Katie Thrasher
As a child, the diseases her grandparents suffered from seemed no different from cataracts or artist did not know that diabetes and heart disease were chronic conditions. Or that they limited blood flow to certain parts of the body, ultimately leading to death. She learned all that later.
“My grandma lives with diabetes and my grandpa has had several heart attacks. They are the main reason I do this research,” Take said. Her work now involves finding biochemical solutions for those at risk of Type 2 diabetes, cardiovascular diseases, and stroke.
That work is what culminated in an article published last month in Nature Communications.
Today, Take works at one of Stanford University’s signature terracotta-roofed buildings, ones fringed by palm trees, and by sidewalks where students whiz by at a frenzied clip on bicycles.
Vascular health through protein therapeutics as she was nearly seven years ago when she stepped into Aaron Baker’s lab at the University of Texas at Austin.
Then a recent graduate from the Tokyo Take was awestruck by Baker, his lab, his work on regenerative therapies, and specifically his research using stem cell factor (SCF) proteins to improve blood vessel growth.
The cure that worked too well
The project was not if or how the SCF therapy would work. There was extensive evidence that it did. Their problem was to address the severe allergic responses seen (due to activation of mast cells, a type of white blood cell important in immune response) in many people with no history of allergies who received a specific SCF therapy.
And so it began. The research. The trials. The waiting.
Take team finally discovered what was triggering the mast cell activity. It was a reaction to the rapid delivery of proteins from the soluble stem cell factor. The therapeutic proteins were immune system overreacted as it fought back against the onslaught of proteins. It was as if you had torn open a bag of mini chocolate chips and dumped it directly down your throat.
Pic courtesy Stanford University
The delivery of the SCF proteins had to be slowed. The answer lay in using a transmembrane (spanning the cell membrane) version of SCF that delivered the protein much more slowly than standard SCF. It seemed like a great idea, but the transmembrane SCF was insoluble and clumped together when put in a solution for injection.
“It was a puzzle,” Take said. And while it was clear what needed to be done, the path to get there was a labyrinth of unexplored terrain.
Fat as a sorter
So the team developed a carrier system made of fats, or lipids, to prevent from clumping. Measured packed in either a 450 nm diameter fat bubble (called a liposome), or a 150 nm diameter lipid disc
The research team essentially used a bag of mini chips to make chocolate chip cookies. The delivery of the protein was slowed, the body was not overwhelmed.
There were no notable setbacks or fantastic failures or epic disasters, though the process to develop the new delivery system was painstakingly lengthy.
Stem cell factor (SCF) is a cytokine that regulates hematopoiesis and other biological processes. While clinical treatments using SCF would be highly beneficial, these have been limited by toxicity related to mast cell activation. Transmembrane SCF has differential activity from soluble SCF and has not been explored as a therapeutic agent. We created novel therapeutics using embedded or lipid disc models of anaphylaxis revealed based therapies did not activate mast cells and improved the revascularization Photo preferentially acted on endothelial cells to induce disc had greater activity in inducing stem cell mobilization and recruitment to the site of injury. The type of lipid disc used altered the relative cellular uptake pathways and signaling in a cell type dependent manner. Overall, we found based therapies can provide therapeutic benefits without off target effects.
Introduction
Over the past three decades, protein therapeutics have emerged as a powerful approach to drug development1,2. The first use of a therapeutic protein developed was insulin, used as a therapy for diabetes mellitus3. Since then, over 200 protein-based compounds have been approved for clinical use and over 250 proteins are currently in various stages of clinical evaluation4,5. This has been particularly the case with as these molecules are natively found in the complex lipid bilayer of the cell membrane and often require this environment for proper function and solubility7. Virtually all disease processes involve membrane as receptors, co-receptors, or membrane bound factors that are needed to transmit cellular signals8,9,10. Thus, the delivery of membrane protein therapeutics may provide a rich strategy for enabling next generation therapeutics.
Stem cell factor (SCF) is a hematopoietic cytokine that signals through the c-Kit receptor (CD117)11, and is also known as Kit ligand, Steel factor or mast cell growth factor. Signaling through SCF induced c-Kit activation is key to the maintenance of the hematopoietic stem cells (HSCs) and progenitor cells in the bone marrow13,14. There are several potential uses for SCF in therapeutic applications including improving the survival and expansion of HSCs following exposure to radiation15,16, inducing neuroprotective effects following stroke17,18,19, and enhancing the recovery of the heart following myocardial infarction. However, SCF also has an important role in regulating mast cell maturation and activation20,21. Treatment with exogenous SCF leads to mast cell activation and anaphylaxis in animal studies and clinical trials, severely limiting its therapeutic application22,23,24,25,26,27,28,29.
In the body, SCF is expressed both as a longer isoform that is initially a transmembrane protein but then released as soluble SCF through enzymatic cleavage and as a shorter isoform that remains as transmembrane SCF30. Transmembrane SCF is found in the functions to support the proliferation and survival of progenitor cells31. Soluble and transmembrane SCF differ in terms of their ability to activate the c-Kit receptor, induce cellular responses, and ability to promote adhesion between hematopoietic stem and extracellular matrix11,32. Several reports have further demonstrated can induce prolonged activation
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