A University of Pittsburgh scientist has identified a non-coding single nucleotide variant (SNV) within the histone lysine N-methyltransferase 2E (KMT2E) gene which is significantly associated with elevated risk of pulmonary hypertension (PH), and which may lead to potentially new diagnostic and treatment strategies.
Description
PH is dependent on hypoxia-inducible factor (HIF)-induced vascular dysfunction, where HIF-2? is known to promote expression of the neighboring genes, IncRNA KMT2E-AS1 and KMT2E. These, in turn, can interact to alter epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving metabolic and pathogenic endothelial activity. The identification of this SNV associated with PH, and the crucial role of KMT2E-AS1/KMT2E and H3K4me3 in disease progression, allows for the development of novel diagnostic approaches and treatment strategies for patients with PH.
Applications
1. Pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH)
2. Other diseases linked to HIF-induced vascular dysfunction
Advantages
PH and the more severe form, PAH, are diseases of lung blood vessels linked to hypoxia and the transcription factor HIF. Currently, there is a lack of understanding of the role of genomic, epigenetic, and metabolic factors in disease development and progression.
The identification of key genes involved in the development of PH, including an SNV significantly associated an elevated risk, can lead to better understanding of the underlying mechanisms of cellular damage in PH/PAH. This knowledge could lead to the identification of novel treatment targets for PH including inhibition of KMT2E-AS1, KMT2E and H3K4me3 or genome editing of the SNV as a one-off treatment. This precise approach could be more selective with less risk than broad targeting of HIF-2?, thereby improving patients' quality of life and reliance on medication.
Invention Readiness
Research has identified key components of PH pathology, KMT2E-AS1/KMT2E and H3K4me3. Inhibition of KMT2E-AS1 with chaetocin decreased H3K4me3 levels and ameliorates experimental PAH in vivo demonstrating the potential of this novel treatment approach for PH. Additionally, a non-coding SNV, rs73184087, has been identified as a mediator of HIF-2a epigenetic activity, also providing a target for genome-editing as a one-off treatment for PH/PAH.
IP Status
https://patents.google.com/patent/US20230340463A1
