Eye of the Magpie
Researchers have always stolen shiny new techniques from colleagues in other fields – and some ophthalmologists are particularly effective thieves.
Scientific methods are often applicable in many different areas: hence, developments in one field frequently enable progress in another. Ophthalmology has been one of the biggest beneficiaries of this process. Indeed, without the technologies and instruments we’ve taken from other disciplines and adapted for ocular applications, our specialty would be virtually unrecognizable. I’ve always been happy to acquire new treatment options for the eye; here are some of my favorite examples.
From silicon circuits to corneal surgery
Back in the 1960s, I did my PhD on laser damage to the retina, sponsored by the Royal Air Force (RAF). They were worried about the potential of laser weapons, so I spent a great deal of time developing safety data to protect air crew. This eventually resulted in me working with the International Committee of the Red Cross, addressing the United Nations, and obtaining a Geneva Convention banning use of antipersonnel laser weapons. From there, it was a natural step for me to advise on laser safety in other environments. In particular, I helped develop good working practices for laser-mediated manufacture of microelectronic circuits. And once, during a factory inspection, it struck me that the laser could be a very special addition to the ophthalmology toolkit. I wrote up a patent, and that was the start of excimer lasers in eye surgery. Fifty million procedures later, I think I can say it was a valuable patent!
When we started laser-mediated refractive surgery, however, I had some concerns, particularly with regard to LASIK. The laser was slicing through millions of collagen fibers in the stroma: would that disturb the eye’s biomechanical properties? To answer that, we borrowed from engineering. In that discipline, investigators frequently have to calculate the strain that each component of a system will suffer under a given stress: for example, to assess how the elements of aircraft wheels will respond to the stress of landing. Engineers do this using an incredibly sensitive technique known as interferometry; and we applied it to the eye. With that resource, we could assess the strain associated with any kind of intervention, be it PRK, LASIK, cross-linking or cataract surgery. It was key to validating the LASIK approach.
From military range-finders to macular degeneration
More recently, I helped develop a new laser therapy concept for age-related macular degeneration (AMD). The advance had its genesis in a thorough understanding of retinal maintenance. Remember, retinal cells don’t divide, therefore, they must cope with wear and tear without recourse to cell replacement. Rod photoreceptors get around this through the continual removal of aged pigment material at one end – older material is “bitten off” by pigment epithelium cells – and continual replenishment at the other. When you’re young, the light sensitive portion of your photoreceptors is in effect, replaced every two weeks – even though the cells remain the same. Unfortunately, pigment epithelium cells get “indigestion” in later life and pass semi-digested waste products into Bruch’s membrane: the Bruch’s membrane gets clogged up, interfering with transport processes and contributing to further waste product accumulation and sequelae, such as accelerated ageing, a risk factor for AMD.
My idea was to clean up Bruch’s membrane and thereby rejuvenate the retina. But how? Conventional lasers for treating retinal conditions were all thermal systems and heat flow would destroy the photoreceptors. Short pulsed lasers were designed for posterior capsulotomies, and have their effect by producing cavitation – a kind of micro-explosion. You can’t have that in the retina – it would result in hemorrhage. We had to design a new laser energy delivery system, using concepts derived from military range-finder technology – which I can’t tell you about! Our new laser has a large spot size and an incredibly short (nanoseconds) pulse duration and a pixelated beam. This permits photodisruption of selected regions of the pigment epithelium without the thermal conduction to overlying photoreceptors that you would get with conventional lasers, and without destroying large areas of pigment epithelium (which would starve the overlying photoreceptors). Photodisruption activates pigment epithelium cells to release matrix metalloproteinase, which unblocks Bruch’s membrane and thus modulates associated pathology.
LEAD gives weight to AMD laser therapy
- Trial: Laser Intervention in Early Age-related Macular Degeneration (LEAD)
- Investigational product: Retinal Rejuvenation Therapy (2RT; Ellex’s nanosecond laser treatment for slowing progression from intermediate to late AMD)
- Double-masked, randomized, sham-controlled trial in Australia (five sites) and Northern Ireland (one site)
- Inclusion criteria: Age>= 50 years; diagnosed with AMD; at least one large drusen in each eye; no evidence of atrophy per multimodal imaging
- Recruitment: n=292
- Treatment: 12 laser spots applied to macular region each six months for 36 months
- In patients without pseudodrusen, 2RT was associated with a 77 percent reduction in rate of progression from intermediate to late AMD
Ellex has recently adopted and developed this concept into the Retinal Rejuvenation Therapy (2RT) product. Data from a three-year, randomized, multicentre clinical trial (1) in intermediate AMD are very promising (Sidebar), and I believe that our hypothesis is proven and this approach will have a significant impact and potentially massive savings on the use of drugs to treat neovascularization.
CRISPR, cleaner cornea
Ophthalmology also commandeers molecular techniques where appropriate: for example, CRISPR-mediated gene therapy. This approach, based on modifications of a naturally occurring antiviral defence system found in bacteria, permits precise excision of specific DNA sequences. With CRISPR, therefore, it is theoretically possible to treat autosomal dominant inherited disorders by cutting out the dominant negative mutation. Indeed, if several related defects are positioned closely enough in the gene, we can excise them all in a single step. Thus, as long as the patient has normal sequences on the complementary chromosome, the approach may modulate or even cure autosomal dominant disorders.
CRISPR gene therapy was originally envisaged for simple dominant negative diseases like haemophilia – but now we are applying it to more complex diseases, including ocular conditions, such as inherited retinal dystrophies. My opinion is that the cornea is a more attractive gene therapy target than the retina: rather than dealing with non-dividing neuronal tissue at the back of the eye, you only need to get to the DNA in the easily-accessible dividing cells on the front of the eye. That’s why we are targeting granular dystrophies, which are all caused by mutations in a small region of chromosome 5. As part of this effort, I’m assisting Avellino Labs, which is developing genetic screening for dystrophy, and also working with Tara Moore, our Head of Research at Ulster, to get our new therapy for corneal dystrophy into clinical trials. CRISPR for cornea really is the low-hanging fruit in ocular gene therapy, so watch this space!
I expect ophthalmology to continue stealing from diverse fields. In particular, genetics will have a big impact on refractive surgery, and the development of rapid diagnostic systems will revolutionize healthcare in remote locations. For example, people are working on functionalized membranes that a patient could lick and insert into a smartphone to receive a rapid diagnosis anywhere. That could be a very important way of guiding critical therapeutic decisions in difficult environments, such as a space capsule. In the clinic, for example, in cases of red-eye, you really need to know if the condition is of bacterial, fungal or viral origin, so that you can appropriately treat it – get it wrong, and you could lose the eye. I look forward to seeing these kinds of advances appropriated for eye care, as others have been before them. Basically, as long as human ingenuity continues to produce attractive new innovations, the ophthalmology magpie will continue to feather its nest!