2/16/2017 0 Comments Genetics newsletterThe following was written by Dr. Rod Nowakowski who serves as the Director of Genetic and Advanced Diagnostic Testing for VisionAmerica of Birmingham. Dr. Nowakowski can be reached via email at [email protected] or via phone at (205) 943-4600. Happy New Year! This issue covers some new developments you will hear more about in the coming year. With all the exciting new reports from clinical studies and new technologies, I expect it to be a Happy Genetics New Year for sure. Here's a preview through my crystal ball. FDA Approved Gene Therapy There is no gene therapy in the United States at this time that is FDA approved, but I expect that to change this year. We may see approved therapy for Leber Congenital Amaurosis and possibly Choroideremia as well as some systemic conditions like Severe Combined Immunodeficiency Disease (SCID), hemophilia and others. Three-person in vitro fertilization
(Three-parent gene therapy) Three-person in vitro fertilization has been approved in the United Kingdom but not in the United States. For an eye application, think LHON and other mitochondrial disorders that affect the visual system. Here's how it works: If mom has a pathogenic mutation in her mitochondrial DNA (mtDNA) she might theoretically eliminate the risk of transmission to her offspring by having the nucleus from her egg transferred to an egg from a woman with normal mtDNA but with the nucleus removed. Now dad's sperm is used to fertilize the combination and we have three persons involved but only the mtDNA is from a donor while the nuclear DNA comes from mom and dad. However, the transfer of mom's nucleus is now known to carry some of her mtDNA, including the mutation, along with it and possibly still produce an affected child. This is probably a solvable problem but mitochondria are pretty small so it won't be easy. Check out the article on three-person in vitro fertilization in the United Kingdom here. Gene Tourism "Gene tourism" is the new term for people traveling to other countries for three person in vitro fertilization and other gene therapies not available or approved in the United States. There will likely be a sharp increase in gene tourism in the future. CRISPR-Cas9 and Gene Editing CRISPR-Cas9 is getting a lot of press lately and for good reason. It refers to a methodology that allows one to target a location in DNA with great precision. Here is why that is important: As we know, gene therapy currently inserts a functional gene, but not necessarily where you want it and it does not change the existing malfunctioning gene. Gene therapy for Leber Congenital Amaurosis has resulted in improved vision but the overall degeneration continues. Why? Probably because the malfunctioning gene continues to do its thing so we have gene supplementation without gene correction. CRISPR-Cas9 has the potential to change that by delivering a gene exactly where you want it. The CRISPR portion is a specific sequence that identifies the targeted region of DNA for insertion and Cas9 is an enzyme that cuts DNA so a new gene or genetic material can be inserted. This is an over-simplification, but essentially accurate. The technology is also relativelysimple and affordable and hence accessible to more researchers. It is by no means perfect technology yet, but the major issues seem mostly solvable. If we can change a gene by replacing it, correcting it or turning it off, we technically editing the gene. Gene editing is a type of gene therapy and holds great promise but comes with some ethical concerns. Choroideremia Gene therapy for Choroideremia has had some degree of initial success and is entering Phase II clinical trials at Oxford University. Check out one of the most recent articles here. It is written for laypersons and is a good resource for your patients. You can read more about the phases of clinical trials here. Treatment of Hereditary Eye Disease is Not Always About Gene Therapy Here is a link to information about a drug that might be used for choroideremia in place of gene therapy: ALK-0001 and Emixustat are other possible drugs for use with Stargardt Juvenile Macular Dystrophy and may slow its progression. Speaking of which, your patients with Stargardt should be counseled about avoiding Vitamin A supplementation. You're doing that, right? Another treatment example is enzyme replacement therapy with alpha-galactosidase A for Fabry Disease. This is a treatable genetic disorder that may come to clinical attention during an eye exam because of the corneal whorls. Genetic Testing for Glaucoma With a few exceptions, we do not yet have a genetic test for glaucoma. The MYOC gene has long been a suspect. It produces myocilin which is a protein found in the trabecular meshwork and the ciliary body. Furthermore, up to about 1/3 of people with juvenile OAG have mutations in the MYOC gene and MYOC mutations have been found in some infants with primary congenital glaucoma. A recent study from Australia showed that some variants in the MYOC gene are predictive for POAG. All of this suggests that eventually, and maybe soon, we will have genetic tests for some glaucomas. That would be huge since it means risk could be assessed very early in life. Recall that the pattern ERG (PERG) may reveal glaucomatous damage to ganglion cells years ahead of the OCT which does so years ahead of visual field loss. A genetic test would trump all of that for an inherited form since the mutation would be in one's DNA, present at conception. Now imagine this case history scenario: Doctor: When were you first diagnosed? Patient: As a zygote. (You're laughing, right? Me too, but one day it may not be too far from the truth.) Managing Hereditary Eye Disease Management of hereditary eye disease depends on getting the right diagnosis. For many aspects of management this means getting the right diagnosis at the molecular level via genetic testing and that is a good reason to refer appropriate patients to the VisionAmerica of Birmingham Genetics Service. Keep in mind, however, that genetic testing may not find a cause and that possibility is part of the informed consent process before ordering a test. Not finding a cause is still useful information as we have ruled out some possibilities and it may lead us toward different tests or perhaps a different diagnosis. We also can test again later when technology is better or when we have more information about causative genes and gene variants. Contact VisionAmerica at (205) 943-4600 if you have a patient that you believe may be in need of genetic testing. 1. Genetics Home Reference https://ghr.nlm.nih.gov/gene/MYOC 2. Ophthalmology. 2016 Dec 16. pii: S0161-6420(16)32004-8. doi: 10.1016/j.ophtha.2016.11.011. [Epub ahead of print] PMID: 27993484 Disclosure - I have no financial or other interest in any of the companies or products mentioned in this newsletter.
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