Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines.

Abstract

PURPOSE:

Noonan syndrome with multiple lentigines (NSML) is an autosomal dominant disorder presenting with hypertrophic cardiomyopathy (HCM). Up to 85% of NSML cases are caused by mutations in the PTPN11 gene that encodes for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2). We previously showed that low-dose dasatinib protects from the development of cardiac fibrosis in a mouse model of NSML harboring a Ptpn11Y279C mutation. This study is performed to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a low-dose of dasatinib in NSML mice and to determine its effectiveness in ameliorating the development of HCM.

METHODS:

Dasatinib was administered intraperitoneally into NSML mice with doses ranging from 0.05 to 0.5 mg/kg. PK parameters of dasatinib in NSML mice were determined. PD parameters were obtained for biochemical analyses from heart tissue. Dasatinib-treated NSML mice (0.1 mg/kg) were subjected to echocardiography and assessment of markers of HCM by qRT-PCR. Transcriptome analysis was performed from the heart tissue of low-dose dasatinib-treated mice.

RESULTS:

Low-dose dasatinib exhibited PK properties that were linear across doses in NSML mice. Dasatinib treatment of between 0.05 and 0.5 mg/kg in NSML mice yielded an exposure-dependent inhibition of c-Src and PZR tyrosyl phosphorylation and inhibited AKT phosphorylation. We found that doses as low as 0.1 mg/kg of dasatinib prevented HCM in NSML mice. Transcriptome analysis identified differentially expressed HCM-associated genes in the heart of NSML mice that were reverted to wild type levels by low-dose dasatinib administration.

CONCLUSION:

These data demonstrate that low-dose dasatinib exhibits desirable therapeutic PK properties that is sufficient for effective target engagement to ameliorate HCM progression in NSML mice. These data demonstrate that low-dose dasatinib treatment may be an effective therapy against HCM in NSML patients.

• Authors: Jae-Sung Yi, Sravan Perla, Yan Huang, Kana Mizuno, Frank J Giordano, Alexander A Vinks, Anton M Bennett
• Journal: Cardiovascular drugs and therapy (Cardiovasc Drugs Ther) Vol. 36 Issue 4 Pg. 589-604 (08 2022) ISSN: 1573-7241 [Electronic] United States
• PMID: 33689087 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Dasatinib

Topics

• Animals
• Cardiomyopathy, Hypertrophic (drug therapy, genetics)
• Dasatinib (pharmacology, therapeutic use)
• Disease Models, Animal
• LEOPARD Syndrome (drug therapy, genetics, metabolism)
• Mice
• Mutation