# Intraosseous delivery of lentiviral vectors for hemophilia A gene therapy

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $685,350

## Abstract

PROJECT SUMMARY
Hemophilia A (HemA) results from a deficiency of factor VIII (FVIII) gene (abbreviated as F8 in constructs).
Traditional treatment of HemA patients is repeated infusions of FVIII, which is costly, inconvenient, short-term,
and incompletely effective. In addition, approximately 25% of treated patients develop anti-FVIII immune
responses. Development of inhibitory antibodies (inhibitors) significantly increases morbidity and lowers life
quality for these patients. Treatment for hemophilia inhibitor patients includes use of bypassing agents or immune
tolerance induction (ITI) with high doses of FVIII or new therapies with bioengineered factor Xa, a humanized
bispecific antibody (emicizumab; ACE910), and others. However, frequent infusions of costly reagent are
required, and potential long-term side effects still need to be evaluated. Compared to drug or protein therapy,
gene therapy can achieve a prolonged therapeutic effect with only one or several treatments over the lifetime.
AAV-mediated gene therapy showed very promising results in clinical trials however is not accessible to a
significant portion of patients including pediatric patients and patients with anti-AAV or anti-FVIII antibodies.
Recently ex vivo HSC gene therapy targeting FVIII expression in megakaryocytes (Megs) corrected the bleeding
diathesis even in the presence of inhibitors. This is because FVIII is stored in α-granules and only released at
the injury sites during platelet activation, therefore protected from circulating inhibitors. However, several
limitations exist for ex vivo gene therapy. Our approach to direct long-term expression of FVIII in platelets is
intraosseous (IO) infusion of lentiviral vectors (LVs) (IO-LV gene therapy) carrying a FVIII transgene driven by a
Meg-specific promoter GpIbα (G-F8-LVs). In this in vivo gene therapy protocol, hematopoietic stem cells (HSCs)
were efficiently transduced by LVs in situ, resulting in FVIII expression in Megs and storage in platelet α-granules.
A single IO infusion of G-F8-LV leads to phenotype correction in HemA mice. In vivo delivery of LVs can avoid
many difficulties and potential toxicities encountered by ex vivo gene therapy including low engraftment potential
and pre-conditioning of the subject which induces thrombocytopenia, a particularly undesirable complication for
hemophilia patients. In vivo gene therapy can bypass this significant hemostatic risk.
Previously we have demonstrated very promising results to correct hemophilia phenotype following IO-LV gene
therapy in HemA mice both with and without pre-existing inhibitors. In order to develop a clinically feasible
protocol for human applications, we propose to enhance the efficacy and safety of this strategy in HemA mice.
Furthermore, we will examine the efficacy and safety in human cells using novel humanized NSGW41 and
HemA/NSG/VWFRH/RH transgenic mice. Lastly, we have initiated the study of IO-LV gene therapy in HemA dogs.
We will further improve...

## Key facts

- **NIH application ID:** 10450849
- **Project number:** 5R01HL134321-06
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Carol H Miao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $685,350
- **Award type:** 5
- **Project period:** 2016-08-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450849

## Citation

> US National Institutes of Health, RePORTER application 10450849, Intraosseous delivery of lentiviral vectors for hemophilia A gene therapy (5R01HL134321-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450849. Licensed CC0.

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