Earlier this month I had the opportunity to speak with Cindy Elden, Co-Founder of the Usher III Initiative, which I first learned of from Rebecca Alexander who chronicles her own experience with the condition in her brilliant, recently published memoir, Not Fade Away. This amazing organization, based in Chicago, is dedicated to developing a treatment for patients with Usher syndrome type III, a degenerative disease that can lead to the loss of both hearing and vision. Read on to see what Cindy had to say about Usher syndrome type III, the organization and its history, recent research and developments and much more.
Andrew DeCanniere (AD): For those who may not already know, what is Usher syndrome? What causes it and how does it manifest? What are the symptoms?
Cindy Elden (CE): Usher syndrome is a degenerative disease. That means that it’s progressive throughout the course of your life, and it’s double recessive, which means that both of your parents have to be carriers. It causes the degeneration of both vision and hearing. The usual symptoms begin with early-onset hearing impairment and/or deafness, and later-onset of Retinitis Pigmentosa or RP. Retinitis Pigmentosa is an eye disease where the rods and cones slowly die. It begins with night blindness, and then progresses to tunnel vision — peripheral vision — and can result in total blindness. People with Usher syndrome tend to have some combination of the hearing impairment and vision impairment. Depending on which type of Usher syndrome you have, there are differing levels of severity, and the age at the onset of certain symptoms differs. In the earlier years, they only knew about Usher syndrome types I and II. It wasn’t until the late 90s — almost 2000 — when the Usher III gene was identified.
The largest population with Usher syndrome type III are Ashkenazi Jews. The other largest population of Usher III patients is in Finland. The reason that we really don’t know how many people have Usher III syndrome is twofold. One is that most patients with Usher syndrome are never genotyped. That is something that is really important in this day and age, with all of the technology we have. It’s important that patients get genotyped and find out for certain what genetic disease they have. That’s going to help us be in a much better position when we have treatments. We need to go into clinical trials. Having those patient pools is critical in terms of getting the FDA to approve a potential clinical trial, and is critical in terms of getting a pharmaceutical [company] to partner and develop a drug for that population. They need to see that population exists.
In the old days, I think what happened was that, first of all, we didn’t know what Usher III was, so often a retina specialist would see a patient and diagnose them clinically as having Usher’s. Clinical diagnosis is just based on symptoms and they wouldn’t go to the next step of getting genotyped, or of telling their patient to get genotyped, which is a very simple thing to do. All it takes is a blood sample. So, one of the things we are doing at the Usher III Initiative is really trying to encourage people who have any kind of Usher syndrome, RP or degenerative hearing loss is to go and get genotyped. The other thing we’re encouraging them all to do is to register on the Usher Syndrome Registry because, again, in order to get a pharmaceutical partner or FDA approval for any potential treatments we’re trying to develop and hope to have in clinical trials, we have to have all of that clinical data. By every patient taking the initiative to put themselves on the patient registry, they’ll be helping themselves be in a better position for any potential treatments.
AD: So when and how did you become involved in all of this? When and how did the Usher III Initiative get its start?
CE: I was misdiagnosed as having Usher syndrome type II for most of my life. It wasn’t until I was in my 30s that we found out that I had Usher III. Once we found that out, we looked around to see who was interested in doing research on Usher syndrome, and no one really had a focus on Usher syndrome — and they weren’t doing anything at all on Usher III. So, we enlisted the help of David Saperstein, who is our Chief Scientific Medical Officer. He is a highly regarded retina eye researcher, as well as retina surgeon, who had both the academic and clinical credentials. We also went and met with Michael Milken. I don’t know if you know about him, but he is a guy who is in the finance world who, once he was diagnosed with prostate cancer, kind of revolutionized the way that medical research is done.
Traditionally, medical research had been done very slowly and secretively. A lot of the reasons for that were because academic researchers would sit in their labs and would only get grants if they were secretive and competitive. Only one person’s name is number one in a publication, and that person is going to get the next grant. Michael Milken came along and realized that this wasn’t helping research. This was hindering it. So, he said he wanted to change the way that prostate cancer research is done. He was going to pour money into this, and all of the researchers wouldn’t have to worry about the grants, because he was going to give them the money. However, they had to play by his rules, and his rules were that they had to collaborate and share information, which would move research faster. This idea of teamwork, collaboration and peer review — whenever research is complete, having it be subject to scrutiny from their peers and shared in frequent in-person meetings, where their peers review their work — and then accountability. Only giving money to people who produce. Those were his rules and they produced great results in the medical research world.
My dad knew Milken and we went and met with him and with Howard Soule, who is the head of the Milken Prostate Cancer Foundation (PCF). Howard Soule sat us down and said ‘Here’s how you do it. This is what you need to do.’ That became the model for how we would structure the Usher III Initiative. All of those rules became our rules. We enlisted the best researchers we could possibly get our hands on — an A-list of researchers all over the world — and put them in the same room, and they share information and produce results. So, that was our model.
AD: And as far as the organization’s mission goes?
CE: Our mission was just one mission, which was to develop a treatment for patients with Usher III, which we thought was focused enough and strategic and targeted. As we set out to achieve our mission with that structure in mind, we also believed in being multi-strategy about how we approach this. My father has been in finance for years, and the nature of his business and his business ethic was very multi-strategy. We set out to achieve our mission of developing a treatment for patients with Usher III by going down two roads. One is for a novel small molecule compound — which is basically a drug, a pill that Usher III patients that would hopefully stop the progression of the disease, and preserve what existing hearing and vision that the patients had. The other strategy was a gene therapy, which involved going in and knocking out and changing — you know, using a virus and a vector — delivering a gene and correcting the genetic makeup, also preserving existing functioning. Those were our two strategies, but before we even got to pursue those, we needed to learn more about what caused Usher III patients to lose their hearing and vision. That involved a whole team, but particularly our researchers at Case Western, who were able to tell us a lot more about Clarin.
We have a wonderful researcher, Yoshi Imanishi. He is at Case Western and was able to develop a model of the protein Clarin. He was the one who basically explained much more to us about how it is the disintegration of Clarin-1 which causes the loss of hearing and vision. It’s the same disintegration of this one mutant protein that causes all the problems. Once we knew that — once we had that biomechanical information that we got from Case Western — we were then able to figure out that if we could preserve Clarin, then we could preserve functioning. That began the sort of premise and [helped determine] how we would move ahead in developing a small molecule chaperone that would basically preserve existing Clarin and preserve existing functioning.
Yoshi was able to find an assay of a molecule that did just that — he was able to create an assay based on an existing molecule — which we then put through high throughput screening or HTS, where you screen thousands of compounds to see which ones are a hit for the compound you’re aiming for that would preserve Clarin. It’s through this whole pharmaceutical development process that we are able to get hits that we would then develop into a novel compound with a CRO — which is a Contract Research Organization. We hired one of the top biopharmaceutical companies to start helping us with developing this novel compound that would preserve Clarin. We now have a compound that was one of the lead compounds. We have the intellectual property to it and have been testing it in mice.
What we have found is exciting, because just this year we’ve actually found that, in mice, the small molecule compound does preserve existing hearing. We had a more challenging time proving that it preserves vision, but that has nothing to do with the compound and it has everything to do with mouse models. Mouse is not man, so the goal and the challenge in developing animal models with human diseases is that it’s not always that easy. We genetically have been able to create a mouse that has Usher III, and has the phenotype — which means the physical, clinical symptoms — for the hearing, but we have not been able to develop a good animal model that displays the visual phenotype. There are a lot of reasons why that may be, but what it boils down to is the mouse isn’t an ideal model and a bigger animal would be a better model, but it’s not very easy to develop animal models of diseases like this.
So, this has been an exciting year. Probably the most exciting since we started this, because that’s just the half of it. The exciting bit on the small molecule front is we’ve been able to show our compound works in mice to preserve their hearing. The other exciting news is on the gene therapy front. We’ve been able to do gene therapy in the ear. Again, as I explained, we don’t have the visual phenotype for the mice, so we don’t have the visual data, but we have exciting data regarding the ear with gene therapy. The other difference is when you take the pill, it’s systemic, but gene therapy is delivered locally. You’re only treating the ear. You’re not treating the eye. We’ve been able to show promise of successful gene therapy in the mouse ear with an Usher III mouse model. We have all of this great data showing that both of our strategies work for the ears, and that’s really exciting. It’s frustrating, too. Both of them might also work in the eye, but we can’t prove it yet in scientific data in the mice, and before we’re able to get a pharmaceutical partner or the FDA to approve doing this in humans for the purpose of treating eyes, we need clinical data on an animal to show that this works in the eyes. That’s what’s frustrating.
AD: It certainly seems like it could get there. It’s already working in the ear. It may take some time, but it seems entirely plausible that it could then work for the eyes, too.
CE: Right now where we are is we’ve spent a lot of money on this personally — you know, our family and the fundraising we do for other people with Usher III. We’ve now at a point in the development of both of these treatments where we need a partner. Right now we’re trying to put together a package. Our goal is simply to treat patients. That’s our only goal. We’re now looking for a partner who wants to put money into the next phase of developing either the small molecule or the gene therapy or both. Those usually aren’t the same person, so it’s probably an either/or. Somebody who develops gene therapies is often a gene therapy company, and somebody who develops a drug is a venture capital group or a pharmaceutical company.
As we see how long the road for gene therapy and small molecule has been — and since we’ve had such challenges developing the mouse model with the vision phenotype, and technology is moving so quickly at the same time — a new direction we’ve just begun to pursue is looking at how we can make a difference in, and accelerate the pace of, artificial vision and visual restoration. There are a couple of perks to that, which are that not only is technology moving so quickly — and then you don’t need a mouse model specifically with an Usher III phenotype — but we could potentially get more funding from any other organization that helps any blind population of people, because if we’re working more generally on artificial vision and visual restoration, that is something that is potentially going to help a much broader population of blind people.
There are people in that space right now, but we’re trying to do some research and see what part of visual restoration would make the most sense for our third strategy direction. So, that’s kind of what we’re doing in a nutshell.
We have a Scientific Advisory Board that includes very seasoned biopharmaceutical people — people who are in the industry who have been advising us and have many years of experience developing drugs for the eye, as well as clinical expertise for the eye and regulatory. We have a really strong Scientific Advisory Board. Somebody’s also in the gene therapy development world. Then, developing our small molecule we have Bill Harte. Bill Harte was the person who was helping us take the academic science from Case Western and translating that into developing it into a novel compound — a pill — with a biopharma. He has years of experience at Amgen and then left the traditional pharma world to go into the space of helping basic science laboratories translate their science into something usable for patients — bringing basic science and the academic world to the clinic. He’s been the head of our Small Molecule program, and then most of the gene therapy has been under Bill Hauswirth’s leadership. Bill Hauswirth is in Florida, and he is the one who did the very successful gene therapy for another blinding disease — it’s called LCA, I think — where they restored vision to a dog, and then they’ve done this in humans, and he was involved in the ones done in humans. We have a Board of Directors that includes a very seasoned group of people. I’ve been running this with my father and our team, and now we’re at that point where we’ve got to find the jumping off point with a partner. So, that’s where we are.
AD: It seems like you all have accomplished quite a lot.
CE: Yeah. I’m very proud of our team and what we have accomplished. There’s nobody else — either government or non-government — funding Usher III research. That’s why we created this organization, because nobody else was doing it. We knew it needed to be done, and it needed to be done in a focused, strategic way. I feel proud of the fact that we’ve brought researchers into this disease who weren’t previously in this disease. That’s also part of the Milken ethic. I know we got good minds that weren’t previously into this field into the field, and I’m proud of that. The way I’ve coped as a patient is by focusing on doing something about this. The way my father raised me is not to accept anything just the way it is. Go change the world. That’s always been my attitude. Never settle for the status quo. Change it. The other thing that is a big part of who I am and what I believe is that patients have to be their own advocate. I feel like we have to be our own army, and this is how you fight the battle. You can’t wait for other people to do it, because it’s clearly not happened.
AD: Is there any way that individuals are able to get involved or help support the Usher III Initiative, either through volunteer opportunities or anything else?
CE: We’re always trying to raise money, and we’ve had a couple of fundraisers. We haven’t had one in Chicago, but we’ve had a few in New York. We’ve had a Spin-a-Thon that Rebecca [Alexander] and some of the other Usher III gang all did and that was very successful. That was a few years ago. We haven’t actually done another one. We have basically done private outreach to people, asking them for donations, and we do a big end-of-year push for donations. We send a regular newsletter out, with our latest research and success and progress. We like to keep our donors informed of what our progress is. We haven’t done a lot of events. There are different conferences on Usher syndrome, and we try to take part in those conferences and get the word out. There’s an Usher syndrome conference, usually in Boston, held in June by the Usher Syndrome Coalition, which is a different organization. We partner with them. That’s a little more community, patient and patient family-based. We’re a little more science. We’re tying to raise money, but we don’t really function so much as a community support group. They do that. We really focus on science and treatment development.
AD: Finally, I was just wondering whether there are any other resources you would recommend for people who either have Usher syndrome or for their families.
CE: The Usher Syndrome Coalition is a great support group and they have a wonderful network of people. That encompasses all Usher Syndrome — type I, II and III. So, that’s the whole Usher community, not just Usher III, which we focus on for research. It’s through the Usher Syndrome Coalition that the registry exists. They have a patient registry, which we were involved in and very supportive of and continue to promote. The Usher Syndrome Coalition’s patient registry must be four or five years old now, and we hope it’s growing every day, and more and more patients are putting themselves on that registry — whether they’re Usher I, II or III — because it’s going to make things much easier and faster for them if a treatment is developed. It will be easier to get it to patients. We hope people reach out to them. They also have a conference call every month, and it’s a mix of news and patients and it’s a nice sort of virtual community of Usher patients. Here in New York there are certainly organizations like The Lighthouse for the Blind, and I believe they have other locations around the country. They offer all kinds of services and gadgets that are particularly helpful on a day-to-day basis to patients who are dealing with these diseases of varying degrees of severity. So, I’m a big fan of The Lighthouse.
For people who are at the point where their hearing is increasingly diminished — there’s a point at which many Usher patients consider getting a cochlear implant and then they get one, sometimes two. I got mine five years ago, and it’s the best thing I ever did.
AD: Right. Having read Rebecca’s book, I do know that it’s often one of the biggest, most personal decisions for someone to make. There’s a lot to think about and it’s a lot of work. It seems that not many people know it, but it’s a really big decision. That said, depending on the particular circumstances, I know it really has the potential to make a big difference.
Cindy Elden is the Co-Founder of the Usher III Initiative. She lives in New York City. You can learn more about the Usher III Initiative by visiting their website. You can also find them on Facebook and on Twitter.
Special thanks to Cindy Elden, for taking the time to speak with me; to Rebecca Alexander for suggesting the Usher III Initiative in the first place; to Lindsey Whyte, Project Manager at the Usher III Initiative, for all of her assistance; and to Yoshi Imanishi for providing the 2D model of the Clarin-1 protein.
Photo Credit for 2D model of Clarin-1 protein:
Tian G, Zhou Y, Hajkova D, Miyagi M, Dinculescu A, Hauswirth WW, Palczewski K, Geng R, Alagramam KN, Isosomppi J, Sankila EM, Flannery JG, Imanishi Y. “Clarin-1, encoded by the Usher Syndrome III causative gene, forms a membranous microdomain: possible role of clarin-1 in organizing the actin cytoskeleton.” The Journal of Biological Chemistry, 2009 Jul 10; 284(28): 18980-93. doi: 10.1074/jbc.M109.003160. Epub 2009 May 7.