SNPMiner Trials by Shray Alag


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Report for Mutation R200W

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There is one clinical trial.

Clinical Trials


1 Phase 1 Study of Digoxin for Congenital Erythrocytosis Due to Up-Regulated Hypoxia Sensing

The investigators will study digoxin to inhibit the hypoxic response in congenital erythrocytosis due to germ line mutations that result in up-regulated hypoxia sensing. These forms of congenital erythrocytosis, characterized by augmented levels of hypoxia inducible factor (HIF)-1 and HIF-2, are due to mutations of VHL (von Hippel Lindau), EGLN1 (encoding prolyl hydroxylase 2 [PHD2]) and EPAS1 (endothelial PAS domain-containing protein 1) (encoding HIF-2α). In addition to a high hematocrit, patients have thrombotic complications and early mortality that are not improved by phlebotomy therapy. There is no effective therapy. Digoxin, long used to treat congestive heart failure, is a potent inhibitor of the master hypoxia-inducible transcription factor, HIF-1. The study hypothesis is that pharmacologic doses and levels of digoxin will decrease hemoglobin and hematocrit, decrease need for phlebotomy, decrease the propensity to thrombosis and decrease pulmonary pressure in patients with erythrocytosis due to up-regulated hypoxic responses. The clinical trial consists of 24 weeks of digoxin therapy in patients with hypoxic response-related erythrocytosis. The complete blood count, safety, symptoms of headache and lack of energy, echocardiogram, physical performance, and plasma products and blood cell expression of HIF-1-regulated genes are the outcome variables.

NCT03433833 Polycythemia; Familial Erythrocytosis; Familial VHL Gene Mutation HIF-2alpha Erythrocytosis PHD2 Erythrocytosis Chuvash Erythrocyotsis Drug: Digoxin
MeSH: Polycythemia Hypoxia
HPO: Hypoxemia Polycythemia

Chuvash erythrocytosis (CE), endemic in the Chuvash Republic of Russia and the Italian island of Ischia, is due to homozygosity for a missense mutation of VHL (VHL c.598C>T; VHL R200W). --- R200W ---

VHL R200W impairs interactions of VHL with HIF-α subunits, reducing their ubiquitin-mediated destruction. --- R200W ---

Aim 3. In a corollary study, determine if in vivo achievable digoxin concentrations abrogate in vitro erythroid progenitor EPO hypersensitivity of mutations other than VHL R200W, and if HIF-2α inhibitors (already in clinical trials) abrogate erythroid progenitor EPO hypersensitivity alone or in combination with digoxin. --- R200W ---

Primary Outcomes

Description: Change of 1.5 g/dL or more

Measure: Hemoglobin concentration

Time: 24 weeks

Secondary Outcomes

Description: Change in log Epo concentration of 15% or more

Measure: Serum EPO concentration

Time: 24 weeks

Description: Change compared to baseline

Measure: Plasma concentration of PAI-1 (plasminogen activator inhibitor 1)

Time: 24 weeks

Description: Change compared to baseline

Measure: Granulocyte mRNA (messenger ribonucleic acid) expression of F3 as determined by RT-PCR (reverse transcription polymerase chain reaction)

Time: 24 weeks

Description: Change compared to baseline

Measure: Tricuspid regurgitation velocity determine by echocardiogram

Time: 24 weeks


HPO Nodes


Hypoxemia
Genes 13
SLC35A1 ASCL1 CSF2RA GDNF FBN1 PHOX2B ZFPM2 HBB HBB CSF2RB GATA6 EDN3 RET
Polycythemia
Genes 19
EPO CCND1 ACVRL1 GATA1 VHL EPAS1 EGLN1 FH SLC30A10 SLC30A10 CYB5R3 SH2B3 PKLR JAK2 JAK2 EPOR BPGM ENG VHL