ARVO 2019 Sunday Notes

The Vancouver Convention Center’s West Building

A few words

Similar to my article about the FFB Innovation Summit this post is a gathering of my notes from ARVO 2019. I will not be explaining topics, instead this is meant to be a reference for myself and others within the CRF. However I want these notes to be available to everyone since I think it is vitally important for those affected by disease to be invited into the discussion about research. Even if topics are difficult for the general public to understand, they should not be hidden behind paywalls and inside exclusive meetings. These are talks that I went to, some of which are extremely relevant to choroideremia, others are more generally interesting to me.

Sunday, April 28

The potential and pitfalls of big data

A discussion on big data in ophthalmology. “Big Data -Omics: Approaches for genetics and biological research” was presented by Christopher Hammond. He discussed the UK Biobank and the TwinsUK study. Anne Coleman discuss the IRIS database and its impact. The IRIS registry contains 18,000 physicians and includes 234 million visits. Of particular interest is that she noted that both cataract complications and the prescription of high risk medications to elderly patients declined from the beginning of the IRIS registry. She noted two things related to this: ophthalmologists may be reporting fewer cataract complications because they don’t want the data to reflect them poorly, and they may be prescribing fewer high risk drugs simply because they know they are being tracked. Studying something always comes with the risk of affecting the data when it comes to humans.

• References to explore:
  • Mountjoy 2018, BMJ
  • Han 2019, JAMA
  • Huang 2017, Front. Genomics
  • Hysi 2018, Retina Biology (Redox)

Keynote speech

Randy W. Schekman presented “How cells export proteins and RNA”. He mentioned that ablation of Rab27a (which Rep-1 acts on) in CD26 (?) positive cells can stop vesicle secretion. Need to look into that more.

Protection, Correction, Regeneration: Are combination therapies in the future for IRDs?

This special interest group was initially organized by Randy Wheelock, but after his unexpected passing Ian MacDonald and Chris Moen took over the organization and planning. Ian MacDonald’s prompt for the speakers was “What are your top challenges in your area of research?” The room was completely full.

Jacque Duncan presented “Outcome measures depend on type and stage of disease.” Particularly in choroideremia she gave this overview of how the disease can be studied as it progresses:

Mark Pennisi did not have any slides to present, he just wanted to float the idea of combinatorial therapies by the rest of the panel for discussion. Most clinical trials are studying mono-therapies, but when you look at cancer treatments they regularly use combinations of treatments. So why not treat an eye disease patient with a neuroprotective (or a few) as well as the gene therapy. There may be some resistance from regulatory committees, but he is confident that can be overcome. You may hit real roadblocks when you try to use drugs from different companies since they usually don’t play nice with each other.

Stephen Tsang brought up the issue of sustainability when it comes to gene therapy. He cited some papers that indicate that the current treatment for LCA does not actually halt degeneration (see this paper as well as this one). Is this because cells have already gone past the point of no return and the gene therapy can’t save them? Is this because only a small percent of cells are transfected and the ones that aren’t continue to die? Is this because the cells silence the transgene (maybe through CMV promoter methylation)?

Thomas Aleman’s plane was delayed, so he arrived just in the nick of time to give his part of the talk. One big issue he raised with choroideremia (and some other diseases) is that the degeneration is not symmetrical. One eye may all of a sudden begin deteriorating more quickly than the opposite eye. Aleman talked about the phase I/II clinical trial he administered for choroideremia patients, which I will discuss later since he presented complete findings on wednesday.

Jasmina Kapetanovic presented robot assisted retinal surgery. She showed videos using a robot from Preceyes to deliver a subretinal injection and an inner limiting membrane peel. When delivering a subretinal injection the robot allows the doctor to hold the needle steady once the bleb has been created in order to deliver the gene therapy over a long period of time. By slowing the injection down and holding the needle steady the surgeon can minimize trauma to the retina.

During the question and answer session these topics were discussed:

• Why did Aleman not see any visual acuity gain in his patients, like in the Nightstar clinical trials? Was it that he selected patients with visual acuity that was too good?
  • Aleman never expected to see a gain in visual acuity in these studies
• Robert MacLaren asked “How long does metabolic recovery take in choroideremia cells?” (These cells haven’t had Rep-1 their entire life, so they are diseased even if they aren’t dead yet). He posed the thought to Tsang that the decline seen after LCA gene therapy may be due to a low transfection rate.
• Are we treating enough of the retina in patients with LCA?
  • Pennisi responded that not that LUXTERNA is approved, it can be delivered to more areas of the retina at the surgeon’s discretion, potentially using multiple blebs.
  • Someone (I think Pennisi) made the point that immunosuppression is extremely important in gene therapy. You have to give it before you see any inflammation. Once you get inflammation it is too late, you have already damaged and lost a good number of cells.
• Alessandro Iannaccone asked the speakers to comment on what kinds of immunosuppression they were using
  • Generally prednisone at a high dose, tapering off after ~40 days.
  • Pennisi noted that 3-4 weeks is usually when you see inflammation (if it is not seen initially). This might coincide with when vector production really ramps up?
• Is gene dosing important? Should we be worried about giving too much gene therapy?
  • The general consensus was that too much gene therapy is not really an issue at the moment, for one we aren’t really able to give too much. Aleman was cautious about this sentiment. Others noted that there were some animal studies where too much product was delivered (potentially a RHO study?)
• Kapetanovic asked the other panelists how you design a trial for a wide range of patients
  • Aleman pointed out that the different phases of clinical trials generally line up with where patients are in disease state (treat advance patients during early phase I trials).
• Steve Rose asked how multiple therapies would work with institutional review boards and how patients would feel? Would it be difficult to get approval?
  • Pennisi thinks it would not be an issue at all. They give multiple treatments to glaucoma patients! We just need to push.

Cone Outer Segment Reflectance Entropy in Choroideremia - Abstract: 1030

Andrew Huang (working with Jessica Morgan) presented some work using adaptive optics to measure density and reflectance entropy of cones in CHM patients.

Entropy in image processing is the amount of randomness within an image. A sharper image will have lower entropy. This measurement could be a useful way of quantifying CHM patients as an objective endpoint.

Functional and Structural endpoints in clinical trials - Abstract: 995

Donald Hood discussed using optical coherence tomography as a clinical trial endpoint. He used the UK Glaucoma Treatment Study as an example of a clinical trial that actually used OCT as an endpoint, even though they used it as a secondary endpoint. He also discussed using the 10-2 visual field test instead of the 24-2 visual field because it has a higher density of points in the central portion of the visual field (see this abstract for a study on this).

Interesting Posters

• Biodistribution and duration of action of Locked Nucleic Acid oligonucleotides - Sindri Traustason
  • LNAs are RNA nucleotides that have been modified with a bridge that improves binding affinity and decreases nuclease resistance. They tested an LNA through an intravitreal injection in minipigs. They found distribution in all layers of the neural retina and the RPE, as well as significant knockdown of VEGFA (the target) up to 90 days after injection. A reduction of 85% VEGF was observed in the vitreous humor for 120 days.
• The number of RPGR cases remains under-represented - Elise Heon
  • Mutations in RPGR are the most common cause of X linked retinitis pigmentosa. This study removed some of the quality pass filters on the next generation sequencing done on “negative” patients. This allowed them to identify mutations in hard to sequence regions of the RPGR gene (specifically open reading frame 15) which were validated further.
• Development of knock in mouse models of rhodopsin retinitis pigmentosa - Kelly Ziaka
  • This group created a few interesting mutations in the Rhodopsin gene in mice. The different mutations seemed to mirror the severity of the mutations found in humans, but need to be further studied.
• Retina has significant protective mechanisms to eliminate mtDNA heteroplasmy SNPs compared to blood - Cristina Kenney
  • This group looked at samples from 3 individuals and found that the retina contained much lower levels of mtDNA heteroplasmy than the blood. This suggests that the retina has protective measures that help deal with high metabolism and exposure to UV light.