Grants and Grant Recipients
For over 30 years, AAMDSIF has provided research grants totaling in excess of $5.5 million to an international group of more than 100 researchers to help advance the understanding and treatment of aplastic anemia , myelodysplastic syndromes (MDS), and paroxysmal nocturnal hemoglobinuria (PNH).
The two-year grants have helped bring forth new insights into the causes and therapeutic approaches for these diseases. These grantee profiles present the grantees by year the awards were granted, and a summary of their grant-funded research projects.
Grant Year: 2014
Rosannah Cameron, PhD
Lindsay Minelli Research Fund, Research is Hope Fund
We do not yet fully understand the process of disease progression in MDS. We know certain genes are involved because mutations in those genes have been found in MDS patients. We need to understand which genes are important early in the disease and which ones act later. Our goal is to identify the genes that act early in MDS, so that ultimately, our research will lead to new treatment options that are more specific and effective.
Youmna Kfoury, PhD
Lisa Lancaster Research Fund
Myelodysplastic Syndromes (MDS) are a group of diverse and incurable pre-leukemic disorders. Even though a deregulated bone marrow microenvironment is thought to participate in the disease, its role remains elusive. Since the microenvironment is better understood in mice, we have identified a subset of cells in the human bone marrow that is equivalent to those cells in mice which, when perturbed, lead to MDS. We propose to characterize these cells in patient samples at the cellular and molecular level. This will provide a better understanding of the abnormal signaling pathways involved in MDS, and eventually identify therapeutic approaches.
Patrizia Ricci, PhD
PNH Research and Support Foundation
PNH is a rare hematological disease characterized by spontaneous destruction of red blood cells (intravascular hemolysis), poor functioning of bone marrow, and thrombosis. Recently, the availability of the complement inhibitor eculizumab has dramatically improved the treatment of PNH. Nevertheless, about half of the patients treated with eculizumab shows a persistence of clinical signs of the disease. We have recently described the reasons underlying the limited efficacy of current anti-complement treatment for PNH. With this proposal we aim to complete the pre-clinical development of a novel complement inhibitor which targets early events in complement activation, the component-3 of the complement cascade.
Chao-Yie Yang, MD, PhD
PNH Research and Support Foundation
Uncontrolled complement activation caused by a gene (PIG-A) mutation in hematopoietic stem cells has been characterized in PNH. Patients suffer from hemolysis, thrombosis and bone marrow failure. Current FDA-approved only treatment for PNH is eculizumab which is expensive, unable to eradicate PNH clone, not orally available, requires clinic-bound infusions via iv access and lifelong therapy. In this proposed work, we will discover and make rational designs to small molecules guided by protein structures to develop complement inhibitors. The promising small molecule inhibitors identified from this work will be evaluated and used to develop orally-available therapeutics to treat PNH patients.
Grant Year: 2013
Andrew Dancis, MD
Research is Hope Fund
Myelodysplasia is a bone marrow failure syndrome with a
tendency to progress to leukemia. A characteristic finding in blood cell
precursors of some individuals with myelodysplasia is the ringed sideroblast, a
cell that accumulates large amounts of toxic iron in mitochondria. Recently, the
presence of these abnormal mitochondria has been correlated with mutations of
the splice factor SF3B1. We plan to investigate the mitochondria of these cells
with perturbed SF3B1, aiming to gain insight into mitochondrial causes of
myelodysplasia. This may point to new therapies.
Hideki Makishima, MD, PhD
PNH Research and Support Foundation
PNH is a disease in which a mutation
in the gene called PIG-A is acquired in the stem cells (mother cells of all
blood cells) in the bone marrow of patients.
As a result the blood cells produced by this stem cell are
defective. While previous discover of
the PIG-A gene mutation has helped to explain the symptoms in the disease, it
remains unclear how PIG-A mutation makes the PNH stem cells outcompete healthy
stem cells. In this project we propose
to apply a very efficient sequencing technology to examine all genes in PNH
stem cells to see whether additional mutations will explain how PNH
develops. In the initial experiments we
have identified such additional mutations.
They may help to devise treatments to eradicate PNH stem cells from the...
Rosario Notaro, MD
Amber Lynn Wakefield Research Fund
Aplastic anemia and Paroxysmal
Nocturnal Hemoglobinuria (PNH) are two serious blood disorders that share one
important feature: the bone marrow
cannot always keep up with the body’s needs for blood cells. We call this feature bone marrow failure
(BMF); it means that there may be anemia, low white cells (particularly
neutropenia, entailing the risk of infection), low platelets (with risk of
bleeding). Recently we have analyzed in
depth a type of lymphocyte cells called T cells in patients with PNH, and we
have found that they have an excess of a very rare subset of T cells that are
able to recognize a specific glycolipid molecule (a molecule that contains both
a sugar moiety and a fat moiety) – we have called them GPI-reactive T
cells. We now plan to...
Eirini Papapetrou, MD, PhD
Research is Hope Fund
Progress in understanding the
etiology and effective treatment of MDS is currently hampered by the scarcity
of tools to study this disease. Our goal
is to harness cutting-edge human pluripotent stem cell and genetic
engineering technologies to establish
new models of an MDS subset characterized by loss of chromosome 7 material and
use them as a novel platform to identify genes on chromosome 7 that are
critical for this disease. These models
should provide a powerful resource to the MDS community to investigate the cell
biology, molecular pathogenesis and genetic basis of MDS, identify new
therapeutic targets and perform drug screens.
Read more about this study.
Akiko Shimamura, MD, PhD
Torry Yahn Research Fund
Currently aplastic anemia is treated
with immunosuppressive therapy (IST) or a bone marrow transplant. Approximately 30% of aplastic anemia patients
treated with IST are refractory to treatment or develop myelodysplastic
syndromes (MDS) and leukemia. Tests to
predict which patients will fare poorly to immunosuppressive therapy would
inform upfront treatment decisions. We
will utilize cutting edge genomic technologies to screen for genetic markers
predictive of poor outcomes with IST.
This study will develop a novel diagnostic tool for aplastic anemia to
guide treatment decisions with the goal of improving patient survival.
Grant Year: 2012
David Araten, MD
PNH Research and Support Foundation
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a disorder in which bone marrow failure is an important feature. The bone marrow failure in PNH is similar or identical to that which occurs in aplastic anemia. However, PNH has a few other features, some of which are well understood and some of which are not . One of the features that is not well understood in PNH includes the expansion of an abnormal stem cell clone in the bone marrow (called clonal expansion) which can by itself provide a very large percentage of the patient's blood cells. This clone has as its feature the presence of a mutation in a gene called PIG-A. Different patients have different types of mutations in this gene, but it is always in this gene. It has long been suspected that there may be other genes...