Reviewing Leber's Congenital Amaurosis with Stephen Russell, MD

Stephen Russell, MD

Leber’s congenital amaurosis (LCA) is a rare inherited eye disorder affecting children at birth. The prognosis is typically worsening of eyesight.

In the latest episode of The Rare Disease Report, Stephen Russel, MD, of the Institute for Vision Research at the University of Iowa, broke down the basics of LCA, discussing its history, presentations, and the state of screening and treatment.

He gave special attention to LCA 10, the most common mutation of the disease, and referenced new data he and his team presented at the Association for Research in Vision and Ophthalmology (ARVO) 2021 Sessions.

Below is the full episode, including highlights from the conversation.

HCPLIve®: What is LCA? Can you give an overview of it?

Russell: Leber’s congenital amaurosis was one of a number of conditions that was named after a German ophthalmologist [Theodor] Leber. He observed a series of patients who presented at birth without vision. One of the characteristics of LCA, as opposed to an intercranial or an inflammatory cause, was that they had normal appearing retinas.

Once electrophysiology became available, they determined that the electroretinograms flatlined at the time of birth.

So, these children typically present with roving eyes, they tend not to fix on a parent, and they have delayed visual maturation. In the case of LCA, they have progressive visual loss, which starts at birth and progresses thereafter.

Over a period of time, that became recognized that this was a genetic condition, although it is recessive in the vast majority of cases. There have been a number of genes which have been identified in one of the big projects at my university. […] There are at least 17 different genotypes that are all autosomal recessive.

What is the prevalence of LCA?

There are only 3,000 cases in the US for all 17 of the genotypes. Some are much more common than others — for example, LCA 10 (or the 10th one reported) is actually quite common. 

Can you describe the patient experience with this condition?

LCA 10 in particular can be associated with syndromes involving seizure disorder and a number of things — or it can be isolated.

As far as the patient experience is concerned, these are patients who are born blind. It becomes very evident early on that they’re educationally limited if they don’t have a high-quality adaptive teaching environment. They are typically managed that way through the elementary and secondary school systems.

Very few of them are actually on the wall chart in terms of their visual acuity by the time they are 20. So, visual acuity drops rapidly usually when they’re toddlers or in their teenage years.

What do screening, diagnostic, and treatment practices look like for these patients?

LCA is an area of hot interest right now, and the thing that really set it off was the development of gene therapy.

The first gene therapy that was approved for any organ system was a drug called Luxterna that treated an enzyme that recycled the high energy form vitamin A — that’s LCA 2.

And so, since LCA 2 is now a treatable condition, there is tremendous interest now in having all LCA patients genotyped for the potential of having them treated.

A lot of the children that are seen that have decreased visual acuity, relatively normal looking retinas, normal looking optic nerves, and flatlining ERGs are being screened for the LCA panel.

LCA 10, which is a mutation of the CEP290 gene, makes up approximately a third of all the LCAs — so it is the most common one by a long way.

You presented new research at ARVO 2021 regarding LCA 10 — can you describe what the study assessed and found?

One of the things that was particularly exciting about the agent that we were looking at, which is a fragment of RNA that binds to the mutation site, is that it allowed the cells to produce a normal-length outer segment, which appears to be functional.

So, there was pretty good evidence that this drug would be effective in the Phase 1.

What was really surprising in the Phase 1, however, was that we saw things we did not expect — we were looking at patients who were quite advanced. […] We saw visual improvements.

Normally, what you would expect with an inherited condition is that you treat the underlying genetic condition and you stabilize the condition. But to see an improvement, especially an improvement with a structural protein — we did not expect that.

What I presented this year at ARVO was the second eye study. Once we found this surprising improvement in visual acuity, we gave the treatment to patients in the other eye. And we saw improvements in all of the subjects who had their second eye treated.

In general, the improvement in the second eye was of similar magnitude to what we saw in the first eye.

The next step is to do a full Phase 3 trial and see if this effect of improvement can hold up.

What is the referral process? And who cares for this condition?

Within the United States, there are a number of classifications within opthalmology. There is a whole group of folks that are pediatric opthalmologists trained to deal with crossed eyes and young developmental problems and things like that.

Those are typically typically the points of contact — or a retina specialist.

Often, it is a general pediatrics physician who determines that a baby just isn't seeing and needs to be evaluated.

It can often come through the regular pediatric referral pattern or sometimes through the pediatric-opthalmolgy referral pattern.

And finally, there are few people who slip through when they're young, never get really evaluated, and are determined to have retinitis pigmentosa when they're an adult. Once they're genotyped, it's determined that their condition had been going on for a long time and it's, say, LCA 10.

Do you have any final thoughts you would like to add?

There is a tendency for patients to think their vision is going to be normal after they get treated. That's not what any of the research is showing so far.

[From our study,] we're showing significant improvements and stabilization in virtually every case, but we don't know what the long-term side effects might be.

Again, this is still very preliminary. Further research is going to be necessary before we're going to feel confident in our recommendation for this particular medication.

But, the suprises have been on the good side so far.

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