A Potential Cure for Hemophilia
Safety Assessment
Rebecca Walker Comba

A Potential Cure for Hemophilia

The first in vivo genome editing compound is cleared for human trials, a major milestone in the rejuvenated field of gene therapy.

On Dec 1, 2015, Sangamo BioSciences, Inc. received FDA clearance for the first clinical application of an in vivo genome editing therapeutic, SB-FIX, a potentially curative, single treatment therapy for hemophilia B. This is history in the making. While conventional gene therapy approaches have the potential to wash-out over time, necessitating repeated administration, the proprietary In Vivo Protein Replacement Platform™ (IVPRP™) from Sangamo is expected to result in therapeutic levels of human Factor IX (hFIX) for the lifetime of patients with hemophilia B, with only a single treatment with SB-FIX.

Truly efficacious therapies for genetic disease will treat the disease at the source, the genome. Sangamo's IVPRP™ technology takes advantage of zinc finger proteins (ZFPs), the most abundant DNA binding proteins in the body. An individual ZFP recognizes and binds to 3 base pairs of DNA. Several ZFPs can be strung together to recognize and bind to longer target DNA sequences. ZFPs are designed with "exquisite specificity" toward a unique site in the genome and strongly bind only that targeted site. These DNA binding domains are then coupled to a nuclease domain to create a zinc-finger nuclease (ZFN) that binds to and cleaves DNA at a specific spot to allow for the insertion of a gene. Sangamo's modular design of SB-FIX incorporates two ZFNs that are targeted to bind 6 base pairs of DNA in a specific location in the albumin gene of human liver cells. In this case, a correct copy of hFIX is inserted where the DNA is cleaved by the ZFN so that it can produce functional Factor IX protein.

In SB-FIX, adeno-associated virus (AAV) vectors encoding the engineered ZFNs and hFIX, were created to deliver both the nuclease and the correct copy of the FactorIX gene in liver cells. AAV was selected because it is preferentially taken up by the liver when given intravenously and has a history of safe and efficacious use in humans. The manufacturing of AAVs are also well understood. Only a small percentage of the liver cells actually will incorporate and express the hFIX gene after injection of SB-FIX. However, these liver cells, and more importantly their progeny, should express Factor IX for the lifetime of the patient. Because the promoter for the albumin gene is so powerful, the incorporation of the hFIX gene should produce stable, therapeutic levels of Factor IX from this small percentage of liver cells and permanently treat hemophiliaB in patients.

Charles River's role

At Charles River, we feel privileged to have participated in these advancements by completing toxicology studies that supported the safety and efficacy of SB-FIX to win IND clearance for commencing clinical trials. These studies demonstrated that Sangamo's SB-FIX could precisely insert a copy of the hFIX gene into a specific location within the albumin gene of liver cells leading to the stable production of therapeutic levels of Factor IX. We look forward to watching the development of SB-FIX and other therapies incorporating ZFP Therapeutics® strategies. Beyond systemic application for liver-related diseases such as hemophilia and lysosomal storage diseases, there are potential direct tissue applications for treating several other diseases caused by protein deficiencies that could revolutionize treatment for patients.

For more on this groundbreaking scientific advancement and additional therapeutic interventions underway at Sangamo, click here.

How to cite:

Walker Comba, Rebecca. A Potential Cure for Hemophilia. Eureka blog. Feb 3, 2016. Available:https://eureka.criver.com/a-potential-cure-for-hemophilia/