Blood stem-cell gene therapy leads to stable FVIII levels in small study
None of the 5 hemophilia A patients had bleeding episodes during follow-up
An experimental gene therapy using modified blood stem cells helped five adults with severe hemophilia A attain therapeutic levels of clotting factor VIII (FVIII) to prevent and control bleeding, according to a small first-in-human study.
Over the course of the Phase 1 clinical study (NCT05265767), none of the five patients had any bleeding episodes after receiving the engineered blood stem cells which enclose the genetic instructions to produce a working version of FVIII in a lentiviral vector.
“The early results of this clinical study reveal a new opportunity for gene therapy for hemophilia A that can be offered to all patients, possibly at an early age,” researchers wrote.
Findings were detailed in the study “Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A,” which was published in The New England Journal of Medicine.
Because the lentiviral vector is derived from lentiviruses, a type of virus that blends into their host’s DNA, it’s expected that FVIII will continue to be produced at stable levels over time. The researchers noted “longer follow-up and additional clinical trials with more participants can clarify whether these expectations will hold true.”
‘If gene therapy fails, several acceptable options besides gene therapy exist’
“The good news is that if gene therapy fails, several acceptable options besides gene therapy exist,” Johnny Mahlangu, a researcher and professor at the University of the Witwatersrand in Johannesburg, South Africa, wrote in an accompanying editorial published in the same journal.
Hemophilia A is a genetic disorder in which the blood doesn’t clot properly due to a deficiency or dysfunction of FVIII, a protein essential for blood clotting. Standard treatment involves regular infusions of FVIII to prevent or control bleeding. However, these infusions must be taken for life and may become ineffective if the body develops neutralizing antibodies, known as inhibitors, against the delivered FVIII.
Gene therapy works by delivering genetic instructions to patient cells to restore the body’s ability to produce FVIII on its own. While significant progress has been made in gene therapy for hemophilia, less is known about the effectiveness of approaches that use hematopoietic stem cells (HSCs).
HSCs are cells in the bone marrow that can give rise to all types of blood cells. This study tested a new gene therapy approach that uses these cells to treat severe hemophilia A.
The study included five men, ages 22 to 41, with severe hemophilia A without FVIII inhibitors. The researchers used a lentiviral vector to deliver the genetic instructions for producing FVIII into the patients’ HSCs.
These instructions were controlled by a myeloid-specific promoter, which means they were directed to work specifically in myeloid cells, or those that play a role in the immune response and are derived from HSCs. Patients underwent chemotherapy to make room for the modified HSCs, which were then infused back into their body.
Treatment safety, efficacy measured
The researchers then assessed treatment safety by monitoring side effects and how well the modified HSCs took hold. They also looked at how well the gene therapy worked by measuring the levels of FVIII in circulation and how often patients experienced bleeding.
Patients had severely low levels of white blood cells (neutropenia) and platelets (thrombocytopenia) for a few days. In four of the five patients, blood cell counts normalized within one to three months after the gene therapy.
Those who received a transduction enhancer to improve the process of gene delivery had higher levels of FVIII compared with those who did not.
None of the five participants had any bleeding episodes during the follow-up period, which lasted nine to 27 months. This suggests that using modified HSCs can lead to stable production of FVIII in the body, with FVIII activity levels dependent on how well the genetic instructions were delivered.
However, “because this study involved a limited number of participants and a short duration of follow-up, whether F8 gene delivery through a lentiviral vector is a viable alternative to AAV-mediated F8 gene therapy remains unclear,” Mahlangu wrote. F8 is the gene that encodes the FVIII protein.
Current gene therapy approaches use versions of a delivery vector derived from adeno-associated viruses (AAVs). However, this type of gene therapy is limited because it excludes patients who already have antibodies against AAV.
“The use of [a] lentiviral vector to deliver the factor VIII gene therapy not only overcomes the barrier with respect to preexisting anti-AAV antibodies but also opens the door for many more patients, including pediatric patients, to receive gene therapy,” Mahlangu wrote.
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