In previous Vision Tech articles, AccessWorld has described any number of breakthroughs and advancements in vision preservation and restoration. Many of the medications, devices, and other treatment options discussed in these articles were, at the time of writing, in very preliminary stages of development. We often hear about plans to begin clinical trials in a year or two, or that the new breakthrough should be ready for commercial applications soon…and yet it never seems to happen.
Ever wonder what happened to that exciting research that had the potential of helping you personally? In this article we'll try to answer that question. We'll begin with some recent cutting edge research in Great Britain that shows promise of treating the type of retinitis pigmentosa caused by splicing factor defect (RPSFD). We will use this research as a springboard for a discussion of the many hurdles that research may encounter on its way from the lab to your doctor's office. We will end with the story of one woman who is fighting to change the medical establishment and enable more of this research to reach its full potential.
Gene Therapy and Retinitis Pigmentosa
Many forms of RP have been linked to genetic defects. "Unfortunately, there are more than three hundred genes which have been identified to date whose mutations can cause RP," says Majlinda Lako, Professor of Stem Cell Sciences at Newcastle University's Institute for Genetic Medicine.
You can get a thorough overview of these many genetic causes of RP at RetNet.
Lako and her colleagues have been studying a specific kind of genetic mutation known as Splicing Factor Defect. To explain her work, we're going to have to pause, briefly, for a quick refresher course on genetics.
A cell's genes are located on strands of DNA that make up chromosomes. Chromosomes usually come in pairs; humans have twenty-three pairs. As you may recall from high school biology, there are four building blocks to DNA: adenine, cytosine, guanine, and thymine—often abbreviated as A, C, G, and T. These building blocks can combine in an almost infinite order, but every gene has a specific position on the chromosome known as its locus, which is read and interpreted by messenger RNA and used to synthesize the proteins that build and sustain life.
Genes are not the only things to be found on DNA. There is also a lot of useless information located between the genes. These areas are known as introns, and if you are a fan of science fiction, you have doubtless encountered these areas of unused DNA being linked to everything from alien messages to human superpowers we have not yet learned to harness.
In any case, in order for many genes to become useful, bits of them need to be cut away from the useless areas and then recombined, or "spliced" together so they can be used to create essential proteins. This is done via a special splicing factor which is found in every cell of the body.
Sometimes the splicing factor's proofreading skills may be defective due to an inhereted mutation. "In [the case of RPSFD], the splicing factor is defective in every cell, but it only causes problems in the retina," explains Lako. "The gene responsible for creating the splicing factor is dominant, so it only takes one affected parent to pass it along. However there are other genetic factors that can inhibit or accelerate, which is why one family may develop RP early and others remain relatively unaffected."
There are five different gene segments that must be cut and then spliced together to complete the gene which produces retinal pigment epithelial (RPE) cells. These cells are responsible for supporting and nourishing the light-sensing rods and cones. "Think of a movie director taking a lot of raw footage and picking out this part and that, then assembling the scenes into a movie," says Lako. "The damaged splicing factor doesn't make these cuts and splices correctly, so the RPE cells are defective." According to Lako's research, the damage is cumulative, and leads to eventual vision loss.
Lako and her colleagues were able to trace the specific mutation in the splicing factor to an 11 base pair deletion in the PRPF31 gene, located on chromosome 19. "We took skin cells from a person with RPSFD," she says. "We were then able to add several genetic factors to transform these cells into undifferentiated stem cells. We placed these cells into a special medium with tiny depressions to hold them, that caused the cells to re-differentiate into retinal cells."
After six months the researchers had created a "retina in a dish." Lako's team is not the only one to accomplish this. Such retinas are being used by scientists around the world to help in their research. Much of this research is quite exciting. Look for a lot more coverage in future Vision Tech articles.
Using CRISPR, the team was able to insert a healthy version of the splicing factor gene into the stem cells generated from one of the patients, which were further differentiated to retinal cells. The cells began creating healthy splicing factor, which, in turn, began making healthy RPE cells.
The next step is to test whether injection of correct DNA information via a virus into the subretinal space of RPSFD is able to stop disease progression and help maintain vision. Lako's ongoing work is being funded by Retina UK.
The Numbers Game
While thousands of ideas get through basic research, an inordinate number stall once they leave the university. Here in the US most research dollars come from the National Institutes of Health (NIH) Another source is the Foundation Fighting Blindness (FFB), which recently created a Retinal Degeneration Fund with more than $70 million in initial funding to invest in pre-clinical efforts aimed at developing treatments and a cure for inherited retinal diseases and age-related macular degeneration.
"We call the gulf between the laboratory and the marketplace the Translational Valley," says FFB board member Karen Petrou, "and crossing it is not always a scientific issue but rather a financial one.
Most of the cutting edge medical research—not only vision-related, but for all medical issues—is being conducted at universities using endowment money or grants. However even with generous grants, universities are rarely able to take a medical breakthrough all the way from the laboratory to the marketplace, which is to say your doctor or medical center.
"We wind up with a lot of mice who can see the light at the end of their tunnel, but very few people," observes Petrou, whose RP damaged sight has left her totally blind.
Once you get past all your work and can show how the treatment might be made effective, that's where the problems begin. The clinical trials required for FDA approval can cost hundreds of millions, even a billion dollars or more. "Grants aren't enough to fund this," says Petrou. "You're going to need a great deal of capital, and as things stand, the best sources for this funding are either from a large pharmaceutical company or a well-funded startup."
Either of these options comes with issues. Big Pharma, for example, is extremely conservative with their financial resources. They look at the possible success of the treatment, and, perhaps even more specifically, at its potential market, which is to say, "Can we make a profit and satisfy our shareholders?"
A new blood pressure or cholesterol medication would be a potential blockbuster drug. A treatment for a specific form of RP, not so much. Consequently, a large drug company might be willing to fund several different approaches to a new blood pressure pill, and pass on the RP.
There's also a difference between a treatment and a cure. That new blood pressure pill is something the patient would need to take every day, potentially for the rest of his or her life—fueling the company's bottom line for years. Whereas gene therapy for RPSFD treatment offers up the hope of a "one and done" cure. You have to recoup the cost of the treatment itself, plus the hundreds of millions of dollars you have to spend up front bringing the treatment to market. And that only happens if the treatment is proven safe and effective, which isn't a guarantee. Consider hepatitis C. The new treatments are destined to cure this deadly disease. But there are only so many medications the patient will ever need to take to be cured. Consequently the price of these medications is extraordinary.
Between the relatively small patient population and the "one and done" nature of the treatment itself, it's safe to say when it comes to bringing Lako's research to market, it would approach the Translational Valley with two strikes against it. We can debate whether or not this profit-centered model of clinical development is socially responsible. We cannot deny that, at least for now, this is the way things work. However all hope is not lost.
Increasingly these days, breakthrough drugs and treatments are being carried to market by startup companies such as Second Sight, the maker of the Argus II Retinal Prosthesis, and VisionCare Ophthalmic Technologies, maker of the Implantable Miniature Telescope. They still need multimillion-dollar backing to proceed with research, but private investors and venture capital funds are more likely to take a chance, with the hope of making many times their investment, when the startup partners with or is acquired by one of the big pharmaceutical companies.
"Often they are seeking to 'cash out' within five years, whereas most clinical research can take seven, ten years, or longer," says Petrou.
Backing a single experimental treatment is also quite risky. "More startups are going to fail than succeed," says Petrou.
The ideal solution would be to spread the risk among several different companies, and to make the investment more appealing to pension funds, insurance companies, and other institutions with a much longer time horizon. This is how Petrou came up with the idea of Eye Bonds.
Petrou's day job is in banking. Since 1985 she's been at the helm of her own consultancy, Federal Financial Analytics, where she is generally recognized as one of the premier world experts in arcane banking regulations.
Petrou decided to use her lifetime of banking and political connections to develop the idea of Eye Bonds—financial instruments that would be sold to investors like other government bonds. Only instead of funding government programs, the pools of raised money would be invested in a collection of promising startups. "This would spread out the risk and make it more likely that the investments would pay off," says Petrou.
The bill, called the Faster Treatments and Cures for Eye Diseases Act, was introduced in Congress last year. The bill would establish a pilot program allowing the government to guarantee up to $1 billion in loans.
If the pilot program is authorized (i.e., the legislation becomes law), then one bond would be issued each year for four years, after a start-up period of one year in which no bond would be issued, with each bond no more than $250 million, thus totaling up to $1 billion over the four years of issuance/five years of the pilot program. One $250 million bond would be used to fund loans to several research projects each year. The National Eye Institute would select the research projects to be funded and allocate the funds among the projects. Success would then be measured by the market's desire to issue the bonds, researchers' desire to take the loans, and the government's ability to be paid back. "If only one of these projects receives FDA approval and becomes a commercial success, the profit would pay off all the other loans," says Petrou. "The investments would be further protected by using drug patents and other intellectual property rights as collateral."
Petrou predicts the Congressional Budget Office will score the cost of this pilot program as very low because repayment goes first to taxpayers. "The only way Eye Bonds would end up costing the tax payers money is if none of the projects panned out and the collateral becomes worthless over time," she says. "Eventually, Eye Bonds could become a model for funding translational research for other diseases."
For Further Information
Here you can learn more about Eye Bonds, view its current 21 Congressional cosponsors, and lobby your Congressmember to support the Faster Treatments and Cures for Eye Diseases Act (H.R. 6421).
This article is made possible in part by generous funding from the James H. and Alice Teubert Charitable Trust, Huntington, West Virginia.
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- Vision Tech: It's Complicated by Bill Holton
- Vision Tech: Recent Retinal Research by Bill Holton
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