[December 11, 2017] |
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Magenta Therapeutics Presents Preclinical Data from Stem Cell Mobilization and Expansion Programs
Magenta
Therapeutics, a biotechnology company developing therapeutics to
improve and extend the use of curative bone marrow transplant for more
patients, today announced the presentation of preclinical data from its
hematopoietic stem cell (HSC) mobilization and expansion programs at the
59th annual meeting of the American Society of Hematology
(ASH) in Atlanta, Ga.
"Magenta is developing first-in-class, transformative drugs to extend
the curative potential of bone marrow transplant and cell therapies to
more patients. We are building a platform based on decades of research
and clinical experience to lead a new era of transplant medicine," said
Michael Cooke, Ph.D., chief scientific officer, Magenta Therapeutics.
"These three presentations provide crucial new insights into stem cell
mobilization, expansion and engraftment and advance our understanding of
how to potentially optimize patient outcomes in bone marrow transplant."
The Combination of GROß and AMD3100 Leads to Rapid and Robust
Mobilization of Hematopoietic Stem Cells in Nonhuman Primates (Abstract
#1920)
Overview and results, presented by Patrick Falahee, Ph.D., Magenta
Therapeutics, include:
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Transforming the standard of care for stem cell mobilization has the
potential to improve both the process and outcomes of bone marrow
transplant. Magenta is developing GROß, a CXCR2 agonist used in
combination with established mobilization agent plerixafor (also known
as AMD3100), based on the physiological mechanisms that control cell
migration. The current mobilization standard of care is G-CSF, which
requires a minimum of 5 days of treatment and multiple outpatient
visits, and is often associated with bone pain, nausea, headache and
fatigue.
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In these studies in non-human primates, Magenta showed that a single
administration of GROß in combination with plerixafor induces robust
mobilization of a transplantable dose of CD34+CD90+CD45RA-
hematopoietic stem and progenitor cells within four hours of
administration.
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CD34+CD90+CD45RA- HSCs have been shown to be important for
long-term engraftment and hematopoietic reconstitution, both of
which influence patient outcomes in bone marrow transplant as well
as gene therapy and genome editing approaches.
-
These data suggest that GROß with plerixafor may offer a more robust,
safer and more practical alternative to G-CSF in autologous and
allogeneic transplant, which could be particularly important for
diseases such as sickle cell disease or multiple sclerosis, where
G-CSF is contraindicated or associated with severe adverse events.
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Magenta plans to initiate IND-enabling studies of GROß with plerixafor.
Phenotype Does Not Always Equal Function: HDAC Inhibitors and UM171,
but not SR1, Lead to Rapid Uregulation of CD90 on Non-Engrafting
CD34+CD90-Negative Human Cells (Abstract #659)
Overview and results, presented by Kevin Goncalves, Ph.D., Magenta
Therapeutics, include:
-
Generating a higher dose of hematopoietic stem cells (HSCs) for bone
marrow transplant can have a significant impact on engraftment and
hematopoietic reconstitution, both of which influence patient outcomes
in bone marrow transplant as well as gene therapy/genome editing
approaches. Several approaches exist for expanding HSCs ex vivo
to generate higher cell doses.
-
CD34+CD90+CD45RA- HSCs have been shown to be important for long-term
engraftment and hematopoietic reconstitution -- recent studies in
non-human primates have shown that all the short-term and long-term
engraftment activity is exclusively found in this cell population. In
the current study, Magenta scientists extended this finding to human
HSCs and show that for both fresh and ex vivo expanded cells,
only the CD90 positive subset is able to engraft NSG mice.
-
Magenta scientists used this knowledge of HSC phenotype to compare
several small molecule approaches reported to expand human HSCs,
including the aryl hydrocarbon reception (AHR) antagonist SR1; histone
deacetylase (HDAC) inhibitors; and UM171, a small molecule with
unknown mechanism.
-
The data showed that while all methods increased the number of
CD34+CD90+CD45RA- cells in vitro, AHR antagonists led to the
largest increase in engrafting human HSCs in animals. Notably,
cells cultured with HDAC inhibitors failed to engraft despite
containing high numbers of CD34+CD90+CD45- cells.
-
Cell sorting experiments revealed that culture with HDAC inhibitors
and UM171 leads to rapid upregulation of HSC markers (CD90 and loss of
CD45RA) on CD34+CD90-negative progenitor cells. These results suggest
that most of the CD34+CD90+CD45RA- cells generated with HDAC
inhibitors and UM171 arise from upregulation of CD90 rather than
expansion of true CD34+CD90+CD45RA- cells and may explain the
discrepancy between the in vitro phenotype and in vivo
engraftment results observed with these compounds.
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These results suggest that AHR inhibition is an optimal method for
ex vivo expansion of human hematopoietic stem cells. Magenta is
advancing this expanded stem cell product (MGTA-456) in clinical
trials (see abstract #662).
AHR Antagonists Expand Adult Hematopoietic Stem Cells from Mobilized
Peripheral Blood and Bone Marrow and Increase the Dose of CRISPR/Cas9
Gene-Edited NSG-Repopulating Cells (Abstract #3341)
Overview and results, presented by Megan Hoban, Ph.D., Magenta
Therapeutics, include:
-
Gene-modified hematopoietic stem cell transplant (genome editing/gene
therapy) is a promising treatment approach for a number of inherited
diseases but is limited by:
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The inability to generate a sufficient dose of gene-modified HSCs
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The need for myeloablative conditioning to achieve engraftment
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Based on extensive medicinal chemistry work, Magenta Therapeutics
developed a proprietary AHR antagonist as a potential approach to
generate higher gene-modified cell doses by expanding the numbers of
gene-modified HSCs ex vivo.
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In this study, human HSCs from both mobilized peripheral blood and
bone marrow were edited with CRISPR/Cas9 technology, expanded with the
AHR antagonist and then transplanted into NSG mice.
-
Expanded cells showed up to a 34-fold increase in the number of
CD34+CD90+ HSCs during in vitro culture, and when these
expanded cells were transplanted into NSG mice, they resulted in twice
the number of human cells engrafting in vivo compared to
controls.
-
Importantly, the high levels of editing of the expanded cells obtained
during the in vitro culture (~80%) were maintained in vivo, demonstrating
that the expanded-edited HSCs can retain engraftment activity.
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Preclinical studies are ongoing to examine the ability of the AHR
antagonist to expand HSCs transduced with lentiviral vectors.
About Bone Marrow Transplant
Healthy bone marrow stem cells and the blood cells they create are
crucial for survival, but certain diseases can affect the bone marrow,
interfering with its ability to function properly. A bone marrow
transplant is a process to replace unhealthy bone marrow with healthy
bone marrow stem cells. Bone marrow transplant can save the lives of
patients with blood cancers and genetic diseases and is a potential cure
for patients with severe refractory autoimmune diseases. However, the
high risks, toxic side effects and complexity of the procedure currently
prevent many patients from being able to benefit.
About Magenta Therapeutics
Magenta Therapeutics is a biotechnology company developing therapeutics
to revolutionize bone marrow transplant for patients with autoimmune
diseases, blood cancers and genetic diseases. By creating a platform
focused on critical areas of transplant medicine, Magenta Therapeutics
is pioneering an integrated approach to extend the curative power of
bone marrow transplant to more patients. Founded by internationally
recognized leaders in bone marrow transplant medicine, Magenta
Therapeutics was launched in 2016 by Third Rock Ventures and Atlas
Venture and is headquartered in Cambridge, Mass. For more information,
please visit www.magentatx.com.
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