Computationally Guided Design of Biodegradable Drug Eluting Stents for the Treatment and Reversal of Vascular Stenoses in Children with Congenital Heart Defects

Doctor's Name: 
Marlene Rabinovitch, M.D.
Stanford University School of Medicine

This proposal is interested in exploring a new treatment option for children who are born with congenital heart defects that affect the blood vessels. Specifically, we are interested in helping patients with (1) supravalvular  aortic stenosis (SVAS), (2) Williams-Beuren Syndrome (WBS) and those with (3) tetralogy of Fallot (TOF) with pulmonary atresia and major aortopulmonary  collateral arteries (MAPCAs). These patients share a similar problem, in that their blood vessels have a tendency to become narrow over time, limiting blood flow beyond the point of narrowing.


SVAS is narrowing in the aorta (the main blood vessel coming out of the heart) right above the value that separates the aorta from the left ventricle ( the pumping chamber). SVAS is seen in about 1 in 20,000 births and can happen sporadically or can be passed on between generations.

In addition to the narrowing seen in the aorta, these patients can also develop narrowing in other vessels such as the ones that bring blood to the lungs. Besides this, SVAS is also seen in patients with WBS, which is the result of a genetic defect in the gene responsible for elastin. The blood vessel abnormalities seen in SVAS and WBS are identical because both parties have a genetic defect in the elastin gene, resulting in their not making enough elastin.


Elastin, as the name implies, is a protein that gives blood vessels the ability to maintain normal elasticity and flexibility, and also creates the major framework ( i.e. structure ) of the large blood vessels. In addition to this, elastin is also responsible for controlling the growth of smooth muscles, which live between the layers of the elastin framework. If the framework is broken or not enough elastin is made, then the smooth muscle cells start to move, grow and multiply, until they narrow the vessel lumen. This process is responsible for the narrowing of the vessels seen in the patients with SVAS and WBS.


The same phenomenon is seen in patients with MAPCAs. Mapcas are abnormal connections between the aorta and the lung. Instead of bringing blood without oxygen to the lung, these blood vessels bring blood with oxygen back to the lung. These blood vessels, just as the ones seen in SVAS and WBS, tend to form some degree of narrowing, which is progressive over time. The process is also believed to be the result of abnormal elastin production or processing, causing the vessels to narrow.


It is known that there are specific enzymes ( proteins that are capable of degrading and cutting other proteins into smaller pieces ) which are active in the process of vessel narrowing.  These enzymes ( called serine elastases ) can destroy the elastin framework and contribute to vessel narrowing. Work from the researcher’s laboratory has shown that if these enzymes are inhibited, via the use of elafin ( a protein that occurs naturally in our bodies ), we can better preserve the elastin that is made, especially in patients that have a genetic defect, thereby preventing vessel narrowing. It is the researcher aim to test elafin in a setting of congenital heart disease.


As surgical correction is the mainstay of therapy for the above mentioned patients, it would be desirable to design alternate options. By design a biodegradable metal-alloy drug eluting stent

( DES ) containing elafin, the researchers aim is to deliver a treatment modality that can provide the following: (1) a minimally invasive therapeutic approach via catheters, (2) immediate opening of the vessels narrowing provided by the stent, (3) release of elafin to inhibit the enzymes that destroy the vessels elastin structure, and thereby inhibit the excessive smooth muscle cell growth, and (4) a stent that will degrade as the child and the blood vessels grow with time allowing for re-intervention if need be.


This research model will be tested in mice that carry the same genetic defect in elastin as patients with SVAS and WBS. The researchers will then use imaging and computational tools to assess how these vessels react to stent treatment with and without elafin.


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