How to turn muscle into a protein factory for

AMHERST, Massachusetts – In a major new development in the quest for better gene therapies to treat a host of diseases, researchers from the University of Massachusetts Amherst and UMass Chan Medical School recently announced that they have mapped the expression and maturation of the alpha-1 antitrypsin (AAT) protein with unprecedented clarity. The results, which detail the molecular folding of the protein, have been published in the Proceedings of the National Academy of Sciences and will help develop specific therapies to treat an inherited condition known as alpha-1 antitrypsin deficiency, as well as more effectively treat a wide range of genetic conditions.

A revolution in the treatment of diseases has taken place in recent years. It is now clear that there is a whole range of diseases, such as AAT deficiency, that arise when our own bodies produce dysfunctional proteins at the genetic level. Faulty production of AAT or insufficient amounts of AAT can cause serious lung and liver disease. These diseases must be treated either by delivering the missing proteins to the body or, even better, by teaching the body to make the missing proteins itself by introducing an intact copy of the specific protein-producing gene into the DNA of the correct cell. .

But it’s not an easy task to teach the body to make a missing protein. To do this, you must first introduce the correct protein-producing gene into the body, usually via an intramuscular injection – an injection – and into the specific cells that make that protein. Then you have to make sure that once the body starts making the protein it was missing before, that protein is correctly folded into its proper final shape – in the case of AAT, that shape looks like a loaded mousetrap ready to be suspended. Finally, this correctly folded protein must travel from the cell to where it is needed in the body.

It is a series of extremely complex problems that require a research team with expertise in molecular biology, cell biology, protein folding and gene therapy, as well as state-of-the-art research facilities in which to carry out the work, such as the Models to Medicine Center at UMass Amherst’s Institute for Applied Life Sciences, which houses the labs where much of the research has been completed.

“This project is the result of more than a decade of collaboration and spans the gamut from basic science in the lab to the bedside,” says Daniel Hebert, professor of biochemistry and molecular biology at UMass Amherst and one of the co-authors of the article. . Funding for the research was provided by the Alpha-1 Foundation and the National Institutes of Health.

Make a better mousetrap

It starts with Terence R. Flotte, Professor Celia and Isaac Haidak, Executive Vice Chancellor, Provost and Dean of TH Chan School of Medicine. Flotte, a pioneer in gene therapies, has developed a way to use the harmless adeno-associated virus, or AAV, as a vehicle to deliver gene therapies. “We have completed three clinical trials in which we inject AAV containing the normal version of the AAT gene into the muscle to create a ‘sustained release’ of the protein in patients with AAT deficiency,” says Flotte. “But until now, we didn’t understand how much AAT protein is processed in muscle at the biochemical level.”

However, not all cells in the body are able to make all the proteins the body needs. AAT, for example, is best made in the liver. But, since most hits happen in a muscle – think of hits you get in your arm – the team needed to figure out how to get muscle cells to act more like liver cells in their production of AAT, and then how to get the AAT. produced in the muscle to the lungs and liver, where it is needed.

It turns out that Hebert is an expert in these same questions, and, after confirming that muscle cells are poor producers of AAT, he helped develop a technique that increases AAT secretion in muscle cells. about 50% using some kind of chemical. , known as a proteostasis regulator, called suberoylanilide hydroxamic acid, or SAHA. “It’s a way of getting the muscles to do some of the work of the liver,” he says.

And yet, not all proteins are the same. Their shape is crucial in determining how, or if, a protein functions as it should. Throughout her career, Lila Gierasch, a distinguished professor of biochemistry and molecular biology at UMass Amherst, has focused on the process by which a protein takes on a specific shape, called the protein folding problem.

“These protein molecules are absolutely fascinating,” says Gierasch. “They look like little mousetraps and need to be metastable” – imagine a trap you just set waiting for a mouse. “It’s a very special shape, and it has to fit perfectly, otherwise the protein won’t work as it should.”

Although the team focused on AAT deficiency as a case study, their work shows that combinatorial treatments, which include both gene therapies and proteostasis regulators, can enhance the efficacy of gene therapies, not only for AAT deficiency, but for many genetic disorders. more generally.

“Our ultimate goal,” says Gierasch, “is to provide an easy injection that could cure a very difficult and potentially devastating genetic disease. It takes a broadly interdisciplinary team, with expertise acquired both in the laboratory and with the patient, to find an answer.

contacts: Daniel Hebert, dhebert@biochem.umass.edu

Daegan Miller, drmiller@umass.edu

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