Novel viral vectors for targeted gene therapy of cardiomyocytes

Gene therapies aim to cure serious, barely treatable monogenic diseases caused by a defect in a single gene. Medical expectations are correspondingly high. Some gene therapies have already been approved in Europe, for example for spinal muscular atrophy (SMA), a congenital neuromuscular disorder with severe muscle weakness and atrophy. Therapeutic genes are transported directly into the cell using so-called viral vectors. The best-known representatives of these vectors, popularly known as gene taxis, are the so-called adeno-associated viruses (AAV). However, because they are used to this by nature, they target other tissues in addition to the actual target. In addition, they can be recognized as foreign by the immune system and destroyed. Two research teams from the Hanover Medical School (MHH) have developed AAV variants that target heart muscle cells and thus can be used for the precise treatment of heart disease. The results are now published in the journal Molecular Therapy.

Millions of variants examined

“Although AAV vectors are derived from viruses, they only serve as a means of transport,” explains Professor Dr. Hildegard Büning, AAV expert and vice director of the MHH Institute for Experimental Hematology. The AAV vectors couple to the body cell via the vector envelope, the so-called capsid, and transfer their genetic load to the cell interior. There it is read and converted into the corresponding protein according to its blueprint. “The problem with the currently used AAV vectors, however, is that they can attach to different tissues and thus often end up in the liver,” says the scientist. The research team therefore searched between four million AAV variants for suitable candidates with capsid structures that preferentially target cardiomyocytes. In the mouse model, biochemist Dr. Laura Rode used the vectors and investigated which variants mainly end up in the heart and which almost never end up in the liver. “We had several winners in the race and then tested how strongly they were intercepted by the human immune system.”

Not all gene taxis reach their target

Not all vectors that target specific body cells get there. “About 70% of the population has neutralizing antibodies to naturally occurring AAV,” explains Dr. Christian Bär, a molecular geneticist at the Institute for Molecular and Translational Therapeutic Strategies. “Their immune systems intercept the gene taxis before they can deliver the payload into the cell as desired.” The presorted vectors therefore had to prove how well they could escape the neutralizing antibodies in cell culture with human blood plasma. The two AAV variants also survived this test. They were then loaded with a biomolecule called H19, which has already been successfully tested at the Institute for the Treatment of Pathological Heart Enlargement Caused by High Blood Pressure, but with a conventional AAV vector. “The new vector variants actually delivered H19 into the heart muscle cells much more efficiently than the AAV vector we originally used,” notes the scientist.

New vector variants have several advantages

What doesn’t sound spectacular at first glance, however, is important in several respects for a possible therapeutic application. “Gene therapy is an expensive treatment method that can usually only be used once for each vector, because the immune system would recognize the vector as foreign and eliminate it at the latest the second time,” explains Institute Director Professor Dr. dr. Thomas out. Thumb. An additional vector variant offers the chance for a different treatment. Due to the high targeting accuracy of the new variants, a lower dosage is also sufficient. “This greatly reduces the cost per treatment unit.” At the same time, administration becomes much simpler.

“Our goal is for the vectors to find cardiomyocytes so reliable that they can be easily injected into the arm of heart patients and not have to be delivered into the heart through a catheter,” says Dr. Bar. However, until that actually happens, efficacy and tolerability have yet to be confirmed in further studies in large animal models and later in human clinical trials.

Provided by Medizinische Hochschule Hannover