Molecular "Fed-Ex truck" knocks down mutant proteins, delivers genes

Symptoms of many diseases such as cystic fibrosis, Huntington's disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) and Alzheimer's disease can be traced to the problem of "misfolded" proteins. When things are working properly, strings of amino acids fold into the correct three-dimensional structure. But, like everything in nature, sometimes things can go wrong. A misfolded protein can create all kinds of toxic trouble and can have an impact on development of diseases. Now, scientists have figured out a way to knock down these diseased proteins using an adeno-associated virus (AAV) vector as a molecular delivery truck.

R. Jude Samulski, director of the University of North Carolina's Gene Therapy Center, has focused his work on a gene therapy approach to a protein deficiency that causes serious lung and liver disease in children and adults: alpha-1 antitrypsin (AAT) deficiency, or alpha-1. It is caused by an abnormal AAT protein produced primarily in the liver and one out every 2,500 people in the United States have it--often misdiagnosed as asthma or smoking-related emphysema. A buildup of misfolded AAT in the liver is thought to be responsible for alpha-1.

"Alpha-1 antitrypsin plays a very important role in the health of the lungs, preventing fluid build-up, protecting against infections," Samulski said in a news release. "But in some individuals, the protein mutation they've acquired actually creates additional toxicity in the liver. And so, there's a liver pathology in addition to the lung damage. You have two complications going on, and not just one involving a lack of alpha-1 antitrypsin's protective role in the airway."

Samulski and a colleague engineered what they call a "sophisticated molecular Fed-Ex truck that delivers two payloads at the same time: one knocks down the misfolded protein and the other donates a new gene to replace the missing protein activity. They reported successfully knocking down 90% of the mutant AAT. Next, Samulski says, let's "test this cocktail cassette approach in a clinical trial."

- read the release from UNC School of Medicine
- and the abstract in PNAS