Researchers at Children’s Hospital of Philadelphia find that lentiviral gene transfer improves production of human alpha globin to treat alpha thalassemia

The innovative model highlights the potential platform to develop new therapies

PHILADELPHIA, July 1, 2024 /PRNewswire/ — Researchers at the Children’s Hospital of Philadelphia (CHOP) and University of Pennsylvania The Perelman School of Medicine pioneered a new model that provides a potential platform for developing new 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 Southeast Asia, INDIA, Middle East, and the Mediterranean basin. When functioning normally, the genetic trait can provide protection against malaria and result in mild anemia. However, when both parents are carriers of the faulty genes, children face a high risk of severe AT. In the most severe cases, the disease can be fatal without in utero intervention. Children with severe AT often require continuous blood transfusions and extensive medical care.

“New treatments for blood disorders have experienced tremendous success in recent years, particularly for diseases such as beta thalassemia and sickle cell disease. However, despite representing a growing healthcare challenge, alpha thalassemia has attracted far less attention,” said the senior author. Stefano Rivella, PhD, research faculty member in the Division of Hematology at CHOP. “Our hope is that the generation of 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 therapeutic option available for patients with severe AT, and this method also requires a suitable donor. Additionally, until now, research into therapeutic advances for AT was limited in part due to the challenge of creating adult mouse models of the disease.

In this study, researchers designed an innovative model by deleting the alpha globin genes in adult mice using a lipid nanoparticle (LNP) embedded within the mRNA that induced the deletion of the alpha globin genes. This led to the production of defective red blood cells (RBCs) with abnormal hemoglobin, called HbH, which tightly binds oxygen, preventing its delivery to tissues and causing paradoxical hypoxia. The targeting technology of the LNP platform was previously developed by Hamideh Parhiz, PharmD, PhD, a co-author of the study and Assistant Professor of Medicine at Penn Medicine. Her team also generated mRNA-encapsulating hematopoietic stem cell-targeted LNPs for the current study.

After the alpha globin genes were deleted, the mice experienced decreased oxygen levels comparable to individuals with severe AT. Mice were flooded with RBCs that could not carry oxygen, posing an extreme health threat. The researchers confirmed that this model can now be applied to test new or genetic therapies in human patients to improve their clinical care.

Rivella, along with members of his lab, including, Laura BredaPhD, Maxwell ChapelPhD, Lucas Tricoli, PhD, and Amaliris Guerra, PhD, developed a method to perform gene complementation to repair damaged genetic traits through the modification and transplantation of hematopoietic stem cells. The researchers used a lentiviral vector that expresses human alpha globin, called ALS20aI, and found that it produced high levels of human alpha globin in mice, maintaining them and increasing normal hemoglobin production. They also noted that ongoing bone marrow transplantation resulted in continued expression of human alpha globin, indicating that ALS20aI effectively modifies blood stem cells to provide long-term AT corrections.

“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 thank the Core Pathology Laboratory at the CHOP Research Institute for providing histology, immunohistochemistry, and imaging services. The research was funded by the CHOP Research Institute Faculty Bridge Program (AG), National Heart, Lung, and Blood Institute grant 5K99HL156060-03 (KG), National Heart, Lung, and Blood Institute grant 5R61HL156158-02 (OA), and SARG-NKUA code 12260 (AK) and NIH grant R01 CA241762 (to FDB). The authors wish to acknowledge that CD34 cells were supplied by the Fred Hutch NIDDK-CCEH Cell Processing Core, which is funded by NIDDK Grant U54 DK106829.

Rivella, etc. 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 i Philadelphia was founded in 1855 as the country’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and major research initiatives, the hospital has fostered many breakthroughs that have benefited children around the world. Its pediatric research program is among the largest in the country. The facility has a solid track record of providing advanced pediatric care close to home through it CHOP Care Networkwhich includes more than 50 primary care practices, specialty care and surgery centers, urgent care centers and community hospital alliances across Pennsylvania AND New Jerseyand Middleman Family Pavilion and its dedicated pediatric emergency department at King of Prussia. In addition, its unique family-centered care and public service programs have brought the 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 i Philadelphia
(267) 426-6084
[email protected]

SOURCE Children’s Hospital i Philadelphia