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Principal Investigator: Jeremy A Elser
Organization: SHIP OF THESEUS, LLC
Fiscal Year: 2024
Award: $213,500
Funding agency: National Heart Lung and Blood Institute
Hematopoietic stem cell (HSC) transplants (HSCTs) are considered a potentially curative option for patients with
certain cancers of the blood and bone marrow and over 20,000 HSCTs are performed in the US each year.
However, HSCTs are associated with high risk due to the required removal of diseased bone marrow before
transplantation. Until the transplanted cells engraft and proliferate enough to reconstitute the patient’s immune
system, the patient is considered neutropenic during which they are highly susceptible to infection. In addition to
the potentially life-threatening physical risk to the patient, neutropenia necessitates long hospitalization time that
can in part drives the expensive cost of HSCTs ranging up to $400,000 in the US. A current strategy in clinical
trials is to transplant larger pools of donor HSCs to shorten the neutropenic phase. However, these approaches
all rely on ex vivo culturing of donor cells that depend on imperfect man-made culture systems that may disrupt
the proper function of the stem cells and can be prohibitively expensive. Ship of Theseus’ innovative solution is
a drug that will be used for a brief, one-time exposure to donor cells prior to transplantation that improves
expansion in vivo. Our drug is a patented mutant of nuclear transcription factor, Homeobox protein B4
(HOXB4(m)), which promotes HSC expansion without differentiation. HOXB4(m) has improved degradation
resistance, which enables us to overcome several shortcomings of HOXB4 (e.g., short protein half-life and
myeloproliferative disorders associated with genetic overexpression). By elongating its intracellular half-life,
HOXB4(m) is practical for clinical use while potentially avoiding adverse effects induced by constitutive
overexpression. Early preclinical data indicating treating cells with HOXB4(m) can expand all major lineages of
HSCs while maintaining multipotency. However, current delivery of HOXB4(m) is limited by its ability to penetrate
cells and localize in the nucleus, the site of its bioactivity.
The goal of this R61/R33 proposal is to improve efficiency and safety of HOXB4(m) by improving its nuclear
delivery. This will be accomplished through the execution of 3 aims. In Aim 1 (R61), we will perform a library
screen to identify optimal combinations of cell penetrating peptide and nuclear targeting motifs for HOXB4(m)
nuclear localization. In Aim 2 (R33), we will assess in vitro efficacy of the top candidates to select a lead
candidate. In Aim 3 (R33), we will demonstrate long-term hematopoietic reconstitution without adverse effects
or GVHD of our lead candidate in vivo in a mouse HSCT study. Successful completion of this R61/R33 program
will demonstrate feasibility of an improved HOXB4(m) candidate that maintains efficacy at lower concentrations
and briefer exposure periods. This project will provide the necessary data to support future extensive in vivo
efficacy and safety studies necessary for an IND submission. With HOXB4(m), we can circumvent the original
hurdles of HOXB4 and improve expansion in vivo to benefit HSCT patients by shortening the neutropenic phase
to reduce infection, hospitalization time, and cost.
Terms: <ANX5><ANX5 Gene><ANXA5><ANXA5 gene><Abscission><Acceleration><Adverse Experience><Adverse effects><Adverse event><After Care><After-Treatment><Aftercare><Anchorin CII><Anchorin CII Gene><Annexin A5 Gene><Annexin A5 Protein><Annexin V><Apoptosis><Apoptosis Pathway><Apoptotic><Assay><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological><Biological Assay><Blood><Blood Precursor Cell><Blood Reticuloendothelial System><Bone Marrow><Bone Marrow Diseases><Bone Marrow Grafting><Bone Marrow Reticuloendothelial System><Bone Marrow Transplant><Bone Marrow Transplantation><CBP-I><CD34><CD34 gene><Calphobindin I><Cell Body><Cell Nucleus><Cell Transplantation><Cells><Chemotherapy and Radiation><Chemotherapy and/or radiation><Chimera Protein><Chimeric Proteins><Chimerism><Clinic><Clinical><Clinical Trials><Coloring Agents><Complex><Consumption><Data><Disease><Disorder><Dose><Drugs><Dyes><ENX2><ENX2 Gene><Endonexin II><Endonexin II Gene><Engraftment><Excision><Exploratory/Developmental Grants Phase II><Exposure to><Extirpation><Female><Fluorescence Light Microscopy><Fluorescence Microscopy><Fusion Protein><Future><Gel><General Transcription Factor Gene><General Transcription Factors><Genetic><Goals><HPCA1><HSC expansion><HSC transplantation><Half-Life><HeLa><Hela Cells><Hematopoietic><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Progenitor Cells><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Hematopoietic stem cells><Homeo Domain Proteins><Homeobox Family Protein><Homeobox Proteins><Homeodomain Family Protein><Homeodomain Proteins><Homeoproteins><Homeotic Proteins><Hospital Admission><Hospitalization><Hour><Human><IV Infusion><Immune system><Immunodeficient Mouse><In Vitro><Infection><Inflammatory><Inpatients><Intravenous infusion procedures><Lead><Legal patent><Libraries><Life><Lipocortin V Gene><Lipocortin-V><Lytotoxicity><Malignant Bone Marrow Neoplasm><Malignant Bone Marrow Tumor><Malignant Hematopoietic Neoplasm><Marrow Transplantation><Measures><Medication><Methodology><Methods><Mice><Mice Mammals><Modeling><Modern Man><Monitor><Mucosal Inflammation><Mucositis><Murine><Mus><Myelogenous><Myeloid><Myeloid Disease><Myeloid Malignancy><Myeloid Neoplasm><Myeloid Tumor><Myeloproliferative Disorders><Myeloproliferative Tumors><Myeloproliferative disease><Necrosis><Necrotic><Neutropenia><Nuclear><Nucleus><PAP-I><PP4 Gene><Patents><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Penetration><Peptides><Pharmaceutical Preparations><Phase><Placental Anticoagulant Protein I><Placental Protein 4><Predisposition><Programmed Cell Death><Proliferating><Proteins><R33 Program><Recovery><Removal><Resistance><Risk><Safety><Scanning><Site><Source><Staining method><Stains><Surgical Removal><Susceptibility><System><Therapeutic><Thromboplastin Inhibitor><Time><Toxic effect><Toxicities><Toxicology><Transcription Factor Proto-Oncogene><Transcription factor genes><Transplant Recipients><Transplantation><Transplantation Conditioning><VAC-Alpha><Vascular Anticoagulant-Alpha><annexin A5><biologic><blood cancer><blood cell progenitor><blood progenitor><blood stem cell><blood stem cell expansion><blood-forming stem cell><bone marrow cancer><bone marrow disorder><cancer of blood><cancer of the blood><candidate identification><candidate selection><cellular transplant><chemo/radiation therapy><chemotherapy><chemotherapy and radiotherapy><clinical investigation><compare to control><comparison control><conditioning><cost><cytotoxicity><determine efficacy><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy study><evaluate efficacy><examine efficacy><experience><heavy metal Pb><heavy metal lead><hematopoietic cell transplantation><hematopoietic cellular transplantation><hematopoietic progenitor><hematopoietic progenitor cell transplantation><hematopoietic stem cell expansion><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><high risk><improved><in vivo><infection risk><innovate><innovation><innovative><intravenous infusion><lead candidate><male><man><manufacture><mutant><myeloproliferative neoplasm><novel><overexpress><overexpression><patient oriented outcomes><peripheral blood><post treatment><post-transplant><post-transplantation><posttransplant><posttransplantation><pre-clinical><pre-clinical development><preclinical><preclinical development><progenitor cell expansion><progenitor cell function><progenitor expansion><progenitor function><radiation or chemotherapy><reconstitute><reconstitution><resection><resistant><safety study><screening><screenings><stem and progenitor cell expansion><stem and progenitor cell function><stem and progenitor function><stem cell expansion><stem cell function><transcription factor><transplant><transplant patient><uptake>