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Liver Gene Therapy Corrects Heart Symptoms in Model of Rare Enzyme Disorder

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Liver Gene Therapy Corrects Heart Symptoms in Model of Rare Enzyme Disorder

Patients suffering from the rare disorder known as MPS I are deficient in the enzyme IDUA. In a recent research that has been published in two papers, a new gene therapy approach has been outlined by the researchers at the Perelman School of Medicine at the University of Pennsylvania. They have examined the process of systemic delivery of a vector to replace the enzyme IDUA. In the second paper that has been published online in the Proceedings of the National Academy of Sciences this week, it is described that an injection of a vector expressing the IDUA enzyme to the liver can be useful in preventing most of the systemic manifestations of the disease, including those found in the heart.


The first paper of the study was published in Molecular Therapy. It describes how an adeno-associated viral (AAV) vector can be used to introduce normal IDUA to glial and neuronal cells in the brain and spinal cord in a feline model. The aim of the study was to treat the manifestation of MPS relating to the central nervous system. On the other hand the more recent study aims to treat the manifestations of the disease which are outside of the nervous system.


It is known that diseases due to MPS comprises of 50 rare inherited disorders that are characterized by defects in the lysosomes “ these are compartments within cells filled with enzymes to digest large molecules. In case any of mutation of any of these enzymes, molecules that would have been normally degraded by the lysosome starts accumulating within the cell and the recycling of their fragments is also stopped. Many of the MPS disorders have common symptoms, which include speech and hearing problems, hernias, and heart problems .It is estimated that 1 in 25,000 births in the United States has some form of MPS. The life expectancy for people with MPS I show considerable variation.


There are two main treatments for MPS I at the moment namely bone marrow transplantation and intravenous enzyme replacement therapy (ERT). However, both of them have their significant drawbacks and are known to be marginally effective and are clinically impractical. They do not address some of the most critical clinical symptoms, like life-threatening cardiac valve impairments. James M. Wilson, lead author of the paper, MD, PhD, professor of Pathology and Laboratory Medicine and director of the Penn Gene Therapy Program observed that both the paper on gene therapy are the first proof-of-principle demonstrations for the efficacy and practicality for gene therapies that can be translated into the clinic for lysosomal storage diseases. This approach has better prospects than ERT and it can also replace ERT.


Patients suffering from MPS I accumulate compounds called glycosaminoglycans in tissues and it results in various clinical symptoms, which includes neurological, eye, skeletal, and cardiac diseases. The team used a naturally occurring feline model of MPS I and tested the liver-directed gene therapy through a single intravenous infusion to establish long-term systemic IDUA presence throughout the body. The team carried the treatment in 4 MPS I cats which were between the ages of three to five months and administered them with an AAV serotype 8 vector expressing feline IDUA. The sustained serum enzyme activity was observed for six months at approximately 30 percent of normal levels in one cat and in excess of normal levels in the other three cats. It is remarkable to note that the treated animals not only showed reductions in glycosaminoglycans storage in most tissues, but also exhibited complete resolution of aortic valve lesions, an effect which was not seen with current therapies.


These findings point shows hope that with liver gene transfer, the lives of those suffering from MPS I can be changed for the better.