This article is more than 5 years old. Information may no longer be current.
Gene therapy promising treatment for patients with achromatopsia
Click Here to Manage Email Alerts
by Laura Windsor, OD, FAAO
Gene therapy trials are underway to improve the vision of patients with achromatopsia, a rare inherited retinal disease that affects approximately one in 30,000 individuals, according to Sharpe and colleagues.
It is a stable cone dystrophy causing severe hemeralopia, or day blindness, a condition in which any bright light reduces patients’ ability to see. The hemeralopia is the biggest issue facing these patients, and controlling it is key to helping them. They also have reduced visual acuities and severe color blindness, but these are not as problematic as the hemeralopia.
Two types
There are two types of achromatopsia (ACHM): rod monochromatism (RM) and blue cone monochromatism (BCM). RM is inherited in an autosomal recessive pattern, and there are currently six gene mutations currently known to cause it: CNGA3, CNGB3, GNAT2, PDE6C, PDE6H and ATF6.
The CNGB3 gene mutation accounts for about 50% of all cases, while the CNGA3 gene mutation accounts for about 25% of cases (Kohl et al, Wissinger et al.). There are more than 50 different mutations in this gene that are shown to affect color vision. Blue cone monochromatism (BCM) is an X-linked inherited condition. Compared to patients with RM, patients with BCM usually have better visual acuities and are not as light sensitive because they have functional blue cone cells.
Presentation
ACHM often presents with nystagmus around 8 to 12 weeks of age, and the macula and retinal appearance is normal. Nystagmus helps distinguish ACHM from other progressive cone dystrophies (PCD). PCDs usually do not involve nystagmus because it begins later in childhood or adulthood. Nystagmus in ACHM patients will usually lessen significantly as they get older, and it is hardly noticeable later in life.
Because of the nystagmus, these patients will undergo several evaluations, including MRIs, ERGs and other tests, before having genetic testing performed. Many have been misdiagnosed with a hereditary nystagmus or a progressive cone dystrophy. The 2018 Achroma Corp.’s survey, Understanding the Achromatopsia Patient Experience, found that adults with ACHM saw an average of seven health care providers before being diagnosed, and the diagnostic process took longer than 5 years. The same survey also reported that young children with ACHM saw an average of four health care providers before being diagnosed. Most were diagnosed within 3 years of birth.
Additionally, all patients with ACHM have a severe color impairment and will not be able to perform well on the standard color vision tests such as the Ishihara, HRR or the Farnsworth D-15. Depending on their ability to distinguish any colors, patients with ACHM can be further classified as a partial or total “achromat.” A total achromat has no color perception, and a partial achromat can differentiate some colors or hues, with red being the easiest for them to see. Those with BCM can see more colors in the blue spectrum.
Visual acuities in these patients will usually range from 20/80 to 20/200, and patients present with a pronounced squint even indoors in normal room lighting. The squinting causes a constriction of their visual field if not wearing the proper colored filters. Their vision loss, however, is stable throughout their life. Patients with ACHM have a wide and varying range of refractive errors from plano to high hyperopia or high myopia. Some also have high amounts of astigmatism as well.
Treatment
Controlling the hemeralopia is critical to helping these patients. Treatment with specialty dark filters in eye wear and tinted contact lenses for both indoors and outdoors have proven to greatly improve their hemeralopia and quality of life. Some patients are even able to become bioptic drivers with the use of these filters.
The future for these patients is in genetic testing and gene therapy. Gene therapy trials for rare eye diseases, including ACHM, are currently underway. Luxturna (voretigene neparvovec), marketed by Spark Therapeutics in 2018, was the first ocular gene therapy drug to get FDA approval for patients with a gene mutation in RPE65. This gene is responsible for 8% of all cases of Leber congenital amaurosis (LCA) and 2% of all retinitis pigmentosa cases (Cideciyan, Ferrari et al, Fahim et al.). Phase 1/2 gene therapy trials for ACHM, caused by CNGB3 or CNGA3 mutations, are currently being conducted by Applied Genetic Technologies Corporation in the U.S. and Israel, and MeiraGTx in the U.K.
The gene therapy treatment uses an adeno-associated virus (AAV) as the vector. These AAVs are non-athogenic, small viruses with a single strand of DNA that is coded with the correct sequence of the CNGB3 or CNGA3 gene. A subretinal injection is performed, and the AAV enters the cone cells, leading to the expression of a functional copy of the missing protein. This gene therapy has shown positive results in restoring some cone function in both dog and mouse models of ACHM (Pang et al., Komaromy et al.).
As eye care professionals, we need to be more proactive in ordering genetic testing for our patients with ACHM as well as other IRDs. The Achroma Corp. survey also concluded that only 58% of adults and 65% of children with ACHM have had genetic testing to confirm their diagnosis and identify the gene mutation responsible for their condition. Genetic testing can be done via a simple blood draw or a saliva sample. Proper diagnosis through DNA testing and then involvement in clinical trials is crucial for the development of future gene therapy treatments for generations to come.
To learn more about the ACHM phase 1/2 gene therapy studies being conducted in the U.S., refer to https://clinicaltrials.gov/ct2/show/NCT02599922 (CNGB3 study) and https://clinicaltrials.gov/ct2/show/NCT02935517 (CNGA3 study)
Additionally, the Foundation for Fighting Blindness offers free genetic testing and a registry of some IRDs. For more information on the FFB registry, go to www.myretintracker.org.
References:
Achroma Corp. announces global survey results of 226 people with achromatopsia. Achroma Corp. https://www.achromacorp.org/PatientJourney.html. Accessed June 27, 2018.
Cideciyan AV. Prog Retin Eye Res 2010;doi:10.1016/j.preteyeres.2010.04.002.
Fahim AT, et al. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993-2019. https://www.ncbi.nlm.nih.gov/books/NBK1417/. Updated January 19, 2017. Accessed July 19, 2019.
Ferrari S., et al. Curr Genomics. 2011;doi:10.2174/138920211795860107.
Kohl S, et al. Eur J Hum Genet. 2005;doi.org/10.1038/sj.ejhg.5201269.
Komaromy AM, et al. Human Molecular Genetics. 2010;doi:10.1093/hmg/ddq136.
Low Vision Centers of Indiana. Achromatopsia: Journey through the light. http://www.achromatopsia.info/. Accessed May 05, 2019.
Morimura H, et al. Pro Natl Acad Sci USA. 1998;doi:10.1073/pnas.95.6.3088.
Pang J, et al. PLoS ONE. 2012;doi:10.1371/journal.pone.0035250.
Sharpe LT, Stockman A, Jagle H, et al. Opsin genes, cone photopigments and colour blindness. In: Gegenfurtner K, Sharpe LT, eds. Color Vision: From Genes to Perception. Cambridge, UK. Cambridge University Press;1999:3–52.
Wissinger B, et al. Am J Hum Genet. 2001;doi:10.1086/323613.
For more information:
Laura Windsor , OD, FAAO, is a partner of the Low Vision Centers of Indiana and Eye Associates Group LLC. She specializes in the care of ACHM patients in the U.S. and internationally. She was the 2011 American Optometric Association’s Young Optometrist of the Year. Windsor can be reached at: drlaura@eyeassociates.com. For more information about achromatopsia, visit her website on achromatopsia at: www.achromatopsia.info.
Disclosure: Windsor reports no relevant financial disclosures.