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Novel TET2-Targeting Approaches to Induce Fetal Hemoglobin in Sickle Cell Disease and Thalassemia

Lead Inventor: Amittha Wickrema

SUMMARY

This technology enables increased fetal hemoglobin production to alleviate symptoms of blood disorders by modulating TET2 enzyme activity through targeted mutation and pharmacological suppression.

The Unmet Need: Insufficient fetal hemoglobin induction for effective sickle cell and thalassemia treatment

  • Sickle cell disease and thalassemia affect millions worldwide and result from defective adult hemoglobin leading to chronic anemia and organ damage; current treatments such as hydroxyurea have limited efficacy and gene editing approaches face high costs and technical challenges. There remains a critical need for more accessible, effective therapies that can induce fetal hemoglobin to compensate for mutant hemoglobin functionality.

  • Advancements in epigenetic modulation and enzyme targeting, alongside repurposing FDA-approved drugs, have created new opportunities to develop safer and more cost-effective treatments that restore fetal hemoglobin production, leveraging current pharmacological frameworks rather than relying solely on gene editing technologies.

The Proposed Solution: Targeted modulation of TET2 enzyme activity using mutagenesis and FDA-approved drugs to induce fetal hemoglobin expression

  • The faculty inventor developed a solution to reduce TET2 enzymatic activity by mutating a key amino acid residue, leading to reactivation of fetal hemoglobin gene (HBG) transcription in adult red blood cells. Additionally, the use of FDA-approved drugs Ruxolitinib and Eltrombopag to pharmacologically suppress TET2 phosphorylation offers an alternative, clinically translatable approach. This method differs from existing therapies by focusing specifically on TET2 modulation rather than generalized cytotoxic agents or costly gene editing.

ADVANTAGES

  • Effective fetal hemoglobin reactivation

  • Novel enzyme-targeting mechanism

  • Potentially reduced treatment costs compared to gene editing

  • Applicability to multiple hemoglobinopathies

  • Preclinical validation using transgenic models

APPLICATIONS

  • Sickle cell disease symptom mitigation

  • Thalassemia management through hemoglobin modulation

  • Adjunct therapy to existing hemoglobin disorder treatments