Highlight: Do our choices or our genes impact the development & progression of AMD?

You may have gotten an email yesterday about this post which said it was password protected.  I keep forgetting that putting a password on a page while it’s being developed doesn’t work to stop an early email.  Sorry!

Facebook group member Vickie Hoecherl (a link to her new Guest Author page below) has gone through the December 2017 article from the award-winning lecture by well-respected and widely-published Dr. Johanna M. Seddon and has shared with the group members some of the researcher’s quotes.   Click here for the full article “Macular Degeneration Epidemiology: Nature-Nurture, Lifestyle Factors, Genetic Risk, and Gene-Environment Interactions – The Weisenfeld Award Lecture”.


Do our choices impact the progression of AMD?  How much of our future is written in our genetic code

Note: If you see (), we’ve left out statistics from Dr. Seddon’s article. You can see them in the full article. Also, we’ve added topic headings to the researcher’s quotes. 
Nature vs. nurture

“Our analyses showed that a high proportion of AMD was attributable to genetics, with heritability ranging from 46% to 71%, depending on the stage of the disease. More advanced disease, as well as larger drusen and greater drusen area measuring 175 μm or larger were highly heritable, with estimates of 71%. The environmental influence on this disease is also notable (19% to 37%). Therefore, both nature and nurture were important in the development of AMD.”

Stop smoking

“The leading modifiable risk factor is cigarette smoking.”

Eat your greens, know your fats

“. . . . a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD. Results suggested an 88% lower risk with higher intake, defined as eating a one-half cup serving at least five times per week. Other foods that are high in lutein and zeaxanthin include dark green leafy vegetables, kale, turnip greens, and collard greens.”

“High total fat intake was associated with almost a three-fold higher risk of progression and saturated and trans-unsaturated fats conferred over a 2-fold higher rate of progression from nonadvanced to advanced stages of AMD. Higher intake of omega-3 fats, which are found in high levels in fish and some nuts, reduced risk of progression to advanced AMD by 25% to 40%, particularly among participants with lower linoleic acid intake.”

Supplements weigh in

“Supplements containing vitamin C, E, zinc, as well as lutein and zeaxanthin are now recommended for individuals with intermediate-level AMD”

Get out the tape measure

“We also evaluated modifiable anthropometric factors, including BMI, waist circumference, and waist-to-hip ratio, in our prospective cohort. A BMI defined as obese (≥30) was significantly associated with a higher risk of progression to advanced stages of AMD (), as was the overweight classification (). A significant trend was observed for higher risk with higher BMI (). The highest tertile of waist circumference significantly increased risk of progression () compared with the lowest tertile. A higher waist-to-hip ratio also increased risk of progression (). In contrast, higher levels of physical activity tended to reduce risk of progression. ”

Genes effect on occurrence and progression

“Genes conferring AMD risk are not only related to the occurrence of AMD as found in case-control studies, but we also found they are important in determining the rate of progression of disease over time, from early and intermediate stages to advanced clinical phenotypes.”

Genes and diet can interplay

“We found the highest quintile of omega-3 intake was associated with a lower risk of progression to geographic atrophy, when compared with the lowest intake, and this beneficial effect was noted particularly among individuals who carried the homozygous risk genotype for ARMS2 (). No protective effect was observed for the ARMS2 homozygous nonrisk genotype. ”

“Additional gene-diet differences were observed with regard to high adherence to a Mediterranean diet (). High adherence reduced the risk of progression to advanced AMD, and specifically among those individuals carrying at least one nonrisk allele at CFH Y402H (). There was no effect of the Mediterranean diet on risk of progressing to advanced AMD among individuals carrying the CFH homozygous risk genotype (CC).”

“In our diet-gene evaluation of dietary folate, high consumption of dietary folate was significantly associated with a lower risk of progression (). We found a protective effect of higher folate intake against progression to geographic atrophy, particularly among individuals carrying the C3 R102G homozygous nonrisk genotype (). The beneficial effect of folate was not observed for those carrying at least one risk allele (G) at this locus.”

“We also recently reported that participants with the highest quintile of dietary vitamin D intake had a significantly lower risk of progression to advanced stages of AMD, and especially NV. This effect also may vary according to genotype.”


Read about Vickie’s journey with AMD

 

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Review of the AREDS & AREDS2 Research Results: An Attempt of Make Them Clearer for Patients and Family Members

In the “If you have…” section below, you will find the stage of each eye in combinations so that you can find your current status.  Under each heading, you’ll find the research done and results, if they are available.

Added 1/3/2018: There is no evidence from either AREDS or AREDS2 that these supplements prevented AMD, reversed AMD or improved the vision of any participants. The results are all about reducing the risk of progression from whatever stage they started the study to advanced AMD at the end of the study.

Disclaimer

We are NOT telling you what to do or what to take, this is NOT to replace a thorough examination & discussion with your eye doctor AND your own research.  We are just trying to simplify the results of 2 important but complex studies.

Notes
  1. Before taking any supplement, please talk to your personal doctor/GP especially if you have other health issues.  These are high-dose supplements which can cause interactions with medications, interactions with other vitamins & minerals and in some cases can worsen other disease processes.
  2. In order to simplify the results of these studies, we have ‘stretched’ the stage assignments from how they were actually done in the studies.  For example, in AREDS, they looked at the lead/most advanced eye & assigned the participant that stage.  So someone with one eye at the intermediate stage & the other with no AMD, early AMD or intermediate AMD would be assigned the intermediate stage.  AREDS2 used a slightly different method.
  3. There are many ‘eye vitamins’ sold as AREDS or AREDS2 but they do not all have the exact ingredients that were a result of the extensive AREDS & AREDS2 research (see References section below for full study articles).  The ingredients & dosages from AREDS were:  antioxidants 400 IUs of Vitamin E, 500 mg of Vitamin C and 15 mg beta carotene.  Because beta carotene was found to be linked to lung cancer in smokers, AREDS2 removed the beta carotene & used 10 mg Lutein and 2 mg Zeaxanthin.  The formulations from both studies included zinc (because of zinc, copper was also included), 80 mg in AREDS and both 80 mg and 25 mg zinc in AREDS2.   It was these exact ingredients that produced the positive results below (“showed reduction of risk  of developing advanced AMD”) so read the labels of any products carefully to make sure they match the study formulation as closely as possible.  There are 2 webpages in References below that compare selected products.
  4. A warning has been issued about the high dose of zinc in the study formulation: “The AREDS supplement was beneficial for most patients, but almost 15% did worse with treatment than with the placebo. This adverse outcome appears to be due to the high-dose zinc component of the AREDS formulation. More research is indicated but, in the meantime, I perform genetic testing to select the optimal nutritional supplement for each patient.” from the Macular Degeneration Association.   For more information about genetic testing, see References below.

If you have…

No AMD Both Eyes
  • In AREDS only (no participants without AMD were included in AREDS2), participants with this combination were put in a separate arm of the clinical trial to study the effect of antioxidants on cataract formation where half got a placebo & half got the antioxidants only (no zinc).  In 2017, AREDS data from the cataract arm was studied by Awh, Zanke and Kustra (2017) and they concluded that taking these high-dose antioxidants may harm those with a specific genotype.  Because of that, the recommendation from study is to NOT take the AREDS or AREDS2 supplements if you do NOT have AMD.  For more information about genetic testing, see References below.
No AMD one eye/early AMD in the other eye
  • There were not enough participants in AREDS to a generate a recommendation. Perhaps results of Awh, Zanke and Kustra (2017) above may apply but it has not yet been studied. There were no participants with early AMD in AREDS2.  If your doctor has recommended that you take the supplement, see “Early AMD in both eyes” below.
No AMD one eye/intermediate or advanced (wet or geographic atrophy) in the other eye
  • AREDS: showed reduction of risk of developing advanced AMD in 5 years. [see notes 3 & 4 above}
Early AMD in both eyes
  • Only studied in AREDS. Not enough participants to generate a recommendation. Perhaps results of Awh, Zanke and Kustra (2017) above may apply but it has not yet been studied. There were no participants with early AMD in AREDS2.   Some eye doctors recommend that those with early AMD in both eyes take the AREDS or AREDS2 supplements.  Please make sure that you discuss the benefits versus the risks (ie, interactions with other medications and/or supplements) with your eye doctor.
Early AMD in one eye/intermediate or advanced (wet or geographic atrophy) in the other eye
  • AREDS: showed reduction of risk of developing advanced AMD in 5 years. [see notes 3 & 4 above}
Intermediate AMD in both eyes
  • AREDS/AREDS2: showed reduction of risk of developing advanced AMD in 5 years. [see notes 3 & 4 above}
Intermediate AMD in one eye/advanced (wet or geographic atrophy) in the other eye
  • AREDS/AREDS2: showed reduction of risk of developing advanced AMD in 5 years. [see notes 3 & 4 above}
Advanced AMD (wet or geographic atrophy) in both eyes
  • No one with this combination was included in either AREDS or AREDS2.   Some doctors tell their patients with geographic atrophy (advanced dry AMD) in one or both eyes to take the supplement to prevent their eyes from progressing to wet AMD (it’s possible to have geographic atrophy AND wet AMD).

If you have any comments or questions, please email me at light2sight5153@gmail.com

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Our Turn is Coming

Happy Monday! Waiting for the van again so forgive me if I run off abruptly.

Back to the pink of health. I revised my evaluation and decided it was food poisoning….again?!?! My dining companion ate her leftovers and also got sick as the proverbial dog.

I was well enough yesterday to accept an invitation to go kayaking. Said if before, say it again, weird weather. There was some guy jet skiing on October 16th! Anyway, it was fantastic to be on the river. Warm breeze. Birds calling. Fishermen shouting greetings across the water. Kids on the bank asking me if it were nice out there. Yeah. It was. Really nice.

To business! I promised you RPE65. The Genetic Home Reference tells us RPE65 is also called retinoid isomerhydrolase. Yeah, whatever. RPE65. RPE65 is responsible for providing instructions for a protein we need to see. It is, obviously, part of the RPE layer.

As I said last time, RPE65 is essential in the visual cycle. Light changes a special molecule called 11-cis into a different substance. Since it is no longer any good for changing light into electricity in its new form, it has to be ‘recharged’ so it can go back to work. That is the job of RPE65.

With me so far?

Failure to convert the end product of the reaction – referred to as all-trans-retinal – leads to a build-up of said all-trans retinal as a waste product and a toxin. In my terminology, it is part of the eye poop. Your visual cycle also stops working. Not good.

Now, I am not saying we AMD folks have problems with faulty RPE65 genes. (Although we might. I am only a dabbler in the field.) Those mutations are found in diseases like Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). What I am saying is every breakthrough in one aspect of vision research might lead to breakthroughs in other areas and – drum roll please! – there has been a breakthrough!

Not all that far away from me, in the City of Brotherly Love, also known to us country folk as ‘Filthydelphia’, Philadelphia to all you other folks, they have found a way to ‘reprogram’ faulty RPE65 genes using gene therapy. Philadelphia is on a roll because this is the second gene therapy its researchers have had recommended for approval. That is the second of two, mind you, EVER recommended for approval by the FDA. Philly researchers have gotten them both. One more and they will have a hat trick! (Go, Flyers!….OK, so their decades were the 1970s, ’80s and ’90s, but it could happen again.)

The first gene therapy recommended for approval was for leukemia. The visual cycle gene therapy is called Luxerna. It is going to be offered to children with early onset blindness in a bid to keep their photoreceptors functional. It has a very high success rate and is still working in phase 1 subjects from four years ago! [click here for an article that talks about this in more detail.]

So what happens now? Luxerna has been cleared to take the final hurdles. According to FDA.gov there are three more steps in a 12 step process. These steps are as follows: review of labeling information, inspection of manufacturing sites, APPROVAL.

Brave New World. Stay tuned. Our turn is coming.

written October 16th, 2017 Continue reading “Our Turn is Coming”

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Research: Dry & Wet AMD

Hello! I am going to get to the article Lin found on BrightFocus Foundation’s website about ‘lamp stuff’ aka lampalizumab but first I wanted to quickly mention a Google Talk by Isaac Lidsky. The title is Eyes Wide Open.

Lidsky began losing his sight to retinitis pigmentosa when he was 13 years of age. Although he has been totally blind for many years, Isaac Lidsky is extremely accomplished and has developed a philosophy that includes all sorts of concepts such as being present in the moment, doing what works and not abdicating responsibility for your life to your personal heroes and villains. His half an hour Google Talk may make some people rethink their attitudes towards their sight losses.

While I don’t expect many people to feel ‘lucky’ they are going blind – and Lidsky does consider his blindness to have been a blessing – Lidsky’s perspective on things can be thought provoking.

OK, onward to ‘lamp stuff’. We have quoted Joshua Dunaief before. One of the most helpful things he does for me in the current article is give us a pronunciation guide for lampalizumab. It is lamp-uh-liz-you-mab. Sort of like “Lamp!…uh, Liz, you mad/b?” You know, what you say when you knock over Elizabeth’s favorite light.

We have gone over the study results already in these pages. Complement factor I variant folks got kickin’ results. The rest of us, not so much. A reason for genetic testing for us before we submit to needles in the eyes, literally!

Dunaief says results are expected in 2018. Yep, December is their target date for publication. He does not mention phase 3 is over this December as is indicated in clinicaltrials.gov.

So, basically, still not really sure what is happening with ‘lamp stuff’ and me. May be offered it in December. May not be. May accept the offer. May not. I would love to know my genotype as compared to the SNPs they found in the experimental sample. Being a responder would be incredible. Being a nonresponder would be very bad. Dilemma.

And information for our ‘wet’ friends for my last 200 words. In JAMA Ophthalmology Jackson, Boyer and Brown reported the results of an experiment with an ORALLY administered vascular endothelial growth factor (VEGF) inhibitor. In other words, they have been experimenting with a pill they hope would do the same thing as your anti-VEGF shots.

The stuff is a tyrosine kinase inhibitor. It caused a lot of upset tummies and diarrhea (5 and 6 subjects out of 35 respectively) but the side effects were not bad enough to stop the experiment. Some people did stop because of liver problems. Those with liver issues would probably not be candidates for the treatment.

Only 40% of the total required rescue shots. Even those people received fewer injections than they had without the pills.

Before you all rush out for your X-82 pills, bear in mind this was a phase 1 experiment. That is safety and tolerability, guys. They are moving on to proof of concept, phase 2, with a bigger n. (n being the number of subjects in the study, remember). Check clinicaltrials.gov if you are interested.

Remember we all do our part in this fight. If you have a strong liver and a strong stomach, X-82 might be your kind of research. You might get to be a lab rat before I do!

written September 2nd, 2017

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The Winner Is…Genetics!

I just tried to read the article listing the different genetic variants that have been associated with AMD. The complementary system in Age-Related Macular Degeneration: A review of rare genetic variants and implications for personalized treatment is declared the winner!

I admit defeat! Maybe I can study genetics for a decade and come back for a rematch.

I can sum up what I learned in about two sentences. The great majority of SNPs associated with AMD appear to be on chromosome 1 where the complement immune system is coded. SNPs cluster around the location of Complement Factor H although there are also large numbers of mistakes in the neighborhoods of Complement Factors i,2,3,9 and B.

The second thing I learned is this: the rare forms of AMD are coded for in other places. These ‘outliers’ are being studied in genetically-isolated groups such as the Amish.

Side note: The Amish are a closed, religious and cultural sect. Pennsylvania is a population center for the Amish. Therefore, here in Pennsylvania they live in association with us although not necessarily among us.

The Amish have all descended from an initial group of about 200 families. Because of the close inbreeding they suffer from a variety of genetically based problems such as dwarfism, Angelman’s Syndrome and several metabolic disorders. Being such a ‘natural laboratory’ for study of the founder effect, the Amish have allowed much genetic testing on members of their community. One of the conditions studied? Age-Related Macular Degeneration.

For more information on the Amish, check Wikipedia or your favorite reference.

OK, so it is not strictly info on AMD, but man does not live by vision loss news alone. I find that sort of stuff interesting. Hope you do, too.

And quickly back to the AMD stuff – because I only have about 200 words left – the Audacious Goals Initiative is still working hard to stamp out blindness. I found a better article on the mouse-zebrafish experiments on their page at the National Eye Institute. This article stressed how the Muller glia cells from the zebrafish had been able to be transformed so beautifully they were electrophysiological indistinguishable from interneurons cells. They had integrated well on both ends of the connection required and were sending signals to the brain. In other words, the zebrafish cells had changed and connected so the blind mice could now see.

Very preliminary work but exciting. The article cites a lot of problems such as: there are not quite enough zebrafish eyes to satisfy the demands of potential research. It might be best to find ways of coaxing regeneration of existing cells in our own eyes. Save the zebrafish!; you understand.

Just one more amazing bit of research and discovery that some day will eliminate Age-Related Macular Degeneration and allow people to see….I’m just glad there are people out there who are a helluva lot smarter than I am to do the research. Now, anyone want to explain the genetics to me?

written August 27th, 2017

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Another Potential Treatment

The more I look into this, the more overwhelming it seems! I am glad I never tried to be a geneticist!

What am I talking about? The latest information on treatment for geographic atrophy suggests there is another gene being targeted. The gene is C3.

Remember how I have been saying Age-Related Macular Degeneration is looking not like one disease but like a family of diseases? When I followed up with some background research on complement factor C3, I found a list of – get this – over 3 dozen different SNPs that preliminary evidence suggests have a role in causing AMD. Remember SNPs or ‘snips’ are genetic coding errors. Some are beneficial. Some are neutral and some can really screw thing up.

Anyway, it appears there are literally dozens – if not more – of ways we can be ‘wrong’ to get AMD. Right now that means they are working on finding dozens of ways to intervene. May be a panacea sometime in the future, but right now they are nibbling at the problem a piece at a time.

And the piece they are nibbling on now is C3. According to a short article by FierceBiotech, Apellis has finished phase 2 – the proof of concept phase – trials with intravitreal injections of a drug they are calling APL-2. Later it will get a trendy brand name but for now look for APL-2.

BusinessWire identifies Apellis as a company “developing a platform of novel therapeutic compounds for the treatment of autoimmune diseases” so I guess people are coming around to see AMD as an autoimmune disease. APL-2 is described as a complement factor C inhibitor. It “binds specifically to C3 and C3b, effectively blocking all three pathways of complement activation (classic, lectin and alternative).” That sort of sounds like it is suppressing ‘friendly fire’ sooner in the process and may be closer to the ‘one treatment fits all’ that we would like to see. Not anywhere near there, but closer.

The results were very promising. At 12 months they showed a 29% reduction in growth as compared to sham.

But the weird – and great! – thing that happened was this: during the second six months of the study, the reduction rate was 47%! For some reason, the effects of the treatment appeared to be cumulative. Pretty cool.

Now I am not sure what type of genotype you have to have to profit from treatment with APL-2. The researchers are not sure at this point either. They decided to do some searching for genetic markers. Being the suspicious sort, I am wondering if they had star responders and non-responders just like they did with lampalizumab. Would make sense. Why do genetic testing on an ‘n’ of 246 people if you don’t have to? It’s expensive.

And speaking about money, there is a lot of money to be made with this drug. Apellis wants to get APL-2 to market quickly so it can compete with eculizumab, a treatment for PNH, a blood disease. (Apparently PNH is also related to complement factor C). Their competition, Soliris, was predicted to bring in more than $3 billion in 2017. Sometimes a little greed is a good thing! $3 billion can really motivated people.

So, there you go. It seems they have found one more way to save some of the sight of some of the people some of the time. Number two potential treatment for our ‘untreatable’ disease. The wall is coming down a brick at a time. There is hope.


Here’s another article about APL-2 that says “APL-2, a complement C3 inhibitor, has met its primary endpoint in its phase 2 clinical trial, reducing the rate of geographic atrophy (GA) associated with age-related macular degeneration (AMD).”

written August 27th, 2017 Continue reading “Another Potential Treatment”

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Genetics of AMD

Genetic Rant & Roll – The Miniseries

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