Gene editing strategies begin to look more viable, as biotech Sangamo Therapeutics begins recruitment for 3 different gene editing trials
Patients with 3 conditions, Hemophilia B, Hurler syndrome, or Hunter syndrome are to undergone gene editing in 3 separate trials with specially designed zinc finger nucleases - in order to delivery a functional copy of the affected gene. While Hemophilia B is caused by a deficiency of coagulation factor IX, which is involved in blood clotting, Hurler and Hunter syndromes are caused by an inability to break down complex polysaccharides called glycosaminoglycans.
“This is the first time someone could have a new gene put into their liver. It’s a privilege and a responsibility to do these trials"
Increasing accuracy in gene therapy
All of these new trials hope to target the liver and delivery fresh copies of the genes, alongside the zinc finger nucleases. These will form a targeted DNA break at a predetermined site, which the gene will then integrate into through a natural process called homologous recombination. The researchers predict that while only a small proportion of liver cells (hepatocytes) will be transduced with the therapy, the high protein expression within these should be sufficient to correct the disease.
Why zinc finger nucleases?
The main advantage of this strategy is that it integrates a gene into the patient's genome in any cell successfully transduced. This means these healthy genes will persist through cell division and be passed down. Most gene therapy approaches today deliver a non-integrating gene which only remains until a cell divides. This is because of fears of problems caused by random integration. Gene editing technology enables us to pick and choose a safe region of the genome to slot a new gene inside. This is not a perfect system, but it drastically decreases risk of any untoward integration. In this case, the 'safe' site is the albumin gene, which is one of the most highly expressed proteins in the body.
Zinc finger nucleases are indeed more complex and expensive to product in comparison to the famous CRISPR-Cas9 system, but they are more accurate and overcome certain targeting limitations too. One of the biggest remaining challenges however, which will be analysed in these upcoming trials, is how to effectively deliver enough of these fairly sizeable proteins into the cells you need to reach. This is perhaps the largest roadblock to effective therapies as we move to clinical use.
“Whether you’re using zinc finger nucleases or similar proteins called TALENs or the CRISPR system, you have a delivery problem, meaning, how do you actually get your product of interest into specific cells and not others.That’s been a challenge for gene therapy no matter what you’re trying to do”
Read more at The Scientist