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Choroideremia (CHM) is a rare genetic impairment of the CHM gene, located on the X sex chromosome, that affects vision, as the retina, a crucial part of the eye involved in sight, loses functionality. This condition affects 1 out of 50,000 to 100,000 and is 4% of all causes of blindness in humans (GHR, 2017). Choroideremia is a sex-linked recessive trait, which means that females who do not express the trait are called carriers because only one of their X-chromosomes has the recessive trait, which is masked by the dominant trait of not having the condition. For males, it only takes the mother’s affected X-chromosome to become affected by CHM for life (GHR, 2017). With the assistance from adeno-associated virus gene therapy, conditions like Choroideremia can be treated and cured.
The CHM gene on the X-chromosome is responsible for producing the Rab escort protein-1 (REP-1), however if the CHM gene is mutated or absent, the lack of REP-1 CHM is supposed to produce causes cell death in the retina, causing Choroideremia (Mura, 2007). Escort proteins are the cell’s ‘traffic’ facilitator, regulating intracellular proteins, organelles, and matter. Rab proteins are characterized by their geranylgeranyl functional group, a fundamental structure involved in prenylation, which is important in binding proteins (Preising, 2005). REP-1 allows for other essential proteins to enter cells, allowing for cellular processes to occur. Choroideremia occurs when the CHM gene fails to produce the REP-1. If there happens to be a lack of REP-1, the body has a backup, REP-2, that can perform nearly all of the same processes as REP-1, except there is little to no REP-2 present in the retina, which is why Choroideremia exists. With the absence of REP-1, the cells lack the facilitator required for them to do their work, resulting with premature cell death, or dystrophy (NCBI, 2016).
Choroideremia can be treated, and possibly cured, with the use of adeno-associated viruses (AAV) because of its ability to target locations on chromosomes. The adeno-associated virus was discovered in the 1960s as a contaminant of adenovirus (Weitzman and Linden, 2011), and was seen as a useless virus because it required the assistance of another virus in order to replicate (Gonçalves, 2005). However, the adeno-associated virus is admired for its useful abilities. The adeno-associated virus is admired for its simple structure, consisting of single-stranded DNA with genomes that are controlled by ‘hairpin shaped’ telomere structures (Cotmore and Tattersall, 2014). Another characteristic of the AAV is the precise targeting of Chromosome 19; in fact, the AAV is known as one of the only viruses with such capacity to specifically act upon on one chromosome nearly 96% of the time (Daya and Berns, 2008). A crucial aspect about the adeno-associated virus is that it lacks ‘pathogenicity,’ which means it does not cause disease in its host nor does it cause cell death. It is the lack of ‘pathogenicity’ that has allowed medical professionals to pursue new treatments for genetically caused diseases.
Because AAVs can act on a specific location on a chromosome without killing the host cell, treating sex-linked traits has become a reality. A clinical study used stem cells from patients with CHM and experimented the virus’ abilities with an in vitro model using CHO cells, which transferred the hCHM, human CHM DNA, into mice eyeballs to view the precision of genetic transfer. The results revealed that the CHO cells had elevated levels of the REP-1 protein levels, indicating that the introduction of AAV was able to specifically target the X-chromosome and alter the CHM gene. For the hCHM, it responded well to the application of AAV, as REP-1 proteins increased with regular dosage of AAV and compared to control cells, there was a 50-fold amount of REP-1 protein levels with the treated hCHM cells, indicating that AAV is a very promising option for gene therapy (Vasireddy, 2013). A 2014 clinical trial decided to directly administer an AAV ‘encoding’ REP-1 to six mature males with Choroideremia (all with little ability to see), waiting for six months after the trial to evaluate the effects of ‘raw AAV administration.’ The results reveal all of the test subjects gained eyesight from the treatment, as their lines of vision increased as well as increased levels of retinal sensitivity (MacLaren, 2014). With a single mutation in a genetic sequence, life-changing conditions, like Choroideremia, leave people impaired for the remainder of their lives. However, with the assistance of adeno-associated viruses, researchers are able to treat and cure such conditions permanently.
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Mura M, Sereda C, Jablonski MM, MacDonald IM, Iannaccone A. Clinical and functional findings in choroideremia due to complete deletion of the CHM gene. Retrieved Retrieved January 11, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/?term=17698759
MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial.
Retrieved January 11, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/?term=24439297
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