# Clinical trial of AAV8-mediated FVIII gene transfer for hemophilia A

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $669,282

## Abstract

Abstract
We propose an open label, dose-escalation, phase I/II study in which a single dose of the novel
recombinant AAV vector, AAV2/8 HLP FVIII-V3co, will be administered into a peripheral vein of 
adult subjects with severe hemophilia A . Our premise is that this will be a safe and efficacious 
approach for limiting the bleeding propensity of these patients . Hemophilia A (HA) is an X-linked 
recessive bleeding disorder that results from a defect in the factor VIII (FVIII) gene. FVIII encodes a
glycoprotein procofactor which, when activated by thrombin, interacts with factor IXa in the coagulation
cascade, leading to clot formation. Clinically, the disease is characterized by frequent spontaneous
bleeding, which can be life-threatening. There are several novel aspects to our approach to liver-targeted
AAV-mediated FVIII gene transfer, including 1) a unique FVIII cDNA that meets the size constraints of AAV
and mediates synthesis of fully functional FVIII protein, 2) an expression cassette that improves the efficiency
of FVIII expression and secretion and 3) an improved method of recombinant AAV vector production. Our
extensive studies in murine models and rhesus macaques have shown that AAV2/8 HLP FVIII-V3co vector
safely establishes therapeutic levels of FVIII in these animals. In addition, we now have the unique
experience of having conducted a successful phase I/II clinical trial of liver-targeted, AAV-mediated FIX gene
transfer for hemophilia B that has provided new insights to the design of our AAV-mediated FVIII gene transfer
trial. We propose to test three dose levels: 6x1011, 2x1012 and 6x1012 vg/kg. The primary objective of the
study is to assess the safety of systemic administration of this vector while the secondary objectives are:
1) to determine the dose of vector particles required to achieve stable expression of FVIII ≥5% of normal; 2)
to explore the impact on quality of life, emotional health and neurocognitive function; 3) to describe the
immune responses to the FVIII transgene product and AAV capsid proteins and 4) to assess viral shedding
into various body fluids. Recruitment will be limited to adults (≥18 years of age) with a confirmed diagnosis
of severe HA caused by a mutation in the FVIII gene not associated with a high incidence of inhibitor
formation. In addition, participants must have had ≥50 exposure days of treatment with FVIII protein
concentrate without having developed an inhibitor. Dose escalation will proceed based on safety (primary)
and efficacy (secondary) criteria. Immunosuppression will not be given routinely to patients receiving the
lowest dose of vector; rather, only for those low dose patients who develop ALT elevation >1.5-times
baseline. However, based on our AAV2/8 FIX experience, all patients in the intermediate and high dose
cohorts will receive prophylactic steroids from weeks 6-13. Stopping rules are in place which include: 1) the
occurrence of Grade IV or V toxicity in one patient or Grade III ...

## Key facts

- **NIH application ID:** 9838289
- **Project number:** 5R01HL140295-03
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** ANDREW M DAVIDOFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $669,282
- **Award type:** 5
- **Project period:** 2018-01-10 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838289

## Citation

> US National Institutes of Health, RePORTER application 9838289, Clinical trial of AAV8-mediated FVIII gene transfer for hemophilia A (5R01HL140295-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9838289. Licensed CC0.

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