# Developing hemophilia A therapeutics by targeting translational and posttranslational regulation of FVIII

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $518,074

## Abstract

Title of project: Developing hemophilia A therapeutics by targeting translational and posttranslational
regulation of FVIII
Abstract: Hemophilia A (HA) is an X-linked inherited disease due to mutations in the gene encoding the blood
coagulation factor VIII (FVIII), which affects 1 in every 5,000 male births. The majority of HA mutations are
nonsense mutations, which introduce premature stop codons leading to no or truncated FVIII protein expression,
and missense mutations, which are marked by excessive misfolding and degradation of FVIII protein. Current
HA treatments include FVIII concentrate or bispecific monoclonal antibody infusions. However, these treatments
are extremely costly and may require frequent office visits. The high cost precludes 80% of the global hemophilia
population from routine access to care. Alternative approaches utilizing small molecule drugs offer several
advantages, including greatly reduced costs and ease of delivery, which can enhance accessibility and patient
compliance. We hypothesize that specific pharmacological molecules can enhance the expression, folding, and
trafficking of certain nonsense and missense mutants, leading to increased coagulation factor levels sufficient to
restore hemostasis. Gene therapy holds promise for a long-term cure for HA. However, FVIII is intrinsically
difficult to express, requiring a high dose of adeno-associated virus (AAV) to produce therapeutic levels of FVIII
in HA patients. A high AAV dose can trigger an immune response against the vector, causing complications and
limiting FVIII expression. We have identified FVIII variants with 6-fold enhanced expression over the currently
used B-domain deleted FVIII. We hypothesize that incorporating these FVIII variants in gene therapy can result
in higher plasma FVIII activity levels with lower viral vector doses, offering a superior alternative to the existing
FVIII variants. In Aim 1, we recently identified compounds that effectively rescue certain nonsense mutations of
FVIII by drug-induced ribosomal readthrough. We will systematically test the most common nonsense FVIII
mutations to identify candidate mutations and sequence patterns that will predict candidate mutations for
effective readthrough therapy. In Aim 2, after screening compound libraries, we identified proteostasis regulators
(PRs) that enhance the secretion of FVIII missense mutants. We will further identify common HA missense
mutations that can be rescued by PRs and their molecular mechanism. We will validate in vitro results of both
aims in mouse models. Aim 3 will further characterize the high-expression FVIII variants and explore the
synergistic effects of combining these variants with existing strategies to boost FVIII expression. The efficacy
and safety of candidate variants will be tested in HA mice through AAV-based gene therapy applications. Taken
together, these studies will validate the use of small-molecule approaches for HA treatment, tailoring them to
each pati...

## Key facts

- **NIH application ID:** 10882022
- **Project number:** 1R01HL169427-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Bin Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $518,074
- **Award type:** 1
- **Project period:** 2024-03-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882022

## Citation

> US National Institutes of Health, RePORTER application 10882022, Developing hemophilia A therapeutics by targeting translational and posttranslational regulation of FVIII (1R01HL169427-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10882022. Licensed CC0.

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