ZFP Transcription Factors (ZFP TFs)
At Sangamo we create ZFP TFs - novel transcription factors that mimic the natural mode of gene regulation. We engineer ZFPs to recognize a DNA sequence close to or within a gene of choice. By attaching a functional domain such as a naturally occurring “gene activation” or a “gene repression” domain to that ZFP we generate a ZFP TF that can regulate the expression of the target gene up or down.
Regulating an endogenous gene (i.e. a gene in an organism’s genome) with a ZFP TF mimics the way a cell normally regulates the gene which has important implications for the biological outcome that we are trying to achieve.
For instance, we are developing a ZFP TF which upregulates the gene for Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor that has shown promise in preclinical testing to slow or stop the progression of PD. By using a ZFP TF to turn this gene on, we can increase production of the patient’s own GDNF protein thus avoiding potential immunogenicity issues associated with recombinant protein. We are currently testing this ZFP TF in preclinical studies in non-human primates.
We are also developing ZFP TFs that turn gene expression off. We have programs in neuropathic pain focused on the repression of pain receptors, Trk-A and PN3, and these ZFP TFs are in preclinical testing.
What are the advantages of ZFP TFs?
We believe that our ZFP TF technology platform has several technical advantages compared with other technologies. Among the advantages of our ZFP TF-based approach to gene regulation are:
- ZFPs normally and naturally regulate genes in all higher organisms
- ZFPs can be designed to recognize unique DNA sequences within a large complex genome
- ZFP TFs can both activate or repress genes, enhancing their versatility
- ZFP TFs can be used to regulate the genes of humans, animals, plants, microbes and viruses
- ZFP TFs have proven effectiveness from cell models through to the corresponding animal models
- ZFP TFs have been tested in humans and to date have an excellent safety profile
- ZFP TFs can themselves be regulated, allowing conditional and reversible regulation of a gene
- ZFP TFs can be used to regulate an endogenous cellular gene rather than a transgene and thus provide a workaround solution for genes whose cDNAs are patented