Rare Disease Report

New Model For Progeria Could Speed Up the Drug Discovery Process

AUGUST 15, 2017
James Radke
Approximately 250 children in the entire world have Progeria (Hutchinson-Gilford Progeria Syndrome). Currently, about 75 of them are in clinical trials. which is somewhat of a miracle and a testiment to the Progeria community coming together. But with only 75 patients able to participate in trials and a very short window of time to conduct those trials (most will not live past their mid-teens), a more efficient way of finding drugs for these patients is needed.
Progeria is an accelerated aging disorder due to a mutation in the Lamin A gene that leads to the accumulation of the progerin protein in cells. Children with the condition age quickly and, without treatment, death occurs at an average age of 14.6 years.
As advances have been made in understanding this condtion and how to manage it, some progeria patients are able to live a few years longer, but it is still considered to be fatal.
While there are potential Progeria therapies in development, the mathematics of the condition imply that only a few can be properly tested. There simply are not enough patients, in the right location, of the right age, with the right symptoms to test for more drugs. Because of this, determining which of the drugs being tested in preclinical studies should advance to clinical trials is a problem.
Bimedical engineers at Duke University are hoping to fix that problem.
Today, in Scientific Reports, Leigh Atchison and colleagues have published data for a small blood vessel model they developed that exhibits many of the symptoms and drug reactions associated with the blood vessels of Progeria patients. It is hoped that this model can be used to test drugs in the earlier stages of drug development, so that only those with a higher likelihood of success are put into clinical trials.
As pointed out by George Truskey, Professor of Biomedical Engineering at Duke University, "There are currently 75 children in clinical trials, which is amazing given the rarity of the disease. But with 15 compounds under consideration for trials, the math just ultimately won't work out. You can't try all of these drugs or various combinations of them in humans, so we're hoping our platform will provide an alternative way to test them."
Given that most Progeria patients die from cardiovascular problems, having a model that replicates the cardiovascular abnormalities in Progeria is vital. Current preclinical models for Progeria are not ideal and do not fully replicate the blood vessel problems that occur in Progeria so having a blood vessel model for testing drugs for Progeria could further fine tune the selection process for advancing drugs to the clinical phase.
The model they developed is a functional 3-dimensional model of Progeria that replicates an arteriole-scale tissue engineered blood vessel using induced pluripotent stem cell (iPSC)-derived smooth muscle cells from an Progeria patient. Further, the endothelial layer consisted of human cord blood-derived endothelial progenitor cells from a separate, healthy donor. The end result was a tissue engineered blood vessel that had reduced vasoactivity, increased medial wall thickness, increased calcification and apoptosis similar to that observed in Progeria patients.
Schematic diagram of the procedure to produce iPSC-derived smooth muscle cell tissue engineered blood vessels (TEBVs) from healthy and Progeria (HGPS) patients. (A) A fibroblast biopsy from either healthy (young or old) or HGPS individuals (B) is converted to induced pluripotent stem cell (iPSC) cultures. (C) iPSCs are then differentiated into induced smooth muscle cells (iSMCs) using a 31-day process (D) iSMCs are then incorporated into a dense collagen gel construct that is seeded with human cord blood-derived endothelial cells from a separate, healthy donor on the luminal surface to create iSMC TEBVs (E) iSMC TEBVs are then incorporated into a flow loop and perfused with steady laminar flow at a shear stress of 6.8 dynes/cm2 for 1 to 4 weeks for maturation and functional characterization studies. (F) Photographic images of Progeria iSMC TEBVs in the custom perfusion chambers under perfusion conditions.

The researchers also tested the model on a drug currently in a Progeria clinical trial, Affinitor (everolimus) which is being testing in combination with lonafarnib by the Progeria Research Foundation.
Adding everolimus to the tissue, the researchers found that the drug improved contractability and reduced progerin levels but had no affect on calcification and apoptosis. The researchers speculated that this observation may indicate that other treatments and/or different dosing may be needed. Regardless, the results do indicate that the model is a great additional tool for Progeria researchers.  

Effect of Everolimus (RAD001) treatment on Progeria (HGPS) iSMC TEBVs structure and function. (A) Functional response to 1 μM phenylephrine and 1 μM acetylcholine of HGPS iSMC TEBVs seeded with hCB-ECs after 3 weeks of normal perfusion and 1 week of treatment with 100 nM everolimus (RAD001) compared to untreated MSC TEBVs (B) Representative images of immunofluorescence staining with Progerin, α-smooth muscle actin, and calponin on HGPS iSMC TEBVs at week 4 untreated or treated with 100 nM everolimus (Scale bar, 50 μm). n = 3 TEBVs. *P < 0.05.
Per Duke University, lead author Leigh Atchison, a doctoral candidate in biomedical engineering at Duke University said, That's why our system could be so useful. It could tell us exactly what the drug is doing in a quicker, more high-throughput manner, and whether we need a second treatment to address other aspects of the disease."

Atchison L, Zhang H, Cao K, Truskey GA. A Tissue Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome Using Human iPSC-derived Smooth Muscle Cells. Sci Reports. Published online Aug 15, 2017. DOI: 10.1038/s41598-017-08632-4.

Figures from Atchison et al's open source article published in Scientific Reports.
For updates on the latest published studies, follow Rare Disease Report on Facebook and Twitter.     

Stay informed on the latest rare disease news and developments by signing up for our newsletter.
Copyright © RareDR 2013-2018 Rare Disease Communications. All Rights Reserved.