromatography can successfully isolate platelet EVs (pEVs) of clinical grade from activated platelets, which retain the regenerative properties of the parent cell. LEAP‐isolated pEVs display the expected biophysical features of EV populations and transport essential proteins in wound healing processes, including insulin growth factor (IGF) and transforming growth factor beta (TGF‐ß). In vitro studies show that pEVs induce proliferation and migration of dermal fibroblasts and increase dermal endothelial cells' angiogenic potential, demonstrating their wound healing potential. pEV treatment activates the ERK and Akt signalling pathways within recipient cells. In a first‐in‐human, double‐blind, placebo‐controlled, phase I clinical trial of healthy volunteer adults, designed primarily to assess safety in the context of wound healing, we demonstrate that injections of LEAP‐purified pEVs in formulation buffer are safe and well tolerated (Plexoval II study, ACTRN12620000944932). As a secondary objective, biological activity in the context of wound healing rate was assessed. In this cohort of healthy participants, in which the wound bed would not be expected to be deficient in the bioactive cargo that pEVs carry, all wounds healed rapidly and completely and no difference in time to wound closure of the treated and untreated wounds was observed at the single dose tested. The outcomes of this study evidence that pEVs manufactured through the LEAP process can be injected safely in humans as a potential wound healing treatment, and warrant further study in clinical trials designed expressly to assess therapeutic efficacy in patients with delayed or disrupted wound healing.https://doi.org/10.1002/jev2.12332extracellular vesiclesfirst‐in‐human platelet EV therapyplatelet EVswound healing |
| spellingShingle | Jancy Johnson Sam Q. K. Law Mozhgan Shojaee Alex S. Hall Sadman Bhuiyan Melissa B. L. Lim Anabel Silva Karmen J. W. Kong Melanie Schoppet Chantelle Blyth Hansi N. Ranasinghe Nenad Sejic Mun Joo Chuei Owen C. Tatford Anna Cifuentes‐Rius Patrick F. James Angus Tester Ian Dixon Gregor Lichtfuss First‐in‐human clinical trial of allogeneic, platelet‐derived extracellular vesicles as a potential therapeutic for delayed wound healing Journal of Extracellular Vesicles extracellular vesicles first‐in‐human platelet EV therapy platelet EVs wound healing |
| title | First‐in‐human clinical trial of allogeneic, platelet‐derived extracellular vesicles as a potential therapeutic for delayed wound healing |
| title_full | First‐in‐human clinical trial of allogeneic, platelet‐derived extracellular vesicles as a potential therapeutic for delayed wound healing |
| title_fullStr | First‐in‐human clinical trial of allogeneic, platelet‐derived extracellular vesicles as a potential therapeutic for delayed wound healing |
| title_full_unstemmed | First‐in‐human clinical trial of allogeneic, platelet‐derived extracellular vesicles as a potential therapeutic for delayed wound healing |
| title_short | First‐in‐human clinical trial of allogeneic, platelet‐derived extracellular vesicles as a potential therapeutic for delayed wound healing |
| title_sort | first in human clinical trial of allogeneic platelet derived extracellular vesicles as a potential therapeutic for delayed wound healing |
| topic | extracellular vesicles first‐in‐human platelet EV therapy platelet EVs wound healing |
| url | https://doi.org/10.1002/jev2.12332 |
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