Novel viral vectors for cardiac muscle cell targeted gene therapy

Nuevos vectores virales para la terapia génica dirigida del músculo cardíacomolecular therapy (2022). DOI: 10.1016/j.ymthe.2022.07.003″ width=”800″ height=”530″/>

Graphically Abstract. Credit: molecular therapy (2022). DOI: 10.1016/j.ymthe.2022.07.003

Gene therapies aim to cure severe and barely treatable monogenetic diseases caused by a defect in a single gene. Medical hopes are correspondingly high. Some gene therapies have already been approved in Europe, for example for spinal muscular atrophy (SMA), a congenital neuromuscular disease with severe muscle weakness and atrophy. With the help of so-called viral vectors, therapeutic genes are transported directly into the cell. The best known representatives of these vectors, colloquially known as gene taxis, are the so-called adeno-associated viruses (AAV). However, as they are naturally accustomed to doing, they also target tissues other than the actual target. Furthermore, they can be recognized as foreign by the immune system and destroyed. Two research teams from the Hannover Medical School (MHH) have developed AAV variants that target heart muscle cells and thus can be used for the targeted treatment of heart disease. The results have already been published in the journal molecular therapy.

Millions of variants investigated

“Although AAV vectors are derived from viruses, they serve exclusively as a transport medium,” explains Professor Dr. Hildegard Büning, AAV expert and Deputy Director of the MHH Institute for Experimental Hematology. AAV vectors attach to the body cell through the vector envelope, the so-called capsid, and transfer their genetic payload into the cell. There it is read and converted into the corresponding protein according to its model. “However, the problem with currently used AAV vectors is that they can adhere to different tissues and are therefore often found in the liver,” says the scientist. Therefore, the research team searched among four million suitable candidate AAV variants with capsid structures that preferentially target heart muscle cells. In the mouse model, biochemist Dr. Laura Rode “trained” the vectors and investigated which variants primarily reach the heart and are almost never lost 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 goal

Not all vectors that target specific body cells get there. “Around 70% of the population have neutralizing antibodies against natural AAV,” explains Dr. Christian Bär, molecular geneticist at the Institute for Molecular and Translational Therapeutic Strategies. “Your immune system intercepts the gene taxis before they can deliver cargo into the cell as desired.” Therefore, the shortlisted vectors had to demonstrate how well they could escape neutralizing antibodies in cell cultures with human blood plasma. Both 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 Enlargement of the Heart Caused by high blood pressure—but with a conventional AAV vector. “The new vector variants actually delivered H19 much more efficiently into heart muscle cells than the AAV vector we originally used,” says the scientist.

The new vector variants have several advantages.

What does not sound spectacular at first glance is, however, important for a possible therapeutic application in several respects. “Gene therapy is an expensive treatment method that can usually only be applied once for each vector, because the immune system would recognize the vector as foreign and eliminate it a second time at the latest,” explains Institute Director Professor Dr. Dr. Thomas Thum. Another vector variant offers the possibility of another treatment. Due to the high targeting accuracy of the new variants, a lower dose is also sufficient. “This greatly reduces costs per treatment unit.” At the same time, administration becomes much easier.

“Our goal is for vectors to find heart muscle cells so reliable that they could simply be injected into the arm of cardiac patients and would not have to be administered into the heart through a catheter,” says Dr. Bär. However, until that actually happens, efficacy and tolerability still need to be confirmed in additional studies in large animal models and later in human clinical studies as well.

New way forward for gene therapy

More information:
Laura Rode et al, AAV capsid engineering identified two novel variants with enhanced in vivo tropism for cardiomyocytes, molecular therapy (2022). DOI: 10.1016/j.ymthe.2022.07.003

Provided by Hannover Medical School

Citation: Novel Viral Vectors for Heart Muscle Cell Targeted Gene Therapy (Aug 2, 2022) Retrieved Aug 2, 2022 from -heart.html

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