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Friday, September 25, 2009

Gene therapy for retinal disease: What could it mean for Usher patients? Part I

By Jennifer Phillips, Ph.D.

As promised, I’m going to write about some good science news here. However, I must implore you not to forget everything I’ve told you about the pace of research. Cautious optimism is warranted, so feel free to do a little chair dance if you must, but please don’t call your Ophthalmologists straightaway and ask them about this new cure you’ve just read about on the Usher Syndrome Blog. Although the research I’m going to describe below might, in time, get us closer to a cure, we’re not quite there yet.

The research I want to share with you involves gene therapy for another retinal disease that shares some similarities with Usher syndrome. However, before I jump right into the research findings, I need to fill you in on some general information about gene therapy. My plan is to use this post to give you the background and describe the research, and then connect the dots to Usher syndrome in my next post.

So let’s start with some basics: what is ‘gene therapy’, anyway? When we talk about gene therapy we’re usually referring to ‘gene replacement’, whereby a healthy, normal copy of a gene is introduced into the body of an individual whose own copies of this gene are absent or abnormal in some way. There are several different delivery systems under study, but the ones that have been the most efficient overall have been modified viruses.

A virus, as you may recall from Biology 101, is unlike anything else that we consider strictly ‘alive’ in that it isn’t composed of cells, and thus lacks the molecular machinery that allows every other form of life to survive, function, and proliferate. Instead, viruses require a host cell to do their replicating for them. Viruses are streamlined for this task, consisting of genetic material (in the form of DNA or RNA) wrapped up in a package of proteins that help it enter the cells of its target host. Once a virus has gained access to a cell, its genetic information can be copied and used to build functional proteins in the same ways that a cells makes functional proteins from the information encoded by their native genes. You can think of a virus as kind of a freeloading office worker who slips a few of his personal papers in with a large copy job for the company.

In using viruses for use in gene therapy, scientists have essentially turned the tables on the viruses. Viruses have exploited the cellular machinery of all living things on this planet for millions of years. Now, because the mechanisms of viral infection are so well understood, we can exploit what is useful about them, e.g. getting genetic material into cells, and inactivate or remove the other parts of viruses that aren’t so wonderful, e.g. their tendency to replicate like crazy, stimulate your immune system, and make you sick.

During the modification process, the viral genes that promote the formation of new viruses and invasion of more host cell are removed and, replaced by the coding information for a complete, healthy gene of interest. Once this is complete, the next steps involve introducing it into the host cells. Once inside, the virus and its cargo will be replicated, serving as a blueprint for making biologically active levels of the protein that was previously missing or defective. Here’s a diagram of this process:
Figure 1: A modified adenovirus is used to deliver a new gene into a cell. The ‘vector’ is the virus, and the knobly exterior that resembles a ball of yarn with knitting needles sticking out of it represents the viral proteins surrounding the genetic material that enable the virus to enter the cell.

The particular kind of virus used in the above schematic, an ‘adenovirus’, may sound familiar to you because adenoviruses in their unmodified forms are the ones that cause the common cold, among other things. I hope it gives you some degree of satisfaction to know that their hitherto irritating power to infect is even now being harnessed to benefit humankind.

The next detail to deal with is the matter of getting the virus, and therefore the gene, into the right tissue. The disease being treated will usually dictate where the replacement gene is needed. If the symptoms are particular only to the brain, or the bone marrow, etc. efforts are made to deliver the gene to those specific locations. This often requires getting the viruses to infect cells in a petri dish in the lab and then introducing the cultured cells into the appropriate body tissue. For retinal delivery, however, researchers have found that directly injecting a small volume of liquid containing many copies of the viral vector into the back of the eye is effective in allowing the viral vectors to reach their target host cells in the retina.

So, with all those details in mind, on to the results:

Last year, two groups of researchers who have been working for some time on gene therapy for a type of Leber’s congenital amaurosis (LCA) reported some preliminary results from their first clinical trials. Like Usher patients, individuals with LCA suffer from progressive vision loss beginning in childhood. Although the specific molecular reasons for this are quite different from what happens in Usher syndrome, the end result is the same—diminishing visual response over time, and a gradual thinning of the retina due to the death of photoreceptors. Importantly, the visual abnormalities (e.g. diminishing ERG response) in at least some types of LCA precede the cell degeneration. That is, the defective gene is present from birth, but it takes a long time—years, even decades—for the photoreceptors to actually die from the lack of a functional LCA protein. Again, this is very similar to what we see in at least some types of Usher syndrome. Yet another similarity between LCA and Usher syndrome is that a number of different genes can be responsible for the disease.

These researchers gave a lot of thought to which of the known LCA genes they would use in their study, selected a good candidate (RPE65, the gene implicated in LCA type 2), and tested it out in animal models—first rodents, and later dogs, all of which had mutations in this same LCA gene and as a result had a similar retinal defect to human LCA patients prior to their treatments. This part of the study took years, not only to perfect the delivery technique, but to monitor safety, determine effective doses, and evaluate short and long term changes in the vision of these test animals. At the end of this pre-clinical testing period, the animals were doing well, suffering no ill effects from the treatment, and showing improvement in their symptoms. Such positive results, at least in terms of safety, are required before moving on to human subjects. In this case, the pre-clinical results were very strong, and approval was given to begin Phase I Clinical Trials.

The number of subjects in a Phase I trial is usually very small: in each of these parallel LCA Phase I trials, three patients were analyzed. The subjects of these experiments were young people between the ages of 17 and 26. All had experienced vision loss, and all had some thinning of their retinas due to cell degeneration. However, they were all young enough that a good number of retinal cells remained, even though many of those cells were already functioning poorly and contributing to their visual symptoms.

All subjects underwent the ophthalmic surgery (under general anesthesia) to inject the viral vector into the space behind the retina of one eye. The other eye was left untreated so that ‘before and after’ type comparisons could be made in the same patient. The patients were monitored in the days and weeks following the surgery to make sure than none suffered any adverse effects from the surgery itself or the fact that a modified virus had been introduced into their bodies. All did well during and after the procedure, and beginning about one month after the treatment, one patient from one study and all three patients from the other began to exhibit improved visual function. These patients showed significantly increased responses to light in the injected eyes, and they experienced expansions in their visual fields. Both of these responses suggest that the presence of a healthy copy of the LCA2 gene was able to restore some of the function of the surviving retinal cells. Also encouraging is the fact that these effects seem to be long-lasting. So far, the improvements in visual function that were originally observed and recorded a few months after the procedure have now persisted for over one year.

Phase I trials such as this are primarily designed to test safety and effective doses in humans, hence the small number of subjects to start with. You don’t want to give a drug or treatment to a large group of people until you have a pretty good idea of what it’s going to do to them. However, if everything goes well, safety-wise, in a Phase I trial, some data can be obtained on the effectiveness of the treatment as well. Happily, this was the case with these LCA trials, and even though the sample size is small and the data are still preliminary, the results were promising enough jto warrant publication. Here’s a short (~10 minute) video of one of the researchers, Dr. Robin Ali, describing the trial:

So, to sum up the results of the studies: A gene that is defective in a progressive retinal degenerative disease can be safely introduced via viral vector into the retina, and can improve visual function for a sustained period of time. Several more phases of clinical trials must occur before this particular gene therapy can be offered in a clinical setting to LCA patients, but the promise of a cure is exciting indeed.

Yet as happy as we are for those LCA patients who might soon see a benefit from this treatment, you must be wondering, ‘what about Usher syndrome?’ What will it take to begin similar types of experiments for the disease that we care about most? In the next post I’ll plan to do a little speculating on these questions, and although I’ll have to throw in some cautions and caveats along the way—not to be mean, but because that is just how we scientists roll—I do think there is reason for us all to be hopeful that these studies will be useful to developing a similar treatment for some forms of Usher syndrome.

Bainbridge et al., (2008) Effect of gene therapy on visual function in Leber’s congenital amaurosisThe New England Journal of Medicine 358 (21):2231-2239.
McGuire et al., (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. The New England Journal of Medicine 358 (21):2240-2248.
Cideciyan et al., (2009) Vision 1 year after gene therapy for Leber’s congenital amaurosis. The New England Journal of Medicine 361:725-727.

Monday, September 21, 2009

The Human Touch

by Jennifer Phillips, Ph.D., Mo.M.

Ok, this is the week where I officially stop being such a wet blanket. Even as you read this, I’m working on a post containing some promising news from the world of science. While I’m putting the finishing touches on that opus, I just want to briefly respond to Mark’s last post, specifically regarding the relative expertise and motivation of Usher researchers vs. parents, siblings, teachers, social workers, mentors, or other members of the support network surrounding an individual with Usher syndrome.

Leaving aside for a moment the fact that there are actually a few Usher researchers out there with a personal, vested interest in the outcome of their experiments, it is generally true that many of us view Usher syndrome on more of an academic level than a personal one. It is true in my case, certainly. I don’t pretend for a minute that all the research I’ve done on the various Usher genes and associated pathology enables me to understand the disease on the level of real life consequences that Mark or most of the readers here do. In addition to being a Ph.D., however, I am an ‘Mo.m’ as well. I can’t presume to know what it’s like to have a child with Usher’s, but every poignant word Mark writes about his parenting experience resonates with me as a mother first, scientist second.

Figure 1: Two kids + one Ph.D. = Five years well spent.
As I read Mark’s post, I realized that I may not have done a very good job in expressing my empathy for the parents reading this blog. Mark is so adept at writing those inspirational posts, and rather than trying to follow suit, I’ve tried to provide some contrasting professional perspective: a Spock to his Kirk, a Science Nerd to his Homecoming King, my Facts vs. his Feelings. I think this balance is what we were both looking for in this collaboration, so while I’m not going to change my M.O. all that much in the future, I do want to assure you all that I have abundant respect for your expertise as parents of children with Usher syndrome. I am here to inform, but I am also here to learn from you. I value your unique contributions to the cause we all share, and I appreciate the personal connection to Usher syndrome that I can glean from parents discussing their hopes, fears, and frustrations. It provides a new dimension to my work, and some valuable perspective on what is at stake, beyond my individual satisfaction at exploring the molecular mysteries of Usher syndrome and the benefits to my immediate environment that such explorations can yield.

I’ll be back to my regularly scheduled facts and figures later this week. Please stay tuned.

Thursday, September 17, 2009

The Importance of Titles

By Mark Dunning, Da.D.

It’s been great having Jennifer contribute to the blog. I’m not a Ph.D. so I don’t have the same perspective on the process that she brings. I’ve been thinking a lot about those letters lately: Ph.D. See I’m just a Da.D. and I often wonder what in the world makes me qualified to talk to anyone about Usher syndrome.

I have no formal training in ophthalmology or otolaryngology. I can hardly even spell them. Until Jennifer’s post last week I knew next to nothing about the difference between basic, transitional, and clinical research. I didn’t know about any controversy at NIH. And despite desperate attempts by some top notch professors and doctors to teach me, I’m still a neophyte when it comes to genetics and molecular biology. I’m neither a therapist nor an educator. In fact, I am so desperately unqualified that I often feel ill-equipped to even observe conversations between researchers.

But the truth is that we, you and I, hold the truly important titles. Being a Da.D. or an Mo.m. or having Us.h. makes you the unquestioned expert on Usher syndrome. Folks like Jennifer, thankfully, spends 8-10 hours a day every week day working on Usher syndrome. You spend 24 hours a day living with it. A Ph.D. might spend a decade working toward a degree. A researcher might spend thirty years of his or her life investigating it. But in the case of a person with Usher, you have never taken a breath without it. Not a single heart beat. No researcher can say that.

More importantly, you already have answers to questions that researchers desperately want to know. It is a fact that even people with the same genetic mutation have different rates of vision loss. We know that much to be true. What we don’t know is why. It might very well be environmental. A certain level of light exposure, maybe, or dietary preferences or certain medications you take or some weird combination of things. But something is causing people with the same mutation to lose their vision at sometimes wildly varied rates and you hold that answer.

Jennifer wrote last week about the length of time it takes science to get from the bench to a treatment. It is very hard to find the one needle in a stack of needles that is the beginnings of a cure. Normal scientific process is to take each needle from the stack, one by one, test it and discard those that don’t hold promise. Eventually you come across the right needle, but clearly that process takes a lot of time.

But there are ways to speed up that process. There are literally thousands of compounds that might help slow the vision loss or present a cure. The needle method is to test every one, one at a time until we find one that works. However if we can find every Usher patient and learn their natural history; when their night vision problems started, their rate of vision loss, their lifestyle, their diet, etc, we can narrow that search. If we know, for instance, that everyone who eats Doritos and likes to square dance has a slower rate of vision loss than the average Usher patient, we at know where to start looking. We might not know why the combination of Doritos and square dancing help, but we’re able to dramatically shrink that pile of needles that folks like Jennifer have to sort through. Now instead of every compound, they can focus on just those that make up Doritos and those generated by square dancing.

(By the way, before you go on the Dorito diet and start taking square dancing lessons, please realize that I completely made that up. I can just imagine a hundred families wearing checkered skirts and bandanas with bright orange fingers and lips at our next family conference.)

So, again, the pace of scientific progress can be disheartening and can feel very distant. It shouldn’t. Usher patients and their families can absolutely effect the rate of discovery and they’re involvement in the process is the most critical component.

Don’t feel unimportant. Stay involved. Mo.m.s and Da.d.s and, most of all, Us.h. are the most valuable titles of all.

Tuesday, September 15, 2009

Finding Time

By Mark Dunning

I had to work late tonight. I'm still in the office, actually. I decided to write this to assuage my guilt. I'm not going to see my kids tonight before they go to sleep. That's another day of Bella's usable eyesight that I missed. It's another day that I could have been doing something to help find a cure; fund-raising, cause promotion, something, but instead I worked.

Among the many symptoms of Usher syndrome is guilt. Parental guilt, that is. It starts when you learn that your child has an autosomal recessive disorder. It's your genes that are causing her problems. You feel like it's your fault.

Then it's all about the ticking clock. Without a cure, Bella will lose her eyesight. So I feel pressure to travel, to take her to see the world before it's too late. I also feel pressure to advance my career because vacations take money and career advancement brings a higher income. And I feel pressure to help find a cure because finding a cure would eliminate all the concerns and let Bella live her life at her pace.

But all three of these things conflict. Time at work is time not spent with Bella, sharing a memory that she can draw on should things go bad. Time with Bella is time not spent raising money or awareness or volunteering to assist with Usher related projects, projects that could find a cure. And time spent on Usher projects is time not spent at work which limits my career and earning ability which, in turns, limits my time with Bella and limits what I can contribute.

It all feels impossible to resolve, which is why I write these words from my office at 8:30 at night. I wanted to comment on Jennifer's last post. I'm sure it felt like a brace of cold water, illuminating and staggering at the same time, but that's why she's here, to explain the scientific reality of Usher research to we families. And she's right, of course. All this research takes time, years, decades. But we don't have years and decades so what do we do?

The message to take from Jennifer's post is not one of hopelessness or panic. It's one of resolve. The point is that this is a long march and we'd best get in that mindset. We can not delude ourselves in to believing that some mystical cure will suddenly appear without our help. It won't. It's going to take a lot of time and a lot of effort, not just from the researchers, but from Usher families as well.

But what can a concerned person with limited time and financial means really do?

Well, we can do exactly what I'm doing tonight. We can steal fifteen minutes and we can do something positive. Most of the posts I write are about empowering families to get involved and stay involved. The reason? There's power in numbers. We all have fifteen minutes a day we can spend on helping researchers like Jennifer move the cause forward or to help raise a few more dollars.

It doesn't seem like much until you imagine a world where all Usher families are involved. It is estimate that there are 30,000-50,000 Usher patients in the United States alone. Those Usher patients have parents and siblings and grandparents and aunts and uncles, all of whom have fifteen minutes a day. That makes our numbers more like 200,000. Well, 200,000 people times fifteen minutes is nearly 850 hours a day. That's the equivalent of 100 people full time.

In other words, your fifteen minutes a day will result in the equivalent of a hundred people dedicated full time to finding a cure for Usher syndrome. Is there any doubt we can move the process forward more quickly, that we could turn those decades into years?

I think not.

Now if you'll excuse me, I have to go home and kiss my daughter good night. I've got one more rah-rah speech in me for my next post, then I promise to follow Jennifer's lead and get back to some substance.

Thursday, September 10, 2009

The Long Road from the Bench to You

By Jennifer Phillips, Ph.D.

No other season prompts me to reflect on the passage of time like Fall. The kids are returning to school, the days are growing shorter, and we’re beginning the slippery slide toward the end of the year, hastened by the flurry of activities that the coming months will bring. But while everyone is looking ahead to academic and sporting events, and the parade of Holidays that will soon be upon us, I find myself looking back over the past year, examining the discarded days that can never be revisited, marveling at how quickly it all went by, and lamenting, always, that I didn’t do nearly as much as I could have with this time.

Part of this seasonal malaise is an occupational hazard: Science is slow, ponderous work. Even though I’m regularly obtaining results from ongoing experiments, none of these are hugely significant in and of themselves. Each individual result informs the design of subsequent experiments, and those results dictate more experiments, and over time the picture of the process being illuminated by all of these findings is clear enough for us to publish our data, which can sometimes inform the design of a whole new set of studies. And while the results of any one of these experiments may be cause for smiles and high-fives (or, occasionally, sobs and ‘headdesk’s) within the lab, few have been stand-alone, paradigm shifting discoveries. The degree to which any single finding might impact the field is largely informed by the context provided by the other data points surrounding it, which can lend support, relevance and strength to the conclusion.

Accumulating such a body of work, even for very focused, specific research questions, takes time, and obtaining sufficient context for it to be applied to human medicine takes even longer. In the hierarchy of research, illustrated in my last post, the levels at the bottom of the steps are generally thought of as ‘basic’ research. Basic research can be characterized as ‘research for the sake of discovery’, or ‘pure research’, which translates loosely as ‘research that is not specifically targeted toward developing a treatment for human disease’. This, of course, is distinct from ‘clinical’ research, which is all about establishing new treatments to improve human health. As discussed last time, the upper tiers can’t exist without the lower ones, and in fact the whole system is more of a continuum than a stepwise process, at least with respect to intent. Most funding proposals for ‘basic’ research these days won’t get a second look unless they include a well developed section on the relevance of the proposed studies to human health. However, identifying a particularly promising research finding and conveying it through the tiers often involves a third category of research, between basic and clinical: translational research. The concept of translational research is fairly straightforward—it acts as a bridge between the lab bench and the patient’s bedside, identifying promising discoveries from the former and devising ways to optimize their application to the latter.

Delineation of translational research as a separate entity from either basic or clinical research has gained a lot of popularity in the past several years, as researchers and grant organizations alike try to reconcile their eagerness for finding treatments and cures with their limited budgets. Translational research as a field has become increasingly popular, and the numbers of physicians in training opting for the combined MD/PhD programs that give them experience and insights into the laboratory seems to be at an all-time high. Translational researchers have, in a way, been cast as ‘efficiency experts’, with the hope that they will be able to accelerate the progress through the research tiers and provide more human health benefits on a shorter time scale.

I should take a moment here to declare that I have infinite respect and admiration for those clinician scientists who are straddling both worlds, and I do believe that they possess a unique set of skills that neither the average basic PhD researcher nor the average MD clinician can offer. That said, I’m not completely sold on the idea that the influx of translational researchers into the breach will significantly impact the speed of scientific progress. Not because these researchers aren’t qualified to do the job, or because there’s no niche for them to fill, but because of the nature of science itself. Based on what I’ve already told you about the time scale of research and the winnowing process of data as it proceeds up the chain, I hope at least some of you are also cocking your eyebrows a bit, thinking “if only it were that easy!”

We’re not alone in our opinion, either. In an article* appearing in the journal ‘Science’ last fall, John Ioannidis took a look at the time spans between initial research findings and the application of treatments based on each of those discoveries in human patients. The researchers confined their analysis to the development of high profile therapies, things like cancer drugs, high blood pressure and heart treatments. I’ll spare you the blow by blow of the statistics he and his colleagues employed to study the research timeline, but briefly, they identified the year in which a seminal work that eventually led to a human treatment was first published or patented, and then compared that with the year in which the treatment had been established as effective. This latter time point was measured by how many times the paper describing the clinical findings had been cited in other papers—evidence that enough other physicians were obtaining similar results from routine use of the treatment to categorize it as ‘widely accepted’. The time between these two points—understood to be the time during which translational researchers were in play--was dubbed ‘translational lag’ time and the median length of this ‘lag’ was…24 years.

Ioannidis sums it up as follows:
"Despite a major interest in translational research (1-3), development of new, effective medical interventions is difficult. Of 101 very promising claims of new discoveries with clear clinical potential that were made in major basic science journals between 1979 and 1983, only five resulted in interventions with licensed clinical use by 2003 and only one had extensive clinical use (4)."

Not surprising, given what we’ve been discussing here over the past month, but hardly encouraging. Ioannidis confirms what we already knew—that there really aren’t any shortcuts in this process, and to pretend otherwise is counterproductive:
"Our analysis documents objectively show the long length of time that passes between discovery and translation. As scientists, we should convey to our funders and the public the immense difficulty of the scientific discovery process. Successful translation is demanding and takes a lot of effort and time even under the best circumstances; making unrealistic promises for quick discoveries and cures may damage the credibility of science in the eyes of the public."

This last bit really resonates with me. For various reasons--attempts to phrase new research findings in language the public can appreciate, a wish to give patients hope, or the desire for an exclusive, splashy headline—new findings in science and medicine are often inaccurately presented. I think this ends up working against scientists—and science itself--not only because trust is lost, but because when people hear so many stories about miracle cures and earth-shattering breakthroughs, they tend lose appreciation for the basic reality that I’ve tried (perhaps laboriously and tediously) to drive home here—that science is a long, hard process, and there are a limited number of shortcuts one can take without compromising quality. Unfortunately, habitual sensationalizing and overstating of findings has misled the public into thinking science can, in the right hands, happen quite rapidly. Thus, the fact that the cures aren’t coming out fast and furious lead some to believe that scientists are so insulated from real world problems (aka clinical needs) that they lack the motivation to work faster, or that they are more concerned with their own job security than with the greater good of advancing human health (as was argued, infuriatingly, here).

At the end of all this doom and gloom, however, there are some silver linings. There are, truly, some legitimate reasons to hope that the treatment timeline for Usher syndrome might be shorter than some of the treatments analyzed in the Ioannidis study. For one thing, technical advances over the past decade have definitely improved the speed at which science can happen. The process is still slow, to be sure, but new technologies can definitely enable us to cut time without cutting corners. Perhaps if a similar analysis to the one I’ve been discussing were published in 2019, it would reveal a diminishing ‘transitional lag’. Moreover, we don’t yet know where—or when—the starting point will be for such a cure. There is a chance that some already existing piece of information is going to be the one that leads to an improved diagnostic or therapeutic development.

There is even a chance that it’s sitting on my lab bench right now, so I’d best get back to work.

D. G. Contopoulos-Ioannidis, G. A. Alexiou, T. C. Gouvias, J. P. A. Ioannidis (2008). Life Cycle of Translational Research for Medical Interventions Science, 321 (5894), 1298-1299

*this article is behind a pay-wall. If you’re interested in reading the full text but don’t have access, please email me and I’ll see what I can do.