“Stem Cell Treatment Cures Blindness?” No, not quite.

by Jennifer Phillips, Ph.D.

I spend an average of 15-20 hours a week reading scientific literature. Most of this is extremely specialized stuff, pertaining either to my specific area of research or to some detailed experimental method I want to learn more about. However, I’m always on alert for a science story that will have broader appeal to our Usher Blog audience, and maybe implications for the future of therapeutic Usher research.

One such story was published in the prestigious medical journal, The Lancet, a few weeks back. It’s a very nice—albeit preliminary—finding that is unambiguously deserving of attention and admiration. But what’s actually in the paper is only part of the story. The other part is my ongoing lament about how badly the media can botch science reporting. I’ve grumped about this before, and this is yet another example of this unfortunate phenomenon.

The paper, entitled ““Embryonic stem cell trials for macular degeneration: a preliminary report” has made quite a splash in the international news. For the first time, a retinal cell type derived from human embryonic stem cells (hESCs) was used in Phase I Clinical Trials as a potential treatment for two types of Retinal Degeneration. This is noteworthy in and of itself, given that using hESC-derived cells for any therapies is a nascent field. I’ve written previously about risks, benefits, and open questions in this field, and studies such as this add volumes to our body of knowledge about stem cell biology. Being able to harness the potential of pluripotent cells which can:

A) differentiate into a functional, specialized cell type

B) integrate into a human organ/tissue without being rejected by the immune system

C) not form tumors and

D) beneficially impact the progression of a degenerative (or, really, any) disease

is a really, really big deal.

Achieving item A above, along would with adequate and successful safety testing in animal models, would be a prerequisite to any clinical trial. Recall that in a Phase I trial, safety and tolerance for various doses are the primary objectives. In a Phase I trial involving Stem Cells, therefore, you’d want to focus mainly on items B and C above. But, as we’ve seen before with Phase I trials, if something really remarkable approaching the realm of ‘D’ happens during the Phase I study, the researchers might be inclined to publish a preliminary report and share the news. The LCA gene replacement study published in 2009 is one such example. So is that also the case with this new Lancet paper? Let’s dive in and see.

Recall, if you will, the title of the article: “Embryonic stem cell trials for macular degeneration: a preliminary report”. Fairly understated, wouldn’t you say? Well, this is a stodgy medical journal, after all. So you can hardly blame the media for gussying up the story just a bit with headlines such as “Giving sight to macular degeneration patients , or ”Once they were blind, now they see. Patients treated with cells from human embryo: Controversial medical breakthrough restores vision – now doctors hope to repeat the success”

This would obviously be fantastic news if it were true, but let’s tune out the sensational journalism for a moment and establish what the Lancet article actually reports.

The Study Design

The paper in question is actually reporting preliminary results from two simultaneously conducted Phase I trials. Both trials are using Retinal Pigmented Epithelial (RPE) cells derived from hESC lines as a potential treatment for two different types of retinal degeneration: Age Related Macular Degeneration (ARMD) and Stargardt’s Macular Dystrophy. Blindness in both of these conditions results from defects in the RPE, which causes the photoreceptors to degenerate, thus it makes good sense to attempt to replace the defective cell type in an attempt to ultimately rescue the photoreceptor loss.

Differentiated RFE cells in culture.  From Schwartz et al., 2012

As with all Phase I trials, both of these trials are primarily concerned with safety, tolerance of the treatment, and optimizing the dosage. Both studies are ongoing and anticipate a total of 24 patients (12 in each study), who will receive different dosages. In these two studies, the ‘dosage’ is defined as the actual number of RPE cells that are surgically introduced into the retina—a procedure performed on one eye (the other eye received no treatment and thus served as an experimental control) at the beginning of the study. Patients are then followed for several months and examined for any tissue damage related to the treatment as well as for abnormal growth of the implanted cells.

The Results

The Lancet paper reports results from two patients—one from each of these Phase I trials—who were followed for four months after their procedures. The first half of the paper’s results describes the preparation of the RPE cells and safety testing conducted in mice. The patient data dealt principally with the fact that neither of these subjects, both females with significant loss of central vision typical of end-stage macular degeneration, experienced any adverse reactions to the treatment. No swelling, no pain, no abnormal cell growth, no immune response to the implanted cells. All good news.

The authors then go on to report the findings that got the International News all churned up. Both of these patients—again, each with a different type of severe macular degeneration—reported improvement in their vision after the procedure. What kind of improvement, exactly?

The ARMD patient was able to read more letters on the chart in the weeks following her treatment, which must have been tremendously exciting for her. These results must be interpreted with some caution, however, because this is a pretty subjective test, for one, and there were no other clinical findings to support the improvement—no changes were detected in her retina when compared to her preoperative condition. Further confounding these results was the fact that this patient experienced an improvement in her ‘control’ eye as well—the one which received no treatment at all. Thus, it is a possibility that at least some of her perceived improvement was derived from the placebo effect of having had surgery and postoperative care.

Reported improvement in the Stargardt’s subject were less ambiguous, and could be verified by clinical examination in addition to the subjective visual perceptions of the patient. Prior to the procedure, this woman’s vision was so diminished that she could perceive a hand being waved in front of her, but could not make out details like individual fingers or letters on an eye chart. Several weeks after the procedure she began to be increasingly able to count individual fingers. She also reported an improved color perception after the transplant. Encouragingly, tests on her retina revealed that the implanted RPE cells had integrated into her retina, ‘filling in’ a portion of that cell layer which had previously been destroyed by the disease. The Stargardt patient’s improvements were limited to her operated eye.

The Bottom Line

It’s really cool stuff, on several levels. This is the first time that a cell population derived from hESCs has been successfully used in a clinical trial. This is also the first time that RPE cells have been successfully introduced into a diseased human eye. Previous attempts at RPE replacements, using mature adult or fetal RPE cells, have been made in ARMD patients but have been unsuccessful, so it’s very exciting preliminary data on that front. And of course the fact that visual function improvements seem to be occurring in these subjects is more important still, particularly considering the advanced stages of their respected diseases. Indeed, once the procedure is optimized through these trials, the treatment is actually intended for patients with less advanced MD, in order to prevent vision loss, rather than aiming to restore it. End-stage patients were chosen for these Phase I trials precisely because their vision is already so bad it’s unlikely that it could be further compromised if something were to go wrong with the procedure. Preliminary though these results may be, it would be wonderful if the recipient pool of the developed treatment could be expanded to include patients with more severe manifestations of these types of diseases.

But….

It’s really preliminary. This is two patients we’re talking about, and while we can celebrate the fact that they came through the procedure without any adverse side effects (so far) AND some apparent improvements in their vision, it is too soon to apply these results to a larger population. This preliminary report allows us to be cautiously optimistic that the additional results forthcoming from these studies will be consistent with the promising findings from these two test cases. It does NOT allow us to declare that ARMD and/or Stargardt’s has been “cured” by stem cells, or even that sight/vision has been “restored”, as the headlines declare.

What this means for Usher patients

Directly and immediately, nothing. Usher syndrome is not a disease of the RPE, so this particular cell line would not likely be effective in forestalling photoreceptor degeneration in USH patients. In the longer term, though, I think we can be encouraged by the fact that the generation of these cells from hESCs has been far more successful than any other cell-based treatment to date. In time, other cell types could be procured in a similar manner and, potentially, treatments that could benefit Usher patients could be developed.

What it also means is a modicum of caution. Given the buzz that this story has created, it would not be surprising if some charlatans around the world used the early success of this trial to sell ‘stem cell’ treatments for all sorts of degenerative conditions for which there currently are no cures. Don’t believe it. We’re not there yet. But we’re working on it. Be encouraged.

Addendum

2/27/12 - After this article was posted, a reader sent this link in the blog comments.  It's such a great talk we wanted to give it more visibility. It's a talk from a recent stem cell research conference, given by the lead investigator on the stem cell therapy referenced in this post. 

The presentation is geared to a professional audience, so it might be a bit dense with jargon in parts, but well worth the 20 minutes. Enjoy! - Jennifer

Reference: Steven D Schwartz, Jean-Pierre Hubschman, Gad Heilwell, Valentina Franco-Cardenas, Carolyn K Pan, Rosaleen M Ostrick, Edmund Mickunas, Roger Gay, Irina Klimanskaya, Robert Lanza. Embryonic stem cell trials for macular degeneration: a preliminary report. The Lancet published online January 23, 2012; DOI: 10.1016/S0140-6736(12)60028-2.

The Bella Chronicles, Part IV: Middle Age

by Mark Dunning

I’m 43 years old and smack dab in the middle of middle age. I can tell you from experience that middle age stinks. I don’t see as well as I once did. I had the eyes of a hawk when I was younger. Now I need glasses. When I take Bella to one of her frequent ophthalmologist appointments, I have to squint just to read the same lines on the eye chart that she does.

My hearing isn’t as good, either. I find myself turning up the volume on the TV or the radio. It’s not all the time, just certain voices or sounds. Some frequencies aren’t as clear.

And I have come to love a good nap. Actually, that’s not true. I’ve always loved a good nap. No, no. I’ve come to need a good nap. I just get tired more easily than I once did. A good walk, some yard work, a long day at work, a long drive, or even just some fresh air and I need an hour on the couch. I’ve started to plan my weekends this way. If I do X in the morning, I’m going to be too tired to do Y in the afternoon unless I get a nap.

I think I noticed middle age the most in sports. For most of my life I improved at sports. At some point in my twenties I plateaued physically, but my ever improving knowledge of the games meant that I still played better even if I wasn’t getting faster or stronger. Around thirty-five, though, my body started to decline faster than my mind could improve. I knew what I should be doing but I couldn’t get my body to do it.

I eventually gave up organized sports, but I did not quit because of my declining physical abilities. It was the frustration that got me. I felt like I was disappointing the players who had known me when I was younger. I was no longer meeting their expectations. And I felt embarrassed in front of the players who only knew me when I was older. I wanted to explain to them that I wasn’t always this way. I used to be a better player.

If I sound like I’m whining about this, I’m not. It’s just part of life. All my friends are experiencing the same things. Joints ache, bellies bulge, hair recedes. I tell Bella she’s the reason I’m going gray, but it’s not really her. It’s middle age. We complain about it, we joke about it, but we accept it. It happens to everyone.

Usher syndrome, as we know, does not happen to everyone. And unfortunately for a thirteen year old girl, at times it can seem a lot like middle age. Bella has never been big on team sports. She likes to ride horses more than anything. But she used to take gym and this year she does not. The exercises have gotten more challenging and the other kids are bigger. They move faster and throw harder. Suddenly gym is more about avoiding getting hurt for Bella than it about physical fitness. So the other kids go the gym and Bella goes to the library.

The school work is harder, too. There are fewer pictures and more words. The subject matter takes longer to explain. The homework is dense. It’s challenging for everyone, but especially for the kid with Usher. The other kids adapt more quickly. They can hear the teacher and read the materials at the same time. Bella cannot. They can take their own notes. Bella has to focus on the teacher so she can read lips. She gets the notes after class. They can read the photocopied worksheets. Bella needs them enlarged. It’s all just easier for her peers than it is for her.

Bella gets frustrated. The other kids don’t ask for help. The other kids don’t ask the teachers to give them the notes or to repeat what they said or to make second, darker, larger copy of the homework just for them. The teachers expect her to keep up. She feels she is disappointing them. And those new kids, the ones she doesn’t know, she wants to explain to them that she is really just like them. Last year she didn’t need feel like she interrupted class as much. She wants them to know that. She used to be just like them.

All of this is exhausting, of course. Bella is more tired now than she used to be. The other kids keep going, but she’s out of gas. She wants to go ride her horse, but some days she’s just too tired when she gets home. She’s disappointing the riding teacher, too. She’s sure of it. And the homework. There is so much of it now and she’s already so tired. She just wants to sink in to the couch and rest. It didn’t used to be this way. She used to have so much more energy.

It all sounds familiar to me. It’s a lot like middle age. The difference is I knew it was coming. I was a mature adult who had already experienced life. I say things like ‘when I was younger, I could do that.’ But Bella IS younger. She still expects to do be able to do that, whatever that might be. Her expectations are different than mine. I expected to be dealing with this. She did not.

I’ve learned to accept my situation. It’s hard to advise Bella that she should accept hers. She’s too young to be old. She shouldn’t accept her situation, but she does need to adjust. And that starts with advocating for herself, which is what we’ll discuss in the next post.

The Bella Chronicles Part III: A Necessary Evil?

by Mark Dunning

For Usher treatments to be found, someone is going to have to take a risk. Someone with Usher syndrome is going to have to be part of a clinical trial. Someone is going to have to be the first human being ever to try a particular treatment. Oh, it will be tested on animals and the researchers will have vigorously studied it. They would never try it unless they had real hope that it would turn out to be a viable treatment. But the fact remains that until a treatment is tried in a human body, no one knows for sure the result. So for us to find viable treatments for Usher syndrome, someone is going to have to take a great risk.

That someone will not be my daughter Bella. Well, at least I know that someone won’t be Bella before she is an adult. After that, it’s her call. But while it’s my decision, she won’t be participating in a phase I clinical trial. I’ll do a lot to support Usher syndrome research, but that is just a step too far for me.

That is not true for other parents. The first step in a clinical trial is a safety trial. This is done to make sure that there are no unexpected and seriously adverse effects of a treatment. These safety trials are usually done only on consenting adults for obvious reasons. But I have had parents ask me if I would help them pressure researchers to accept their kids in such trials. They want a treatment as soon as possible and they are willing to take the risk. I won’t do it, of course, but they believe their actions are in their child’s best interest. It’s not a step too far for them.

I know other parents who have taken their kids to India, the Dominican, and China in search of treatments that are questionable and very risky. Most of these are not approved by the FDA and in some cases are illegal in the US and Europe. But these parents think the risk is worth it. Again, that’s further than I would go and not something I would ever recommend. (plus it drives Jennifer insane)

There is one risk that we have taken with Bella in trying to find viable treatments. We have willingly had her participate in videos, speak in public forums, and written about her in, ahem, certain blogs. We made the decision to involve her in these things because we feel it is the best way to help her.

Readers of this blog know that I am a vocal advocate of creating an Usher syndrome community. To find treatments for Usher syndrome we need two things: 1) We need to better understand the disease and 2) we need people willing to participate in clinical trials. We just discussed how difficult it can be to find people to participate in clinical trials. You need a large group of people to find those few who are a) willing to participate, b) able to participate, and c) appropriate candidates.

Understanding the disease is no less difficult. Deafblindness carries a stigma and it is a terrifying proposition. Historically, people with Usher syndrome have either kept to themselves or been socially isolated by the disease. We need the opposite. We need them to be visible and open in discussing the disease. We need them to take them time to visit with researchers and answer all manner of personal questions and take all manner of tests so we can better understand their condition and how their lifestyle may have contributed to it.

We also need them to talk publicly about their condition because that helps bring others forward. It raises awareness.  Usher syndrome is a rare disease. To find viable treatments, we’re going to need everyone to participate. Hearing from others with the disease is what draws people out. Seeing the success of others makes the future less frightening.

I write about this a lot, but we also walk the walk, as it were. We organize family conferences and Bella not only attends, but sometimes she participates in family panels. She meets other people with Usher, sees adults with canes, sees parents cry, hears about fears and difficulties. She participates in promotional videos and has to talk to her Dad when he’s writing some silly blog post about her.

There are benefits to this, of course. She gets greeted warmly by people who she doesn’t know but who know a lot about her. She gets invited to visit people in exotic places, people she has never met but who have heard her speak or read about her and been inspired by her. It’s nice to be an inspiration.

But there is a cost to this as well. Bella is thirteen years old and knows more about Usher syndrome that just about any other thirteen year old out there. She knows adult things about Usher syndrome. She knows people with a cane and a dog. She has seen parents cry and adults tear up. She wonders if she’ll be able to drive. This is a lot for a thirteen year old girl to process.

And being told you are an inspiration and feeling like one are two different things, especially for a gangly adolescent struggling to pupate from a child to an adult. Teenagers make LOTS of mistakes. They do unintentionally foolish things and they are very aware of how they are perceived. It is hard to be a teenager. It is harder to be a teenager with Usher syndrome. It is nearly unbearable to be a teenager with Usher syndrome who knows an entire community is watching you.

We’ve had a lot of team meetings with Bella’s teachers, guidance counsellors, and myriad others who support her in school this year. We discussed the pressure Bella feels being one of the faces of Usher syndrome, of knowing all that she knows about the disease. One of the counsellors said, “I can’t imagine how hard that must be for a thirteen year old girl to deal with.”

I felt like a terrible parent. Worse still, I felt like a fraud. I advocate sharing as much about Usher syndrome with your children as they can handle. I have written in this blog about what to tell your child about Usher syndrome. That post was picked up by a number of different mediums and reprinted in a couple of other languages. And there I was, discussing my daughter’s problems in school, and realizing that I was a contributor to the problem. Not only that, but I may have just given terrible advice to a lot of others. It’s bad enough messing up your own kid, but to think you may have messed up the lives of others, too, is an awful feeling.

On the ride home I talked to Bella about all of this. The quotes are paraphrases as I wasn't taking notes at the time, but I remember the conversation well and confirmed the message with Bella.  I asked her about the public speaking and the videos. She’s thirteen years old, I said. She can make her own decisions about participating from now on. She smiled and said “I like doing the videos. My friends are all jealous that I get to be on camera. And I like to talk in front of people. I like to make them laugh and make them feel better.” Which, of course, made me feel better. “I was just tired in San Diego,” she continued, “And I was nervous. I didn’t think I did a very good job. I don’t like feeling that way.”

Then I asked her about the family conferences. She’s met adults with canes. She’s heard a lot of people talk about their fears. Does she worry about going blind? “Sometimes,” she said, “but I don’t really think about it. I make friends at the conferences. I hear all the things you are doing. I know you are doing everything you can to help me. I know you’ll take care of me no matter what.”

And with that, a weight lifted. I might still be a fraud on many levels, but I wasn’t wrong about talking to your child about Usher syndrome. Talking about it was a comfort to Bella. It was the right thing to do.

I’m still uncomfortable using Bella to raise awareness about Usher syndrome. Well, maybe ‘using’ her isn’t the right term any longer. It may have been at one time, when we chose to have her participate in videos and we chose to have her attend family conferences and we chose to have her speak in front of people. But now she’s thirteen and in many ways she’s grown up. She’s taller than my wife and she’s braver than me. She’ll continue to be involved in raising awareness about Usher syndrome, but from now on, she’ll be a partner in determining the risk. She’ll be involved in making the decisions.

Then Bella will decide how far she’ll go.