A novel collaboration between the industry and the academic world has made possible human clinical trials of a new drug for a rare class of blood diseases called myeloproliferative disorders (MPD), which are all driven by the same genetic mutation and can develop into leukemia
The study led by Catriona H.M. Jamieson, M.D. Ph.D., assistant professor of medicine at the University of California, San Diego and Director for Stem Cell Research at Moores UCSD Cancer Center, identified an inhibitor that can cease over-proliferation of blood cells leading to problems with blood clotting, heart attacks and leukaemia.
"As a clinician, I asked myself who is going to get this disease, and what can we do to stop its progression, instead of waiting until it evolves into a deadly cancer? This project has been so extraordinary, because a small pharmaceutical company took a big chance on a rare disease," said Jamieson.
The findings of the study led to development of the inhibitor by TargeGen, a San Diego pharmaceutical company that conducted the research in collaboration with a number of clinics and universities.
Usually, a MPD patient makes too many blood cells, due to a mutation expressed in the stem cell, the early stage cell that goes on to differentiate to become either red or white blood cells.
In an earlier study it was discovered that a mutation in the JAK2 signalling pathway in patients with a type of MPD called polycythemia vera (PV) allows cells to evade the process which would normally regulate the production of red blood cells. Due to this defect, the bone marrow produces excessive numbers of red blood cells.
However, in the current research, the researchers transferred human cord blood stem cells, designed to contain the mutant JAK2 gene, into mouse models with a suppressed immune system to find whether over-expression of a single gene could drive, or initiate, the disease.
These stem cells were introduced directly into the liver, the main site of blood development in the newborn mouse. Thus, the stem cells over-expressing the mutant gene led to overproduction of human red blood cells, and the mice developed a disease that looked like PV. These results were substantiated by injecting actual stem cells from patients with PV into the same mouse model, achieving similar results.
"We found that the JAK2 mutation was necessary and sufficient, by itself, to drive the disease," said Jamieson.
Speculating that blocking this mutation would prevent overproduction of red blood cells, TargeGen developed a selective JAK2 inhibitor called TG101348. This therapy was shown to halt over-expression of the gene and reverse excessive production of red blood cells. As TG101348 selectively targets the JAK2 protein that causes the disease, side effects have been minimized.
"Pre-clinical testing at the UCSD and Harvard University Schools of Medicine confirmed the therapeutic potential of TG101348. The compound was rapidly advanced into the current, ongoing human clinical trials being conducted at major research institutions across the country," said John Hood, Ph.D., Director of Research for TargeGen.
"This unique industry-academia collaboration has helped guide a new drug from bench to bedside, from evaluating the compound's efficacy on cancer stem cells to its evaluation in patients bearing a disease which otherwise has very limited treatment options," he added.
The study is published in the journal Cancer Cell.