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A novel approach to Mesenchymal Stem Cell Transduction

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41HL155004-01A1
Agency Tracking Number: R41HL155004
Amount: $248,452.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NHLBI
Solicitation Number: PA20-265
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-09-20
Award End Date (Contract End Date): 2022-03-19
Small Business Information
151 10TH ST
San Francisco, CA 94103-2604
United States
DUNS: 080199257
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 (317) 278-0501
Business Contact
Phone: (415) 513-5535
Research Institution
United States

 Nonprofit College or University

Mesenchymal stem cells (MSC) are in clinical development for cardiovascular, neurologic, orthopedic, and
other indications. Ossium is developing a novel source of MSC from vertebral bodies (vbMSC). Genetic
modification of vbMSC using lentiviral vector (LV) has the potential to improve the therapeutic potential.
Understanding how genetic modification might alter the vbMSC phenotype will be critical to ensuring LV do
not initiate premature senescence or diminish their therapeutic properties. Moreover, an important safety and
regulatory barrier to clinical implementation of gene modified vbMSC will be estimating the risk of insertional
mutagenesis. Gammaretroviral vectors used to modify hematopoietic stem cells (HSC) led to leukemia in at
least 4 clinical trials. While lentiviral vectors appear safer, clonal expansion of HSC and mature T cells have
now been reported. Ossium seeks to address important safety and efficacy issues in this Phase I proposal.
We hypothesize that (1) A HIV-1 based LV pseudotyped with a novel foamy viral envelope (LV-FV) will
efficiently transduce vbMSC with less change in cell phenotype compared to LV pseudotyped with VSV-G;
(2), the LV integration pattern, distribution among cancer associated genes and ability to induce cell
immortalization, will be similar to that seen in other cell types. To study this, we propose: Specific Aim 1:
Assess the Effect of LV Gene Transfer and Vector Pseudotype on vbMSC phenotype. LV expressing green
fluorescent protein (GFP) pseudotyped with VSVG and FV will be used to transduce vbMSC. Cells will be
assessed for gene transfer (vector copy number) and expression (GFP by flow cytometry), viability,
expansion capacity, MSC-associated surface markers, secretome, and ability to differentiate into three
lineages (bone, adipose and cartilage). Specific Aim 2: Evaluate Insertional Mutagenesis Risk in LV
transduced vbMSC. This aim seeks to investigate the genotoxicity of LV vectors in MSC. Specific Aim 2A.
Evaluating LV-transduced vbMSC for Integration Pattern and Cancer-Associated Gene Preferences.
Comparisons between LV and gammaretroviral vectors in low and high passage vbMSC will be compared
to published data on HSC integrations. Specific Aim 2B. Evaluating LV-transduced vbMSC for
Immortalization. In this sub-aim we will seek to develop an assay for assessing IM risk by evaluating vbMSC
after gene transfer. The findings will have broad applicability given the number of disease states in which
MSC may play a therapeutic role. This proposal also uses a variety of innovative technologies, including a
novel LV-FV, a novel stem cell source (vertebral body MSC), and will be the first study aimed at assessing
the risk of immortalization in MSC.PROJECT NARRATIVE
This proposal seeks to address safety and efficacy studies important to clinical development of gene
modified vertebral body derived Mesenchymal Stem Cells (vbMSC). Ossium will evaluate vbMSC
genetically modified with different lentiviral pseudotypes seeking to minimize changes in the MSC
phenotype previously reported after vector transduction. Secondly, given that leukemias and clonal cell
outgrowth have been reported in clinical trials of retroviral and lentiviral transduced hematopoietic cells, we
will begin to assess the risk of insertional mutagenesis using high throughput sequencing of transduced
vbMSC. We also seek to develop a detection assay for vector-associated MSC immortalization.

* Information listed above is at the time of submission. *

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