VHL Gene Mutation Clinical Trial
Official title:
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.
The study will investigate 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/or 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, and likely HIF-2. VHL mutations- 15 known patients in the US, 55 in Western Europe, 150 in Chuvashia, in Ischia and 11 in India.4 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). VHL R200W impairs interactions of VHL with HIF-α subunits, reducing their ubiquitin-mediated destruction. HIF-1 and HIF-2 heterodimers increase, leading to increased expression of their target genes, including erythropoietin (EPO). In addition, CE erythroid progenitors are hypersensitive to EPO, the explanation of which is not known. In pilot studies this hypersensitivity is inhibited by digoxin. CE patients are prone to develop thrombosis and early mortality that is independent of the increase in hematocrit. This phenotype is different from the dominantly inherited VHL tumor predisposition syndrome mutations that in combination with acquired somatic mutations result in tumorigenesis. Other homozygous and compound heterozygous VHL mutations that cause erythrocytosis but not tumors have been described. EGLN1 (Egl-9 family hypoxia inducible factor 1) mutations- 5 patients in the US. and 21 in Europe. PHD2 (encoded by the EGLN1 gene) is, along with VHL, a principal negative regulator of HIFs. It targets HIF-α subunits for degradation. The first loss-of-function mutation of PHD2 (PHD2 P317R) was identified in a family in which heterozygotes had mild or borderline erythrocytosis. Since then, 25 additional patients with unexplained erythrocytosis who are heterozygote carriers of different PHD2 mutations have been reported. Almost all patients with PHD2-associated erythrocytosis have normal EPO levels. EPAS1 mutations- 20 known patients in the US and approximately 100 in Europe. Affected patients have heterozygous missense mutations in the coding sequence of the EPAS1 gene encoding HIF-2α that result in gain-of function of HIF-2 and elevated EPO levels. There is heterogeneity in these gain-of-function EPAS1 mutations, but their existence supports the critical role of HIF-2 in controlling the expression of renal EPO. Digoxin as an agent to inhibit HIFs. Digoxin, a common and readily available FDA-approved drug for treatment of congestive heart failure, was found to inhibit HIF-dependent gene transcription by ~90% at a concentration of 0.4 μM; it also inhibits HIF-1α protein translation and blocks HIF-1 activity in vivo. Doses of digoxin that prevent and treat murine hypoxic pulmonary hypertension partially protect from hypoxia-induced erythrocytosis. These doses lead to plasma digoxin levels in mice that are at or below the therapeutic range for humans. In unpublished data, therapeutic doses of digoxin diminished exaggerated erythropoiesis in vitro in a CE subject. The study hypothesizes 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 upregulated hypoxic responses. The proposed study is conducted under IND138480 and is approved by the FDA. Aim 1. Determine if digoxin is safe and will decrease EPO, hemoglobin concentration and pulmonary pressure in patients with congenital erythrocytosis due to up-regulated hypoxia sensing. Aim 2. Determine if digoxin will decrease purified blood cell lineage transcription and reduce plasma levels of the products of pro-thrombotic genes up-regulated by the hypoxic response, including IL1B (interleukin-1 beta), THBS1 (thrombospondin), EGR1 (early growth response 1), NLRP3 (NLR family pyrin domain containing 3), SERPINE1 (serpin family E member 1), and F3 (tissue factor). 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. In summary, this proposal provides an unprecedented opportunity to identify inexpensive therapy for rare forms of erythrocytosis due to up-regulated hypoxia sensing for which there is now no safe, effective therapy. As such, this proposal fully coincides with the goals of the FDA's Orphan Products Program. The research will also help define the role of hypoxia in common maladies of mankind including chronic mountain sickness, obstructive sleep apnea, deep vein thrombosis, cancer associated thrombosis and pulmonary hypertension. ;
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