Dr Philip Gregory, vice president of research at the Californian biotech, recently outlined how the firm is creating novel DNA transcription factors that can bind to genes and then switch them on or off as required, in order to treat a specific disease.
"If DNA is the hard drive of a computer, then transcription factors are the operating system - they control how the DNA is used." he said at the recent drug Discovery and Development of Innovative Therapeutics conference in Boston, US.
Of those transcription factors that occur naturally, by far the most abundant class are zinc-finger proteins (ZFPs). Named after their thin structure, each 'finger' has a highly conserved structure consisting of two beta-sheets and an alpha-helix, held together by a zinc atom.
Four key amino-acids that comprise part of alpha-helix, recognise and bind to a specific 3 base pair triplet sequence of DNA. This precise interaction is akin to antibody-antigen binding, explained Gregory; only in this case, the antigen is DNA.
Although any triplet set of bases can be found throughout our genetic code, by combining the fingers together, they can recognise longer sequences, until they only bind to one certain region of DNA - such as a disease-causing gene.
In order to control gene expression, this recognition domain is then attached to a 'functional domain' that can turn genes on and off. Together they form a ZFP transcription factor (ZFP-TF).
Sangamo also claims that the technology can be used to correct mutations in single genes, such as those which cause sickle cell anaemia, and disrupt a gene sequence - which may prove useful in diseases such as HIV/AIDS.
SB-509 and VEGF-A
In the case of Sangamo's drug candidate named SB-509, the ZFP-TF targets the vascular endothelial growth factor (VEGF)-A gene. Its protein product stimulates the growth of blood vessels. Scientists believe that up-regulating this gene could be used to treat diabetic neuropathy, one of the most frequent complications of diabetes, which can ultimately lead to amputation.
There are around 20 million diabetes patients in the US alone and around 50 per cent of those suffer from diabetic neuropathy.
SB-509 brings an activation factor to the VEGF-A gene, causing it to make more VEGF. Importantly, all normal isoforms of the product are produced - something that would be impossible with a protein therapeutic. This is important because if the ratio of the three main splice variants of VEGF (121, 165 and 189) is varied, blood vessel growth and branching becomes abnormal.
In preclinical studies, the drug has been shown to increase angiogenesis and also protect nerves. Scientists at Sangamo have also recently found that the drug can accelerate nerve recovery in a nerve crush model and improve locomotion in a severe spinal cord injury model.
In a Phase I clinical study, 12 Type-II diabetes patients were treated with the drug (a further 12 on placebo) and a "huge improvement" on placebo was observed.
The drug is currently in two Phase II trials and Sangamo hopes it could help fill a gap in the market, where, apart from strict control of blood glucose levels, current therapies for diabetic neuropathy only seek to address the symptoms, rather than slow or reverse the progression of the disease.
ZFPs represent a new approach to drug discovery: small molecules and monoclonal antibodies (mAbs) target proteins (as well as proteins being used as therapies themselves); antisense molecules, RNA interference (RNAi) drugs and ribozymes target RNA; but it is much rarer for drugs to target the DNA itself, said Gregory.
