Retinal Cell and Gene Therapy Innovation Summit

The 6th annual Innovation Summit organized by the Foundation Fighting Blindness and the Casey Eye Institute at OHSU was packed with exciting research and over 300 attendees. The summit took place in Vancuover, CA on April 26 just before ARVO. I will highlight some research that was relevant to Choroideremia and a few notes on the work.

Gene Therapy

Safety of Luxturna – Dr. Mark Pennesi

Dr. Pennesi reported adverse events that have occurred since LUXTURNA went to market and compared these results to the adverse events in the clinical trials.

As you can see, the percentage of adverse events was roughly the same and were of similar severity. This is encouraging since you hope that complications don’t increase as you move out of clinical trials.

What immunosuppression are you using? – Sara Mary Hall

Instead of presenting a lot of data, Hall emphasized the importance of clearly stating what immunosuppression protocols are being used in the different clinical trials. It is a detail that can often be overlooked but it can greatly effect the safety and even the effectiveness of gene therapy. This sentiment was well recieved by other researchers.

Choroideremia and LHON gene therapy 2019 – Dr. Byron Lam

Dr. Lam discussed the results from Nightstar’s “NIGHT” natural history study and from the phase 1/2 CHM gene therapy clinical trial. The abstract to the clinical trial can be found here (If you are interested in more info you can email me and I can talk about the results). This study showed that “sustained improvement or maintenance of [visual acuity] is achievable in choroideremia.” The natural history study found little change in visual acuity over a 20 month period in patients with choroideremia. Lam concluded that visual acuity could be used as a primary measurement in clinical trials because of this.

Read-through therapies for nonsense mutations – Dr. Matthew Goddeeris

Eloxx Pharmaceuticals is investigating a drug they are calling “ELX-02” which permits cells to read through premature stop codons to produce a full length protein. They are currently working on Cystic Fibrosis, but presented at this summit because this drug has potential for inherited retinal diseases. A similar drug, Ataluren, has been studied on choroideremia models (see this article). If these drugs do work they would be relevant to the portion of choroidermia patients who have mutations that cause a premature stop codon.

Patient Reportet Outcomes for inherited retinal disease trials – Dr. Thiran Jayasundera

Admist all of the tests (visual acuity, fundus autofluorescence, microperimitry, ERG, visual fields, OCT…) during a clinical trial, the patient’s own experience can get lost. How a treatment affects our subjective quality of life is the whole reason clinical trials should exist. The problem is that patient reported outcomes can be hard to quantitatively measure and report on in a study. Some studies do survey patients, but most of the surveys are not tailored towards someone with an inherited degenerative retinal disease. The most commonly used survey now is the VFQ 25. Dr. Jayasundera at the Kellogg Eye institute presented a survey designed specifically for patients with inherited retinal diseases. This work could help to standardize this process and make patient experiences a true clinical finding. The survey will be called the Michigan Retinal Degeneration Questionnaire (MRDQ) and its widespread use will be encouraged.

Preclinical Gene Therapy Studies

Reducing Immune Responses to AAV Gene Therapy – Dr. Ying Kai Chan

Dr. Chan, who works in George Church’s lab at Harvard, presented some viral genome editing which could help gene therapy be safer and more effective. Chan incorperated DNA oligonucleotides into an AAV-8 GFP vector that disrupt a specific immune response (Toll-like receptor 9) that often occurs when an AAV therapy is delivered. When testing this in pigs, Chan found that the immune response was markedly reduced and pathology was decreased. Decreasing immune response makes therapies safer and means that higher doses of vectors could be used.

Intravitreal Gene Therapy for Choroideremia – Dr. Andreas Wenzel

If you have been following research on choroideremia you are probably familiar with 4D Molecular Therapeutics and their work on directed evolution of viruses to facilitate intravitrial delivery. Dr. Wenzel discussed the preclinical work showing decent transfection throughout the retina. 4DMT is currently conducting a natural history study with ~50 choroideremia patients and they are planning a phase 1B safety and tolerability study.

Keynote

Gene Therapy for Retinal Disease – Dr. Robert MacLaren

In this keynote address, Dr. MacLaren discussed the current status of gene therapy, clinical trials for choroideremia, and surgical techniques. MacLaren and others on his team feel confident in their ability to deliver gene therapy through subretinal injection after adjusting their protocol. He remarked that there is always room for improvement but no longer feels that surgery is the hurdle in gene therapy. I was blown away when MacLaren discussed all of the funding that has gone into his and Nightstar’s work. Adding up all of the grants, early funding for Nightstar, and finally the Biogen aquisition, their team has recieved over $1 billion in funding.

Cell Based Therapy

Subretinal Implantation of Retinal Progenitor Cells in RP patients – Dr. Jason Comander

Dr. Commander presented a safety update on his phase 1/2 clinical trial. A small pellet of fetal-derived stem cells was placed subretinally in patients with Retinitis Pigmentosa. Fifteen patients were treated and did not experience any complications during surgery. The pellet of cells started out as a small mound under the patients’ retina, but over a month the deposit thinned out. Five patients experienced a delayed bleb reabsorption, which Commander hypothesized was due to a formulation with a higher osmolarity. The cells need to be frozen for transport, and the osmolarity issue was something that his team was able to figure out and adjust. Commander did not report on the effectiveness of the trial at this point. When asked what happened to the pellet of cells, Commander said most of them end up dying, but some remain viable in a layer under the RPE. I am excited to see the outcome of this work as it has potential for choroideremia patients with little to no vision left.

Subretinal Implantation of an RPE “raft” in dry AMD patients – Dr. Amir Kashani

Dr. Kashani’s work involved placing an ultrathin paralyne “raft” with RPE cells grown on top underneath the retina of patients with dry AMD. The raft is folded to deliver through a small hole in the retina, then expanded and laid down. He reported “minimal or no evidence of systemic or local inflamatory responses”. The abstract to an interem report can be found here.

Hybrid Retinal Prosthesis – Dr. Yossi Mandel

Retinal prosthetic devices like the Argus II promise to restore vision, but always struggle with limited resolution. The device is only able to activate groups of photoreceptors, which means patients are only able to see basic light and dark shapes. Dr. Mandel proposed seeding a “high density electrode array” with glutamatergic neruons. Thus, instead of the device trying to activate patient photoreceptors directly, it can activate the seeded neurons, which then send signals to the photoreceptors at cellular-level resolution. The work he presented was preliminary, but showed that the neurons were able to be seeded, and that after 4 weeks in a normal rat 70% of them were still alive.

Non-viral Gene Editing

CRISPR/Cas9 Genome Editing of CEP290 LCA in vitro – Dr. Eric Pierce

Dr. Pierce started by emphasizing the importance of refering to diseases by their genetic cause instead of their outdated name. Instead of saying he was working on LCA, Pierce emphasized that it was CEP290 he was working on. Choroideremia has the “benefit” of being separated from the rest of the RP causing mutations. Some grouping of diseases is necessary, but distinctions need to be made. Dr. Pierce used CRISPR/Cas9 to disrupt the mutated region of intron 26 of the CEP290 gene in vitro and in nonhuman primates. He found productive editing that was dose-dependent. He also reported little to no off-target gene editing which is always a concern when using CRISPR/Cas9. Editas initiated a natural history study in 2018 to determine clinical trial endpoints.

Suprachoroidal Injection of non-viral DNA nanoparticles – Dr. Viral Kansara

I was very dissapointed when Dr. Kansara did not make a joke about his first name and the fact that he works with non-viral nanoparticles, but I’m sure he has heard it more than he would like. Dr. Kansara works for Clearside Biomedical and presented wotk in rabbits and non-human primates. The injection occurs on the side of the eye, and only penetrates through the sclera so that the liquid can diffuse through capillary action to the rest of the suprachoroidal space. See this article for more info about suprachoroidal delivery. Some concerns were raised in the Q&A about whether a significant amount of product was lost into the blood stream since the suprachoroidal space is not as separated as the subretinal space is. Kansara responded that this treatment has the good aspects of both intravitrial and subretinal delivery. No damage to the retina is done (unlike a subretinal delivery), but you don’t need to deliver an excessive amount of product like you do in intravitrial injections. If this delivery route is as good as advertized it would be amazing. I would have liked to see animal studies that followed the animals for a longer time to see how long expression lasted.

Here is a full list of the speakers, many of whom I did not highlight

• Dr. Steven Bailey
• Dr. Mark Pennesi
• Dr. Bart Leroy
• Dr. Sara Mary Hall
• Dr. Jean-Yves Deslandes
• Dr. Byron Lam
• Dr. Matthew Goddeeris
• Dr. Adrian Timmers
• Dr. Allen Ho
• Dr. Thiran Jayasundera
• Dr. Rob Collin
• Dr. Ying Kai Chan
• Dr. Simon Petersen-Jones
• Dr. Andreas Wenzel
• Dr. Richard Kramer
• Dr. Kourous Rezaei
• Dr. Thomas Reh
• Dr. Robert MacLaren
• Dr. Divya Sinha
• Dr. Jason Comander
• Dr. Eyal Banin
• Dr. Giuliana Gagliardi
• Dr. Amir Kashani
• Dr. Yossi Mandel
• Dr. Trevor McGill
• Dr. Daniel Palanker
• Dr. Michael Byrne
• Dr. Kathleen Chirco
• Dr. Eric Pierce
• Dr. Christina Zeitz
• Dr. Rob Koenekoop
• Dr. Jack Sullivan
• Dr. Viral Kansara
• Dr. Stephen Rose