Editing Genes to Treat Diseases
Problem with current treatment for genetic diseases:
Most genetic diseases cannot be cured and often affect multiple areas and systems in the body. This is due to the fact these mutations in the DNA are present in nearly every cell of the body 1. For example Cystic fibrosis affects a few areas in the body including lungs and pancreas. A person with this condition has very thick and sticky mucus. This can build up in the lungs making that person more prone to lung infections and have difficulty breathing, as well as in the pancreas it can create a barrier for digestive enzymes, meaning less nutrients can be absorbed for that person 2. All the treatment for cystic fibrosis on relieves symptoms without curing the condition. These treatments are medication such as antibiotics and staying up to date with vaccinations to prevent and treat lung infections. Also taking medication such as ivacaftor which reduces levels of mucus and breathing exercises can help to shift the mucus in the lungs 3. Taking medication to reduce levels of mucus could be costly for the NHS to supply regularly to sufferers of cystic fibrosis. Antibiotics can only treat a lung infection I doesn’t prevent or stop future infection and vaccinations can only prevent a few select causes of infection. Breathing exercises could also be time consuming and monotonous for the sufferer. Hunter syndrome is another genetic disorder, which is caused by an enzyme not being produced. The treatment for hunter syndrome is an enzyme transfusion weekly, however within a day enzyme levels drop from the transplant 4. This is a constant treatment that isn’t even close to a cure just like cystic fibrosis treatments. This is problematic because it means people with these conditions have to adapt to different and probably inconvenient life styles because these treatments are not entirely affective.
How does gene editing to treat genetic diseases work:
Gene editing is essentially removing a faulty gene from the DNA and replacing it with a working copy of the gene. This has been done by a biotech company based in California called Sangamo for Hunter syndrome. In this case the DNA helix is snipped using DNA scissors called zinc finger nucleases (ZNFs) which cut the DNA in a specific place an cuts both strands of the DNA helix. Cutting DNA in a certain place means researchers have been able to cut the DNA near the promoter (on off switch for genes) in this case the albumin promoter. The new gene copy that is not faulty, which is the gene for the protein albumin is inserted in this area so its activity can be controlled by the promoter like it would be in the cells of someone without the disorder. The cells incorporate the new gene copy by using it to mend the damage from the ZNFs cutting it. This procedure is performed on a few liver cells as the body does not need huge quantities of the enzyme. By doing this the liver has essentially become a factory for producing the enzyme. This is the first trial to be done on a living patient directly which is called in vivo gene-editing, since it is direct DNA modification a viral vector must be used in this case the adeno-associated virus, this carries the new genes and ZNFs to the cells. This is done as a 3 hour infusion which will hopefully be a onetime procedure that would keep the liver cells producing the enzyme consistently for years.
There have also been studies done using CRISP cuts genes in a specific place and cuts both strands of the DNA just as ZNFs do 4. Trails done on mice have shown the benefit of using CRISP to treat genetic disorders as it seems to have lengthened the time the new replacement gene is present for. Originally in these trails using mice the gene therapy had only been effective for 4-6 weeks, however now results have shown that using CRISP the new gene can last in the genome for at least 6 months (when the study was ended) and it is thought that the gene change would last the life span of the mice. This is most likely part of why researchers from Sangamo think that the gene therapy done on the patient with Hunter syndrome will last for years. Viral vectors also seem to play a very important role in the gene therapy. Viruses are used as they cause problems to us by injecting their harmful DNA into cells, therefore by modifying these viruses in a lab they can instead inject beneficial CRISP and healthy gene copies. Two viruses can be used the adenovirus or the adeno-associated virus (used to treat hunter syndrome). In an experiment on treating muscular dystrophy it was shown that the adenovirus is more effective at delivering new genes as the adeno-associated virus can carry less DNA, although it is easier to modify than the adenovirus. If gene editing was used for a condition that caused blood deficiencies the adeno-associated virus would not be very effective, due to the fact blood proteins are renewed constantly this is unlike muscle cells which is why the adeno-associated virus was sufficient in treating muscular dystrophy 5.
Risks and limitations of research into gene editing:
The treatment done on a patient with Hunter syndrome did correct the enzyme problem however the enzymes still might not enter the brain due to a tight network of cells that are present to protect the brain from pathogens. This makes this treatment limited because just like enzyme transfusions neither can stop brain damage from the condition 4.
1 U.S. Department of Health & Human Services, 2018. How are genetic conditions treated or managed? https://ghr.nlm.nih.gov/primer/consult/treatment (accessed 17/06/18)
2 NHS UK, 2018. Cystic fibrosis.
https://www.nhs.uk/conditions/cystic-fibrosis/ (accessed 17/06/18)
3 NHS UK, 2018. Cystic fibrosis.
https://www.nhs.uk/conditions/cystic-fibrosis/treatment/ (accessed 17/06/18)
4 Sciencemag, 2017. A human has been injected with gene-editing tools to cure his disabling disease. Here’s what you need to know.
http://www.sciencemag.org/news/2017/11/human-has-been-injected-gene-editing-tools-cure-his-disabling-disease-here-s-what-you (accessed 17/06/18)
5 Bioscience Technology, 2018. CRISPR Improves Gene Therapy to Combat Inherited Diseases.
https://www.biosciencetechnology.com/news/2018/04/crispr-improves-gene-therapy-combat-inherited-diseases (accessed 19/06/18)