Promising HIV Therapy in Development: Molecular Scissors Cut Off The “Door Handle”

The gene scissors, part of a “second generation of designer nuclease,” dissect more effectively than enzymes previously used in research. “During testing the dissection was successful in more than half of the cells,” reported Prof. Dr. Boris Fehse from the Interdisciplinary Clinic and Polyclinic for Stem Cell Transplantation at the UKE.

In the coming years this type of somatic therapy, the removal of immune cells, which after being treated and transfused back into the patient, could benefit those with HIV. However, further positive results from future testing are required.

“If the current pre-clinical studies confirm the safety of the procedure, then due to the high rate of efficiency, and the massively improved precision when compared to first generation nuclease, coupled with the relatively simple application, we see a real possibility that we can soon begin with clinical testing,” says Prof. Fehse, head of the Research Department for Cell and Gene Therapy. Stopping the virus at the point of entry is the most promising strategy of today’s AIDS research.

The Human Immunodeficiency Virus (HIV) requires molecules at the surface of the immune cells (more precisely: T-Helper Cells) as a portal of entry. “During the initial stages of infection the chemokine receptor, CCR5, plays an essential role as a co-receptor.” In short, if CCR5 is not present on the surface of the T-helper cell then the HIV virus is unable to dock and infect the cell.

“In cooperation with the Heinrich-Pette-Institute here in Hamburg, we are able to show that the genetic changes caused by our newly developed enzyme provide infection protection against reference strains of the HIV virus.”

Fewer Side Effects Thanks to Messenger RNA

Prof. Fehse and the lead author, Dr. Ulrike Mock, reported in the online edition of the specialist journal “Nucleic Acids Research,” that the enzyme scissors named “CCR-Uco” was successful in destroying the CCR5 gene is more that 50% of the T-cells, a process known as gene knockout. To place the molecular scissors in the T-cell, the research team used a synthetically created messenger RNA, and a gene ferry.

“The use of the messenger RNA is, from a practical standpoint, far less complicated than using a virus for gene transfer,” explained Prof. Fehse. The lifespan of the messenger RNA within the cell is much shorter than that of a virus, and the degrading process is completed faster. This means that there is a notable reduction of unwanted side effects as there is the risk that the scissor enzyme would continue to attack the gene after the therapeutic part of its function has been completed.

Chance Discovery: “The Berlin-Patient”

We discovered that the retroactive removal of the CCR5 receptor could actually cure those infected with HIV by pure chance. In North America and Northern Europe, approximately one percent of the population has no CCR5 on their immune cells as the result of a genetic defect. Therefore, these individuals are almost completely protected against the HIV infection. A patient known in research circles as “The Berlin Patient” is the only HIV infected person known worldwide to have been cured, thanks to this genetic defect. The patient developed leukemia and was treated using a stem cell transplant. In this case, the stem cell donor had this advantageous genetic defect, which was transferred to the patient through bone marrow stem cells.

References:
U. Mock et. al. mRNA transfection of a novel TAL effector nuclease (TALEN) facilitates efficient knockout of HIV co-receptor CCR51, Nucleic Acids Research, 2015 1 (DOI: 10.1093/nar/gkv469)

Contact:
Prof. Dr. Boris Fehse
Head of the Research Department for Cell and Gene Therapy
Interdisciplinary Clinic and Polyclinic for Stem Cell Transplantation
Universitätsklinikum Hamburg-Eppendorf
Martinistr. 52
20246 Hamburg
Telefon: (040) 7410-55518
E-Mail: fehse@uke.de