Slides and Transcript of Presentation by Dr. Michael Tolentino
There are 2 classifications of macular degeneration which is the leading cause of visual loss in the developed world. The Dry form which leads to the to either the advanced DRY vision threatening GEOGRAPHIC atrophy is literally the corrosion of vision and the death of the light receiving cells in the center of the retina called the macula or the WET form which is a fluid blister forming in the center of the vision due to the growth of new blood vessels. Both forms are devastating but the wet form is the fastest and what my career had been focused on trying to stop. I will go over the research that led to my team at Harvard Medical School discovering and developing treatments for this form of Wet AMD.
The dry form is really the corrosion brought about by chronic inflammation andoxidation (rust). I will describe the pathogenesis later in the slide deck.
Current Treatment for Wet AMD involves injecting very expensive medicines. I personally have been involved in all the discoveries in treatment for AMD in the last 2 decades. The cost to society of these injections is astronomical both in terms of treatment burden and also in terms of economic costs. Once a patient develops advanced Macular degeneration, the cost of vision loss is immeasurable but the cost of maintaining that vision is measured in injections. To maintain vision, a patient requires regular injections. The amount of vision that is retained is directly correlated to the number of injections which can cost as much as 2000 dollars per injection. To maintain maximum vision 12 injections are year are often required. If you reduce this to 6 injections a year the visual gains decline and if less than 4 injections a year the gains are not maintained.
Because of the cost to quality of life and the economy, prevention needs to be the primary focus. To prevent disease, one must understand the pathogenesis. Much of our understanding of wet macular degeneration was unraveled in the early 1990’s by my team at Harvard Medical School. It is during that time that we performed the seminal experiments that lead to the development and use of anti-vascular endothelial growth factor (VEGF) injections to treat macular degeneration.
The first experiment that I performed in the Lab of Pat D’Amore was to identify the mRNA expression of Vascular Endothelial Growth Factor (VEGF) in the retina of a non-human primate that had been rendered ischemic. The figure to the right represents my in situ hybridization of VEGF mRNA that is upregulated in a retina rendered ischemic. This was important because VEGF at that time was a molecule known to cause new blood vessels to grow as well increased vascular permeability the hallmark of wet macular degeneration and diabetic retinopathy.
My next experiment was to inject VEGF into the eye of a normal non-human primate eye. In a dose dependent manner vascular leakage, microaneurysms, venous beading, intraretinal microvascular abnormalitie, macular edema and neovacualrization were created. These are all hallmark findings of diabetic Retinopathy and retinal vein occlusion all produced with several intravitreal injections of VEGF. All this work was in collaboration with Genentech and Naplolean Ferrara of Genentech in the Laboratory of Anthony Adamis and Joan Miller.
The most important experiment I performed, was to create laser induced Branch Vein occlusions that resulted in the development of iris neovascularization. We injected a neutralizing antibody which we called A.461 into the vtireous of these non-human primates that had their retinal veins laser occluded and those that received the injection of A.461 did not develop iris neovascularization. A.461 was later modified and developed into a drug called Bevacizumab or Avastin. While I was only a co-author on this paper, I was the main experimentalist that performed the experiment and purified the antibody so it could be injected into the eye.
The problem is that a461 is a recombinant antibody and as a result had too many impurities. These impurities when initially injected into an animal eye would cause massive inflammation and endophthalmitis. It took me 6 months to purify these impurities out of the antibody so that it would not cause an inflammatory reaction when injected in the eye. The purified A.461 antibody was then developed into Avastin for Cancer. Without this purification, the injection into a human eye would have be been devastating. This work served as the pre-clinical process often mandated by the FDA to make molecules safe for intraocular use. This is why Avastin can be used around the world at a much lower expense.
Genentech after I performed these experiments realized the potential cost differentila for a cancer drug and an eye drug which convinced them to stop development of Avastin in the eye and to pursue that for cancer and to invent Lucentis a FAB fragment with origins in Avastin.
So the main question is how did we realize that anti-VEGF injections would work in wet macular degeneration. That answer came from another major paper that I was involved.
Oxidation which I will explain later is the main stimulus for initiation, propogation and amplification of macular degeneration. Working with colleagues in the Folkman Lab we performed a methodical experiment demonstrating the profound ability of free radicals (Reactive Oxygen Intermediates, Singlet Oxygen) to up regulate VEGF in vitro and in vivo. From this experimental result we realized that VEGF was indeed the main player in wet macular degeneration which lead us to look first at Wet macular Degeneration rather than other neovascular diseases of the eye. From the data I presented to you today, my colleagues at Harvard launched the first anti-VEGF drug for the treatment of Wet Macular Degeneration. This drug was called Macugen. Eventually Avastin, Lucentis and Eyelea were develop for wet macular degeneration.
It was this paper that created the impetus for me to start thinking about the whole pathogenesis of disease and to search for the source of chronic macular oxidation. Reviewing the issue with several physicist, the main source of oxidation in the eye is the spectrum of visible light in the Violet Blue range. This is the only wavelength of visible light considered ionizing and is able to cause photo oxidation.
Blue Violet Light was the main link to VEGF up regulation. In the late 90’s the main source of blue light was from the sun. At that time, we did not have LED light bulbs, computer screens or smart phones. So Blue light protection was only necessary when outdoors. Indoor Blue light exposure was minimal. The only source of blue light at that time was fluorescent household lighting which was not ever focused on the macula for an extended period of time.
Then the advent of the LED screen. This LED screen started appearing in our television, computer monitors, then our smart devices – the iPhone, Kindle, Samsung Galaxy, iPads etc. When this happened, humanity’s level of blue light exposure started to grow exponentially as we began to incorporate these devices into all facets of our lives.
The upgraded screens of our smart devices emitted more and more blue light in the pursuit of brighter higher definition screens. As a result, the iPhone 7’s output of blue light peak at the 450 nm range was equivalent to 2 times the blue light emanating from a sunset or sunrise. What is interesting is that we would never stare at a sunset or sunrise for too long due to our correct concept of never staring at the sun. But we have no qualms about staring at our smart device screens or computer monitor for hours.
The other problem lies in the Optical Physics. We stare at the screens and try to resolve the image. By wearing glasses to see the screen clearly we are columnating the light like a magnifying glass used to burn a hole in a leaf or a piece of paper. The magnification of power by our cornea, intraocular lens and our normal lens will be approximately 1.25 million times. So, we take a light from our I phone and magnifiy that damaging light on our foveas by more than 1 million times. Let’s say one photon of blue light results in 1 free radical being formed in the eye. For every second the magnified blue light can be producing 1.25 million free radicals. Let’s say we use the I phone for 2 hours in a day emitting blue light at 1000 lux/second. That would be a total exposure of 120 minutes x 60 or 7200 seconds. Multiply this with 1.25 million x 7200 = 9 Billion free radicals /day all localized to the macula. TO give you an idea of how bad this is, A Cigarette produces10 15 Free radicals. Off course most free radicals end up not in the eye but in other parts of your body especially in the lungs. So, a very small fraction of free radicals can go to the eye and yet smoking is a major risk factor for developing visual loss from age related macular degeneration.
In addition to photo oxidation, 445 NM Blue Light combined with all trans retinal (a visual cycle component) results in the activation of programmed cell death. Every cell in our body has a death switch when turned on will lead to an orderly shutdown of the cell. This shutdown is normally a fail safe so that when a cell is exposed to damaging stimuli and is likely irreparably damaged, will end the cells life in an orderly fashion. I call this molecular cell euthanasia. For cells that contain all trans retinal (found in large quantities in the retina and RPE cells), this cell death switch is triggered.
This recent discovery links exposure to 445 NM blue light with why patients with macular degeneration who develop geographic atrophy which is the programmed cell death [Apoptosis] of retinal cells. The mystery has been why these cells in the fovea and macula just die in a programmed cell death fashion. The mystery was answered with this paper by a group at the University of Toledo. Blue light 445 NM when shone on Retinal within a cell optogenetically (light induced intracellular molecular signaling) initiates the cell death signaling. Similar to the fail safe that is put into robots that will shut them down if they rebel against their creators. [ aka Terminator].
We have now found the smoking gun as well as the initiator of this off switch built into photoreceptor cells. Because the fovea and macula are exposed to more 445 nm Wavelength of light than any other portion of our body because of our optical focusing mechanism that columnates the 445 nm Blue light to our fovea and macula explains why we get macular degeneration not peripheral retinal degeneration.
The pathway to development of macular degeneration begins with ever increasing cumulative blue light exposure. When we are born and we open our eyes, the onslaught begins. Like waves of white walkers in Game of Thrones our natural defenses built into the macula called the macular pigment behaves as the Great White wall where the Nights watch defend the wall from the Night king and his hordes of white walkers. But after years of relentless exposure to blue light the photoxidation weakens the wall and blue light when mixed with all trans retinal convinces the men of the Nights watch to commit suicide. Eventually the wall is destroyed and our patient becomes blind.
The molecular explanation is less exciting than Game of Thrones. It starts with photo oxidation of the cell membranes of the photoreceptor and retinal cells which are made of docoso hexanoic acid (DHA) and poly unsaturated fatty acids (PUFA). Oxidized DHA becomes carboxy ethyl pyrrole which is a toxic oxidative product that activates the innate immune system both complement and macrophage activation. Oxidized pufa produces malondialdehyde (MDA) which is another toxic oxidative byproduct that activates the innate immune system. The problem in macular degeneration patients is that they have a polymorphism (Mutation) in the complement factor H (a protein that inactivates the immune system both the complent and the macrophage component. As a result, when blue light photo oxidation turns on the immune system the shut off mechanism is defective and inflammation is chronically activated especially when the patient is exposing the macula to blue light.
Furthermore the carcasses of the suicidal retinal cells that are signaled to kill themselves after exposure to 445 NM blue light litter the landscape and activate macrophages to phagocytose (eat) the carcasses resulting in geographic atrophy. There are several forms of activated macrophages. The most well studied is the one that cleans up dead tissue and debris. There is an activated macrophage that enhances inflammation and there is a macrophage called M2D whose sole purpose is to produce vascular endothelial growth factor. This macrophage produces wet macular degeneration.
This is how blue light exposure leads, overtime, to end stage geographic atrophy and wet macular degeneration.
Because of this pathogenesis, it is important to protect the macula from exposure to the full spectrum of Blue light. Until recently, technology was not available to accomplish this until Dr. Jim Gallas discovered a way of impregnating plastic with biologic pigment found in human skin and the eye. This discovery enabled the patented technology behind True Blue lenses. Biologic pigment Melanin and ocular lens pigment were designed by nature to absorb blue light which is harmful and reduce the energy and dissipate the light into harmless heat energy. That is why heavily pigmented individuals have better skin since they are protected from photo oxidation and why fewer pigmented patients who develop brunescent cataracts seen often in the developing world do not have any evidence of macular degeneration.
This is very different with older technology which uses pigment to absorb only a partial spectrum of blue light (yellow, orange lenses) or uses a reflective technology which does not reduce the energy and is limited by transparency (Crizal Prevencia, Nikon Cool Blue, Blue Defense). What that means is the light is reflected in proportion to the density of the reflective coating. If the reflective coating is transparent then the blue light can only be blocked a small amount. If the lens is opaque then it blocks more blue light, but only a small spectral band of blue light and not the critical 445 NM band.
TrueBlue protection technology when compared to other lens technologies that claim blue light protection and those that do not make the claim is irrefutably orders of magnitude better then all other technologies both theoretically and practically. The graph shown here presents the spectral transmission of blue light through different lenses. The x axis of the graph is the spectrum of blue light between 400 and 500 nm wavelengths. This graphs different lenses ability to block the harmful wavelengths of blue light.
Almost every lens that claims blue light protection blocks transmission of shorter wavelengths of light less than 420 but wavelengths longer than 420 are not blocked and are transmitted through these inferior technology lenses. You can see at the critical 445 NM wavelength. The best competitor lens block at most 30%. The best TrueBlue Lens True Blue Vista Sun Polarized blocks blue light transmission by 96% at the harmful 445NM wavelength. The Vista Pro Plus indoor lens blocks 80%. This is 300-200% better performance than the best competing technology. I have already reviewed the necessity of blocking 445 NM blue light.
If you superimpose the wavelength of blue light emitted from smart devices, computers and LEDs. What you see is that the peak blue light emission from your iPhone is 450 NM very little is emitted in the 420 or shorter wavelength spectrum. Sample E, the best competitor lens, allows transmission of all the light being emitted by smart device screens. In essence, it does not protect against any significant blue light emitted by smart devices. Furthermore, only TrueBlue lenses block transmission from these smart devices.
For the spectrum of blue light emanating from the noon sun, again only TrueBlue Vista Sun Polarized blocks the full spectrum of the high intensity sunlight. None of the other technologies except for the indoor TrueBlue lenses comes even close to protecting against the intense blue light our eyes are exposed to in the bright sun when we are golfing, hiking, walking.
True Blue protection lenses are the only technology that can truly protect our eyes from the harmful blue light from the sun, computers, smart devices and televisions.
True Blue Lenses represents the REAL blue light protection and consumers, physicians and patients should not be fooled by the claims of the FAKE blue light protection technologies.
While I have been involved in 150 clinical trials in Retina for pharmaceutical companies. The research and time that has been put into developing TRUE BLUE Technology has been supported from my efforts by The Tolentino Eye Research Foundation, whose mission is to develop preventative technologies for blinding conditions such as macular degeneration. Our secondary mission is to educate the consumer, patient and medical profession on the truth of blue lights harmful effects and how to protect the population and their families from the devastating disease called macular degeneration.
Please support the mission of the Tolentino Eye Research Foundation as ambassadors and supporters. This is the foundation that was founded by my father at Harvard Medical School 40 years ago and I have resurrected it to continue the work of innovating in order to stamp out blindness. My father invented a technology called vitrectomy which restored blindness in Millions of patients around the world. I have invented injection treatment for blinding retinal diseases which have also helped millions of people. What I want to leave as a legacy is to prevent people from ever having to undergo vision loss or eye injections. Kind of strange that I want to make my invention obsolete. But the injections have sort of
made my dad’s invention obsolete especially for diabetics. As my teacher Dr. Judah Folkman said for his Harvard Medical students. What you learn in Medical School will be obsolete in 40 years and your duty is to make sure that what we do now is obsolete in 40 years.
By wearing True Blue Lenses early in life, we halt the impending epidemic of macular degeneration from the overexposure of our maculas to blue light. The maculas of the youth of today are exposed to more blue light than all the generations from the beginning of humanity combined. Like cigarette smoking, trans fatty acids and high fructose corn syrup this will lead to unexpected consequences to the health and welfare of the human race. We must act now with education and use of TrueBlue Lenses to side step these consequences.
Please help me spread this message if not for your fellow men and women at least to your family and loved ones.