Innovative model highlights potential platform
to develop novel therapies
PHILADELPHIA, July 1, 2024
/PRNewswire/ -- Researchers at Children's Hospital of
Philadelphia (CHOP) and the
University of Pennsylvania Perelman
School of Medicine pioneered a new model that offers a potential
platform for developing novel therapies to treat Alpha Thalassemia
(AT), a severe blood disorder. The findings were published in the
journal Blood.
Thousands of children are born with AT every year, especially in
South-East Asia, India, the Middle
East, and the Mediterranean basin. When functioning
normally, the genetic trait may provide protection against malaria
and result in mild anemia. However, when both parents are carriers
of faulty genes, children face an elevated risk of severe AT. In
the most severe cases, the disease can be fatal without in utero
intervention. Children with severe AT often require ongoing blood
transfusions and extensive medical care.
"New treatments for blood disorders have
experienced remarkable success in recent years, particularly
for conditions like beta thalassemia and sickle cell disease.
However, despite representing a growing healthcare challenge, Alpha
Thalassemia has drawn significantly less attention," said senior
author Stefano Rivella, PhD, a
research faculty member in the Division of Hematology at CHOP.
"Our hope is that generating animal models will provide a powerful
tool for future research, along with avenues of investigation for
human patients."
Allogeneic bone marrow transplantation (BMT) is currently the
only available therapeutic option for patients with severe AT, and
that method also requires an appropriate donor. Additionally, until
now, research into therapeutic advancements for AT was limited due
in part to the challenge of creating adult mouse models with this
disease.
In this study, researchers designed an innovative model by
deleting alpha globin genes in adult mice using a lipid
nanoparticle (LNP) embedded within mRNA that induced the deletion
of the alpha globin genes. This led to the production of faulty red
blood cells (RBC) with abnormal hemoglobin, called HbH, that binds
oxygen tightly, preventing its delivery to tissues and causing
paradoxical hypoxia. The targeted LNP platform technology was
previously established by Hamideh Parhiz, PharmD, PhD, a co-senior
study author and Assistant Professor of Medicine at Penn Medicine.
Her team also generated targeted LNP to hematopoietic stem cells
encapsulating mRNA for the current study.
Once the alpha globin genes were deleted, the mice experienced
decreased oxygen levels comparable to individuals with severe AT.
The mice were flooded with RBC that couldn't transport oxygen,
posing an extreme health threat. The researchers confirmed that
this model can now be applied to test novel or genetic therapies in
human patients to improve their clinical care.
Rivella, along with members of his lab, including, Laura Breda, PhD, Maxwell Chapell, PhD, Lucas Tricoli, PhD, and Amaliris Guerra, PhD,
developed a method to perform gene complementation to repair the
defective genetic traits via hematopoietic stem cell modification
and transplantation. The researchers used a lentiviral vector
expressing human alpha globin, named ALS20aI, and found it produced
high levels of human alpha globin in the mice, sustaining them and
boosting normal hemoglobin production. They also noted that ongoing
bone marrow transplantation resulted in the continued expression of
human alpha globin, indicating that ALS20aI effectively modify stem
cells in the blood to provide long-lasting corrections to AT.
"This innovative approach represents a much-needed step forward
in the treatment of Alpha Thalassemia," said Rivella. "We look
forward to further research and the promise of improved patient
outcomes with fewer complications over time."
The authors would like to acknowledge the Pathology Core
Laboratory at CHOP's Research Institute for providing histological,
immunohistochemical, and imaging services. The research was funded
by CHOP's Research Institute's Bridge to Faculty Program (A.G.),
the National Heart, Lung and Blood Institute grant 5K99HL156060-03
(K.G.), the National Heart, Lung, and Blood Institute grant
5R61HL156158-02(O.A.), and SARG-NKUA Code 12260 (A.K.), and NIH
grants R01 CA241762 (to F.D.B). The authors wish to
acknowledge that CD34 cells were supplied by Fred Hutch NIDDK-CCEH
Cell Processing Core, which is funded through NIDDK Grant U54
DK106829.
Rivella, et. al. "Use of HSC Targeted LNP to Generate a Mouse
Model of Lethal α-Thalassemia and Treatment via Lentiviral Gene
Therapy." Blood. Online July 1,
2024. DOI:10.1182/blood.2023023349.
About Children's Hospital of Philadelphia:
A non-profit, charitable organization, Children's Hospital of
Philadelphia was founded in 1855
as the nation's first pediatric hospital. Through its long-standing
commitment to providing exceptional patient care, training new
generations of pediatric healthcare professionals, and pioneering
major research initiatives, the hospital has fostered many
discoveries that have benefited children worldwide. Its pediatric
research program is among the largest in the country. The
institution has a well-established history of providing advanced
pediatric care close to home through its CHOP Care Network, which
includes more than 50 primary care practices, specialty care and
surgical centers, urgent care centers, and community hospital
alliances throughout Pennsylvania
and New Jersey, as well as the
Middleman Family Pavilion and its dedicated pediatric
emergency department in King of
Prussia. In addition, its unique family-centered care and
public service programs have brought Children's Hospital of
Philadelphia recognition as a
leading advocate for children and adolescents. For more
information, visit https://www.chop.edu.
Contact: Jennifer Lee
Children's Hospital of Philadelphia
(267) 426-6084
leej41@chop.edu
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SOURCE Children's Hospital of Philadelphia