Gene therapy works by delivering a healthy copy of a malfunctioning gene to a patient.
The therapy that Sangamo is developing replaces a faulty C9orf72 gene. It consists of a zinc finger protein engineered to bind to a particular DNA sequence in the gene. The binding suppresses the abnormal gene.
A major challenge in gene therapy is ensuring that an engineered protein can regulate a faulty gene’s production of protein needed for normal functioning. If the gene produces too little or too much protein, the body continues to be susceptible to the disease that the replacement gene was designed to eliminate.
Sangamo has come up with a new way to achieve the proper regulation of a gene’s protein production.
It involves transcription factors, proteins that can maintain or turn off a gene’s production. Some transcription factors signal that a gene’s activity should continue. Others signal that it should be shut down.
Zinc finger protein transcription factors, or ZFP TFs, are the most common transcription factors that bind to DNA.
Sangamo attached a zinc finger protein that targets a specific DNA sequence to a particular transcription factor. This approach means that the therapy can either maintain a gene’s activity or shut it down, depending on which is necessary.
The partners hope the technology can treat neurodegenerative disorders such as ALS and frontotemporal lobar degeneration that stem from C9orf72 gene mutations. It would do this by preventing the mutated C9orf72 gene from generating faulty protein.
Sangamo and Pfizer want to develop ZFP-TFs that can differentiate between the faulty C9orf72 gene and a normal one, repressing only the mutant form.
“The precision and flexibility of zinc finger proteins enables targeting of virtually any genetic mutation,” Sandy Macrae, chief executive officer of Sangamo, said in a press release.
Under their agreement, Sangamo will be responsible for coming up with ZFP-TF candidates. Pfizer will be responsible for research, treatment development, manufacturing, and commercialization of any gene therapies Sangamo creates. Sangamo will receive a $12 million upfront payment from Pfizer as part of the deal.
The C9orf72 mutation is thought to be associated with 25 to 40 percent of all inherited cases of ALS. Some people with the mutation experience both movement and dementia problems.
Sangamo is also developing ZFP-TFs to treat central nervous system diseases. And it is working on a way to regulate the production of tau, a protein associated with Alzheimer’s disease and frontotemporal dementia.