Last week, we began a new blog feature with one of our medical students offers his or her perspective on the current week’s episode. For this week’s podcast episode, we were joined by Dr. Audina Berrocal for a discussion on a number of topics in pediatric retinal surgery. Of these, one in particular that has received special attention in the media and in ophthalmology communities has been the use of gene therapy to treat children with hereditary retinal diseases such as Leber congenital amaurosis (LCA). The most common hereditary retinal disease is retinitis pigmentosa (RP) and there are current trials ongoing in the United States looking at gene therapy for RP. For our listeners and readers who may be patients, parents, or simply curious, we wanted to provide a basic overview of RP and how this treatment can be used to save some patients’ sight.
Retinitis Pigmentosa: Background
RP is a clinically and genetically heterogenous group of inherited (can be passed down from parent to child) retinal disorders, meaning that there is a good amount of variability between patients with respect to how they inherited the disease and how the disease affects their vision. In general, however, RP involves a progressive (worsening) retinal dysfunction, usually starting with the rod photoreceptors (the “night-vision” part of the retina) and later affecting the cones (for “day-vision”) and retinal pigment epithelium. Thus, patients with RP generally first experience night blindness (difficulty seeing in low-light settings), followed by progressive visual field loss (a sort of “tunnel vision” as shown below).
Retinitis Pigmentosa: Genetics
There are no known risk factors for RP other than genetic predisposition. So what does this mean? We mentioned earlier that RP is “genetically heterogeneous” - indeed, RP can be inherited as an isolated sporadic disorder, or in an autosomal dominant, autosomal recessive, or X-linked pattern.
Isolated Sporadic: a genetic mutation can be passed on, but in order for one to be present and available to be passed on, the mutation has to occur for the first timein some individual of a family. This is called “sporadic” since the mutation occurs, essentially, randomly.
Autosomal Dominant: for most of your DNA, there exists a second “backup copy” for each gene (one from Mom, one from Dad). For autosomal dominant inheritance patterns, if one of the two copies is “bad,” the disease can occur. In general, the purpose of each gene is to make a certain protein that your body needs to function. Think of this as a two-person team at work; if one of your team-members refuses to do his/her work, you may not meet that deadline. In the same way, if one member of the two-protein team (two copies: one from Mom, one from Dad) isn’t cooperating, a disease process can occur.
Autosomal Recessive: in this case, both copies need to be “bad” for the disease state to occur. In other words, one good copy is sufficient to prevent disease. Think of this as being like transportation to work: if your car is broken down but your spouse’s car is running, you can borrow the car and still make it to work on time. For autosomal recessive diseases, if one copy of the gene is “bad” and the other is “normal,” the patient will not have the disease (see image below).
X-Linked: for these diseases, the important gene is located on a particular chromosome called the X-chromosome. For baby boys, they only receive an X-chromosome from their mother. For baby girls, they receive an X-chromosome from both their mother and their father. Since the boy would only have one X-chromosome, he wouldn’t have a “backup” copy in case the copy he received is “bad,” and so he would be more likely to be affected.
Retinitis Pigmentosa and Gene Therapy
Now that we’ve finished our genetics lesson for the day, how does this relate to “gene therapy” treatments for RP? In the episode, Jay and Dr. Berrocal discuss use of RPE65 therapy for some children with LCA. Since this is an autosomal recessive disease, that means that both copies of the gene are “bad” and the so both copies of the protein that they are (supposed to be) making are “bad.”
Gene therapy is a way to allow the patient to create the “good” protein. A special virus (which carries a “good copy” of the RPE65 gene) is used to insert the “good” gene into cells of the patient’s retina. After that, the cells are are able to make the “good” protein, which helps preserve or improve vision!
Looking To The Future
Although Jay and Dr. Berrocal only talked about one specific gene that is being targeted with gene therapy, there are others that are being targeted in current clinical trials (e.g. Dr. Berrocal’s patient with X-linked RP who received gene therapy at Bascom Palmer) or will be in the future. Gene therapy is a bright light for the future, and hopefully will improve the lives of countless patients with a number of ophthalmologic and non-ophthalmologic conditions.
#genetherapy #retinitispigmentosa #leberscongenitalamaurosis #rpe65 #ophthalmology