Modifying our DNA – How far have ZFNs, TALENs and CRISPR/Cas9 therapies approached into clinics?

Fri, 2017 / 10 / 06

Gene therapies, like Glybera, Kymriah and Strimvelis, have started to be commercially available in the U.S. and Europe, but the technologies outside the spotlight of the publicity are continuously developing and improving. The use of viruses to transfer genetic material into cells of the body is the current standard in clinics. However, the newest tools for genome editing, are the so-called designer nucleases. Those genome engineering tools are customized and artificial enzymes, which allow a more precise modification of the DNA. Designer nucleases can be divided into three main classes, the Zinc-finger nucleases (ZFNs), Transcription-Activator-Like Effector Nucleases (TALENs) or the RNA-guided nucleases, such as the CRISPR/Cas9 system.

All three therapies have in common that they can be used as precise molecular scissors. With this property, genes can “easily” be added, corrected or just deleted (knocked-out). There are currently 10 ZFN-, 2 TALEN- and 10 CRISPR/Cas9-based therapies in clinical trials investigating the application of these tools for the treatment of diseases like HIV-1, different types of cancer, leukemia and other blood disorders, such as hemophilia B. As one example, Sangamo Therapeutics, a company dedicated to provide new solutions for genetic diseases, is currently recruiting participants for two pilot studies to evaluate ZFNs for the treatment of HIV-1 infected patients and patients suffering from hemophilia B. Here, the study assesses the feasibility and safety as well as the overall tolerability and effect of the therapy. In contrast to ex vivo ZFN-modified hematopoietic stem/progenitor cells for the treatment of HIV-1, this year, Sangamo Therapeutics conducted the first in vivo human genome editing phase 1 study with their “SB-FIX” product for the treatment of hemophilia B. In addition to the therapeutic transgene, ZFNs, which will be administered intravenously, will be used for the modification of hepatocytes within the patient, with the goal of a lifelong therapeutic production of the missing Factor IX clotting factor, with the possibility of healing.

How successful those genome-editing strategies will be in long-term, has to be evaluated within the next years. In addition to doubts raised about the overall safety and applicability of such innovative but intangible technologies, there is the dilemma of appropriate reimbursement models. Potential reimbursement scenarios and possible solutions will be discussed in “Gene therapy ante portas – Appropriate solutions for the reimbursement dilemma”, published in the new issue of “Welt der Krankenversicherung”.

References and Additional Material:

http://www.Clinical trials.gov

http://www.Sangamo.com

http://www.the-scientist.com/?articles.view/articleNo/49456/title/First-In-Vivo-Human-Genome-Editing-to-Be-Tested-in-New-Clinical-Trial/

http://www.raps.org/Regulatory-Focus/News/2015/12/08/23734/FDA-Authorizes-1st-Human-Study-to-Use-In-Vivo-Genome-Editing-Application/