Helping cells become better protein factories could improve gene therapies and other treatments

The cells in your body are not all the same. Each of your organs has cells with very different functions. For example, liver cells are prime secretors because they need to make and export many of the proteins in your blood to do their job. In contrast, muscle cells are tasked with facilitating the contractions that allow you to move.

The fact that cells are so specialized has implications for gene therapy, a way to treat genetic diseases by correcting the source of errors in a patient’s DNA. Healthcare providers use a harmless viral or bacterial vector to deliver a corrective gene into a patient’s cells, where the gene then directs the cell to produce the proteins needed to treat the disease. Muscle cells are a common target because gene therapy injected into the muscle is more accessible than introducing it into the body through other routes. But muscle cells may not produce the desired protein as efficiently as necessary if the work the gene tells them to do is very different from what they are specialized to do.

We are cell biologists and biophysicists studying how healthy proteins are produced and maintained in cells. This field is called protein homeostasis, also known as proteostasis. Our recently published study describes a way to get muscle cells to behave more like liver cells by altering protein regulatory networks, thereby improving their ability to respond to gene therapy and treat genetic diseases.

Boost protein factories

One disease where gene therapy has great potential is alpha-1-antitrypsin (AAT) deficiency, a condition in which liver cells are unable to make adequate amounts of the protein AAT. It causes lung tissue to break down, which can cause serious breathing problems, including the development of serious lung diseases such as chronic obstructive pulmonary disease (COPD) or emphysema.

Patients are usually treated by infusions of AAT. To do this, patients either have to drive to the hospital regularly or keep expensive devices at home for the rest of their lives. Replacing the faulty gene that caused their AAT deficiency in the first place could be a boon for patients. Current gene therapies inject the AAT-producing gene into the muscle. One of our colleagues, Terence Flotte, has devised a way to use a harmless version of an adeno-associated virus as a vehicle to inject AAT gene therapies into the body, allowing sustained release of the protein over several years.

But muscle cells aren’t very good at making the AAT proteins that the gene tells them to do. Fleet and his team found that one to five years after gene therapy, AAT levels were only 2% to 2.5% of the optimal concentration for a therapeutic effect.

We wanted to find a way to turn muscle cells into better protein factories, like liver cells. We tested a number of different molecules on mouse muscle cells to see if they would increase AAT secretion. We found that adding a molecule called suberoylanilide hydroxamic acid, or SAHA, helps muscle cells make AAT at a production level more akin to that of liver cells. It works because SAHA is a proteostasis regulator with the ability to increase the cell’s protein production.

Later we believe that adding SAHA or similar proteostasis regulators to gene therapies could help increase the effectiveness of these treatments for many genetic diseases.

Beyond gene therapy

Our findings have implications that go beyond gene therapies. The effectiveness of mRNA vaccines, for example, is also influenced by how well each cell produces a particular type of protein. Also, since most mRNA vaccines are administered by injection into the muscle, they can suffer from the same limitations as gene therapy and elicit a less than desirable immune response. Increasing protein production from muscle cells could potentially improve vaccine immunity.

In addition, many drugs developed by the biotech industry, called biologics, derived from natural sources are heavily dependent on a given cell’s protein production capabilities. But many of these drugs use cells that aren’t specialized to make large amounts of protein. Adding a protein homeostasis enhancer to the cell could optimize protein yield and increase the drug’s effectiveness.

Protein homeostasis is an emerging field that goes beyond drug development. Many neurodegenerative diseases such as Alzheimer’s and Parkinson’s are associated with abnormal protein regulation. The deterioration of a cell’s ability to control protein production and use over time can contribute to age-related diseases. Further research into improving the cellular machinery behind protein homeostasis could help delay aging and open many new doors for treating a variety of diseases.

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