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AAV Gene Therapy for Hemophilia A

Optimized Liver-Specific Expression of Modified FVIII

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AAV Gene Therapy for Hemophilia A

  • Overview
  • Target
  • Drug Modality
  • Indication
  • Mechanism of Action
  • Status
  • Data
Drug Name AAV-voyager

A recombinant adeno-associated virus (rAAV)-based gene therapy contains the SQ variant of coagulation factor VIII under the control of a patented liver-specific promoter (ATh promoter).

Target Factor VIII (FVIII)
Drug Modality AAV vector
Indication Hemophilia A
Product Category Gene therapy
Mechanism of Action The modified FVIII sequence is delivered to target liver hepatocytes employing the rAAV vector, allowing long-term stable expression of functional FVIII protein in vivo.
Status Preclinical
Patent Granted

Collaboration Opportunity

Protheragen Inc. is actively seeking partnership for AAV-voyager. Potential collaboration can be strategic alliance, licensing, or marketing agreement.

We look forward to hearing from you.

Factor VIII

Introduction Factor VIII (FVIII) is an essential coagulation protein encoded by the F8 gene, which consists of six domains including A1-A2-B-A3-C1-C2. In the coagulation cascade, FVIII is activated proteolytically by a variety of coagulation enzymes and FVIII functions as a cofactor for the factor IXa-dependent activation of factor X.
Approved Name Coagulation factor VIII
Official Symbol F8
Gene Type Gene with protein product
Synonyms F8, AHF, DXS1253E, F8B, F8C, FVIII, HEMA, coagulation factor VIII, THPH13
Ensembl ENSG00000185010
Gene ID 2157
mRNA Refseq NM_000132; NM_019863
Protein Refseq NP_000123; NP_063916
OMIM 300841
UniProt ID P00451
Chromosome Location Xq28

Clinical Resources

Gene Function

In humans, the F8 gene encodes coagulation FVIII. In patients with hemophilia A, an X-linked recessive disorder, a mutation in the F8 gene leads to abnormal blood clotting. More than 950 unique mutations (insertions, inversions, deletions, and nonsense mutations) in the F8 gene have been described.

Pathway The coagulation cascade
Major Conditions Hemophilia A

AAV Vector-based Gene Therapy

AAV-voyager is recombinant AAV vector-based gene therapy containing a patented liver specific promoter (ATh promoter) and modified FVIll sequence. The ATh promoter and the modified FVIll protein showed better performance than HLP promoter and FVIIl-SQ, respectively.

Recombinant AAV vectors of AAV-voyage are produced by the high-efficiency, self-developed Sf9/One-Bac 4.0 system. This insect baculovirus system through introduction of new strategy of AAV expression element regulation, combined with key process optimization, can achieve high yield, high activity, solid rate, and large-scale production of AAV.

Figure 1. The Structure of AAV-voyager

Modified FVIII Structure

FVIIl-SQ was utilized in the formation of Roctavian. To enhance the FVIIl expression, the FVIIl-SQ sequence was modified, resulting in FVIIl-SQ and FVIIl-SQ-4A variants.

Figure 2. Modified FVIII Structure Schematic Plot

Hemophilia A

Hemophilia is a rare bleeding disorder caused by the partial reduction or total absence of clotting factors, leading to an impairment in the ability to control bleeding through the normal process of coagulation. The disorder may be inherited or, more rarely, acquired spontaneously. Hemophilia A, caused by insufficient or deficient coagulation protein FVIII, is one of the two main types of inherited hemophilia. The other type is hemophilia B that caused by insufficiency or lack of clotting factor IX. Approximately nine out of ten hemophiliacs are type A. The main signs and symptoms of hemophilia are excessive bleeding and easy bruising. Sufferers may experience heavy bleeding after dental procedures, accidents, or surgery, as well as spontaneous bleeding. Internal bleeding in the brain is a serious complication of hemophilia that may develop following a simple bump on the head or a more serious injury. Unless treated promptly, bleeding episodes can lead to crippling deformities of the joints or death. The World Federation of Hemophilia’s global survey of 2014, which includes data on over 90% of the world’s population, identified a global prevalence of hemophilia A of approximately 143,500 patients. The prevalence of hemophilia A is reported to be increasing in recent years.

There is no cure for hemophilia. Although a rare disease, the market for hemophilia A drugs is significant. Acute bleeding can be controlled with replacement therapy, but approximately 30-35% of patients with severe hemophilia A receiving FVIII replacement therapy develop inhibitors, or inhibitory IgG antibodies to FVIII. Inhibitors bind FVIII, impeding its hemostatic activity and limiting its therapeutic effect. Gene therapy for the treatment of hemophilia A involve the transfer of genes that induce the secretion of a functional FVIII protein. Because of the inherited monogenic nature of hemophilia A, gene therapy has the potential to provide an eventual cure for hemophilia A.

AAV Vector Encoding the Modified FVIII Under the Control of ATh Promoter

The monogenic inheritance of hemophilia A allows the use of gene therapy to correct a single gene to alleviate symptoms. In hemophilia A, gene transfer strategies that target hepatic hepatocytes with AAV vectors are safer than the integration of lentiviral vectors (LVs) into DNA, which potentially induce oncogenesis. AAV vectors are engineered from a non-pathogenic, non-enveloped linear, single-stranded DNA parvovirus, which are minimally integrative and associated with a low risk of insertional mutagenesis. The host transcription machinery transcribes the transgene into mRNA, which is then translated into the protein of interest.

AAV-voyager is a recombinant AAV vector-based gene therapy containing a patented liver specific promoter (ATh promoter) and the modified FVIll sequence. AAV vectors deliver the modified FVIII sequences into hepatocytes to allow adequate long-term expression of functional FVIII proteins, with the maintenance of steady-state plasma FVIII concentrations.

Mechanism of AAV-based Gene Therapy for Hemophilia A (Int. J. Mol. Sci. 2022, 23, 10228.)

The Status of AAV-voyager

The performance of liver-specific ATh promoters and modified FVIll proteins was validated in vitro and in vivo.

Comparison of FVIII Expression Driven by ATh Promoters and Other Promoters

The expression levels of FVIIl driven by different liver-specific promoters were measured following a tail vein injection of AAV8-mcherry in C57 mice. The results showed that ATh promoter-driven FVIIl expression was higher than that of TTRm and HLP promoters.

Antigen Levels of FVIIl-SQ Structures in Mice Measured by ELISA over 14 Weeks

Antigen levels of FVIIl-SQ structures in C57 mice during 14 weeks were measured by ELISA. The results showed that the expression levels of FVIIl-SQ-3A and FVIIl-SQ-4A were higher.

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