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Inherited Retinal Disease
Video

Genetic Testing for Inherited Retinal Diseases with Mitul Mehta, MD

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Mitul Mehta, MD:

Hello, my name is Mitul Mehta. I’m an associate clinical professor at the University of California, Irvine and a retina specialist and the fellowship director of vitreoretinal surgery.

Question:

What are the main challenges in managing inherited retinal diseases, considering their societal and familial effects, high costs, and genetic intricacies? How can we effectively assess therapies for these rare disorders, and what strategies might help overcome these challenges?

Mitul Mehta, MD:

The first thing we’re going to think about is the challenges in assessing therapies for rare disorders. The biggest challenge is going to be identifying which disorders have the larger number of patients involved. When you have more patients involved with a specific disease at different levels, you can determine what the impact is going to be of the therapy because these diseases oftentimes have been given very little funding or very little progress has been made on them. We don’t really know how many people actually do have these diseases unless we have registries. Now with the electronic medical record system and we have these larger databases, we can have a better idea of finding out who has what disease. Part of the problem is that large dataset management is only as good as the inputs, and oftentimes, the inputs are not very precise for specific inherited diseases until we actually have gene testing.

When we have genomic testing, and several companies do offer free genetic testing, we can start to have an idea of how many patients there are in a different disease state. Once we have that, then we can start moving on to what are the specific problems of this inherited retinal disease? What is the cause of that problem from a developmental standpoint, from a genetic standpoint? How is it passed on from generation to generation? Is there an environmental component? All of these things can then be addressed once we know how big the problem is and where we can focus our resources. The costs are going to be substantial for all of these diseases, but when you add them all up, it’s a lot of patients who have a lot of diseases who would otherwise be productive members of society, and this is limiting that regard.

It’s important to address these problems now that we’re able to start to develop therapies for it. There are quite a few disease states that I never thought we would have treatments for that are in phase 2 and sometimes phase 3 clinical trials that are for these diseases, that it is seemingly possible to help these patients. Now that the writing is on the wall that an opportunity is coming, we should take advantage of that opportunity. What we’re going to be doing with all of these therapies is we’re going to do a better job of cataloging who has what, how many patients there are in a given trial, what is the exact genetic landscape for this specific disease, what is actually causing this problem, what other genes are being affected in this phenotype of a given version of a genetic disease, and if there’s any of those things we can address along the way.

Hopefully, we’ll able to start doing that. Unfortunately, because the datasets are going to be so large, we’re going to rely on computers and machine learning and artificial intelligence to help us comb through all of this massive amounts of data. There’s going to be some challenges there, especially with patient privacy and recent issues we’ve been having with databases getting hacked. But I think these are all surmountable problems, and once we can put the resources of clinical trial and basic science apparatus in the country as well as internationally, I think we’ll be able to address these issues.

Question:

What key factors should be taken into account when incorporating genetic testing into ophthalmology practice, and how can healthcare professionals best assist patients and their families in understanding and navigating with the outcomes of genetic testing?

Mitul Mehta, MD:

This is something that we’ve integrated into our practice a long time ago, and it’s a lot easier now that the genetic testing is free by several different companies. What is very important in all of these scenarios, with all the different companies that are doing this, is making sure you have at least 1 point person in every office that does the genetic testing, that gets sent to the results. If that person gets sent the results, and obviously we need to have a backup person just in case who’s also getting the copy of the results, and then that gets put into the medical record of the patient.

If those tests are streamlined and that process is streamlined and all of your clinical staff is taught how to do the testing. Nowadays, oftentimes, you just have to do a swab in the mouth. In the past, we would have to draw blood, and that was definitely a limitation to genetic testing in the past, but now that we can just do a mouth swab, anyone in my staff can do that, and as long as it doesn’t take too much time from the clinician standpoint, it doesn’t actually even slow the clinic down.

But equally important to getting the actual physical testing done is what do you do with the results? One of the nice things is a lot of these genetic testing companies include free genetic counseling, and that’s something that’s very useful. It’s helpful to have somebody who specializes in genetic counseling to actually go over the results of this testing because oftentimes, at least in my experience, a lot of the patients come back with several different mutations of unknown significance and what does that actually mean? There’s a big difference between, we’re not exactly sure how significant this is for everybody, but in the context of your specific genetic background and your pedigree and people in your family who’ve had problems, that’s going to change what any given genetic mutation is going to mean. Even if it globally has unknown significance, it could be significant for you if you come from a line of people who have a genetic phenotype that is actually affecting their visual function.

Question:

What is your opinion on emerging therapies like the ABBV-RGX-314 gene therapy, which holds promise in addressing the needs of patients with rare inherited retinal diseases beyond those caused by mutations and the RPE-65 gene, following the success of voretigene neparvovec? How can the success of these treatments be extended to benefit individuals with less common retinal dystrophies, given the challenges of funding and limited attention for these conditions?

Mitul Mehta, MD:

Voretigene neparvovec is commonly known as Luxturna. That is for RPE-65. One of the biggest challenges associated with that specific therapy is the price. It’s a very, very expensive treatment, and it’s a relatively rare gene in the grand scheme of patients who have genetic dystrophies. Because it’s a gene that we’re not seeing every day, all the time, the patients with those specific genetic problems tend to get funneled to a few centers, which works very effectively if you happen to live near one of those centers. But if you don’t, that’s becoming a big issue. That’s going to be one of the things that’s always going to affect all of medicine. Rural healthcare has been an issue for even routine heart disease, diabetes, thyroid disease, just everyday medical problems. There have been issues with access to care in the United States, even with patients who do have health insurance, because when people don’t live close together, you’re not going to have a close by place for them to necessarily go to, especially if they have a rare disease like this.

That’s always going to be an issue. There really is no easy solution for something that is a rare disease, and this is a very, very large country, and people are unfortunately just going to have to travel to get treatments for that. We just need to make sure that their local doctors know that these treatments exist and that they can address that the patient has this problem and identify the correct patient and send them to the right place to triage them and get them into treatments when treatments exist.

Specifically when we’re talking about the ABV-RGX-314, this is a really interesting gene therapy because this is not even a rare IRD. This is for macular degeneration and for this gene therapy, if we can treat more common diseases like macular degeneration with gene therapy, that is just going to open the floodgates to the expansion of other gene therapies. The biggest question is going to be how is the federal government going to regulate it?

If the FDA will be allowing the approval of the platform and let them change the gene with less stringent oversight and requirements in terms of clinical trials, that would make it a lot easier for more gene therapies to get approved. But if they have to go through the whole process of phase 1, 2, and 3 clinical trials with multiple clinical trials in the phase 3 to assess the validity, which is important to do to some extent, that’s going to make it cost prohibitive for these companies to develop these treatments. Investors are not going to invest in these companies when they’re smaller because it’s just too high of a risk with too little of a reward and too much of a starting cost to do that.

That’s going to be the issue when it comes to being able to expand it to less common retinal dystrophies. That’s going to be the overlying thing that’s going to affect us from a private investigatorinitiated research system and pipeline. But with government funding for things like the National Eye Institute and other government sources that are outside the United States, if they can fund those things and that is an opportunity and a possible pathway to make these things possible. I think it’s going to require a lot of concerted effort from a lot of very, very smart people to make that happen.

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