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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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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Snips & Snails & Puppy Dog Tails

Snips and snails and puppy dog tails are supposed to be what little boys are made of. However, now it appears we girls are made of snips also!

Just when I had decided I am not appropriate for ‘lamp stuff’ (lampalizumab) because I do not have the complement factor I (CFI) at risk allele, Lin informed me the snips ArcticDX tested for are not the same ones as in the study! I may be saying I don’t qualify because I don’t have ‘fruit’ but Arctic tested for oranges and the researchers tested for apples. Apparently all ‘fruit’ was not created equal. My CFI test that was fine may not really have tested what should have been tested if I want to make a decision about the study. I am so confused! [Sue talks about CFI & lampalizumab in pages I Want to Be a Mutant and I Am Not a Mutant.]

So what in Hades am I talking about? See above. The part about being confused. Let us delve further into this mystery.

A snip is actually SNP (it is pronounced snip). That is a Single Nucleotide Polymorphism. SNPs are tiny, little parts of genes. They are a variation in the spelling of our genetic code. Clear as mud, right?

Let us try again. The alphabet of genetics is made up of four letters: A, C, G,and T. Each of them is a nucleotide. Vary the order of the nucleotides on an allele and you can get any one of a variety of characteristics being expressed. Life in all of its diversity is written with a four- letter alphabet.

Sometimes Nature doesn’t spell too well. Sometimes she gets sloppy and copies a C for an A or whatever. These spelling errors do not cause disease but they can affect how the cell will function. They can also predict a response to certain drugs.

Spelling errors or SNPs are very common. According to my source, the Genetics Home Reference again, any one of us can happily harbor 10 million SNPs. However, even with that number of errors, Mom Nature still earns top grades in spelling. 10 million letters in error is a drop in the bucket when you consider how many letters were written for each of us.

We have gone from chromosomes to genes to alleles to SNPs. We are getting smaller and more specific as we go. Pages to paragraphs to words to letters. The SNPs are letters in error in the book of Life. Apparently the genetic testing I had found no spelling errors at the top of a paragraph while the researchers found spelling errors at the bottom of the paragraph. These bottom of the paragraph spelling errors caused the fantastic response to ‘lamp stuff’.

Looking at the perfect spelling of words at the top of the paragraph cannot tell me if I harbor those magic mistakes at the bottom. I am back to where I was. Indecisive as to what to do once again.

written July 30, 2017 Continue reading “Snips & Snails & Puppy Dog Tails”

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Piles of Articles

Long, holiday weekend. I am on the second day of four and have gotten pretty much nothing done. Oh, well. Procrastination is us.

Be that as it may, Happy Fourth of July whenever you may be!

Part of the ‘straightening up’ task for me is going through piles of articles I have found interesting and printed out. That word is actually PILES.

Just rediscovered one – Update on Genetics and Age-Related Macular Degeneration by Jerome Dunaierf – that has some good stuff in it. Did you know people with a parent with AMD have DOUBLE the risk of getting the disease? Make sure the kids get their eye exams!

Jerome talks about the complement immune system and does a nice job – much clearer and nowhere near as fanciful – in describing how the ‘friendly fire’ bit works. He shared the proteins that activate the complement system have been found around drusen. (Maybe a demented garbage men analogy would be better? Coming for the trash but hauling away the house?)

Jerome also talks about the ARMS2/HTRA genes. Enticing and mysterious those. No true clue what they do but we with AMD often have certain variants of them.

Other genes that seem to be somehow in the mix include genes that code for collagen formation, cholesterol formation and cell signaling. You might not realize it but the chemical ‘chatter’ going on in our bodies is deafening! Eavesdrop on that and we could intervene in amazing ways.

Jerome agrees with me lampalizumab will open up a HUGE market for genetic testing. (Probably the reason I kinda like Jerome). He shared it is now possible to sequence an entire human genome in a few days. The cost? About $1,000.

Wow. Have your code read and know exactly which drug is going to work on you. How far in the future before genetic sequencing becomes a requirement for getting health insurance? Ethical nightmare that.

And a little filler here: Pubmed published an abstract on a meta analysis of 10 trials about the risks and benefits of aspirin. Bottom line was this: aspirin can keep those of us with cardiovascular problems alive. Proven. Aspirin might, maybe, could have a negative effect on your AMD. The authors, Small, Garabetian, and Shava decided most of us would want to be alive. Their advice was to take your aspirin.

OK. A few more things off the pile. Time to wander off to something else. Maybe some housework. Gasp!

I am staying home from yoga today. Self diagnosis of rotator cuff tendinitis. Doctor’s appointment next week by which time I will not only have diagnosed but also treated myself!

My yogini is digging out a ‘no arms’ practice she found so I can try that tomorrow. Movement continues to be important to – and for! – me. Where there is a will, there often is a way.

That is what is happening here. Hope you are all doing well. Bye!

written July 2nd, 2017

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Thank a Mouse

This page is just me being inquisitive. If you are not up for me trying to figure out biochemistry, you might want to skip this page.

Looking at the medications they are using for wet AMD and the new treatment for dry AMD, lampalizumab, I noticed something.  Most of the generic names end in -zumab. What the hey? What is that????

To begin with, I discovered there are two suffixes, -ximab and -zumab.  Wikipedia actually has a whole list of medical suffixes but I am concerned about two right now. Those are the ones related to drugs for AMD. Suffice it to know that every suffix means something.  -olol for example will always mean a beta blocker. Of the two I am interested in: – ximab always stands for a chimeric agent that responds to more than one antigen;  and -zumab always stands for a humanized antibody.

See what I mean about just skipping this page?

Chimeric.  Now I knew what a chimera is. A chimera is a single organism composed of cells that should have made up multiple organisms. The organism  is made of genetically different cells. According to MedicineNet human chimeras were discovered when it was noted some people have two different blood types. The generally accepted ways a human chimera is formed are for nonidentical twins to share blood in utero or for one to absorb the other.

Once again according to Wikipedia, chimera proteins are produced through the joining of two or more genes that originally coded for two different proteins. The properties of the new derive from each of its ‘parents’. Naturally occurring chimera are often found in cancer cells; thus, it would appear, the wisdom of using manufactured chimera proteins to battle cancer (a genetic version of fighting fire with fire). Chimeric cancer cells happen because of random genetic mutation. Chimeric proteins in drugs happen by design. Read genetic engineering.

Forging ahead here, every drug ending in -zumab is a ‘humanized protein’. And, no, that does not mean it is kinder and gentler. It means that the base protein used in the drug probably came from a mouse. Generations of lab mice have had the very stuff of their being manipulated in the search for ways to improve our health. Think kinder thoughts about the little devils.

Because – actually two becauses – there are a lot of similarities between mouse DNA and human DNA, we can use mouse as the frame for our designer drugs. Because some of their proteins are foreign to us and would cause an allergic reaction, the proteins have to be ‘humanized’. Potentially offending sequences are cut out and replaced by sequences found in humans.

The idea is to produce proteins that will get into a sequence of reactions and somehow change it. In dry AMD lampalizumab weakens the immune reaction. Wet AMD drugs intercept the SOS message being sent by the eye. That is the one saying the eye needs more ‘supplies’ and new ‘supply routes’ (blood vessels) should be built.

So that is the answer to that burning question (you really were dying to know; I know). If you are taking a drug ending in -ximab or -zumab,  you are the beneficiary of altered protein sequences. Be grateful. Thank a mouse.

written July 1st, 2017

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Not Created Equal

We heard from a reader who has vitelliform macular dystrophy. I had never heard of it. Therefore you can image my surprise when I picked up an article I had downloaded last week and – guess what! – the article talked about vitelliform dystrophy! Sometimes the synchronicity in the Universe is scary.

Anyway, it appears the Universe has declared we are to learn about vitelliform dystrophy. Here we go!

I have discovered all macular diseases are not created equal. There are dozens of them and researchers are discovering more on a regular basis.

Vitelliform dystrophy may look like age-related macular degeneration and act like macular degeneration but it is not macular degeneration. (Don’t worry. We are not throwing you out of the group!)

Vitelliform dystrophy is a pattern dystrophy. They are so called because the damage tends to ‘draw’ things on the retina. For example, one manifestation of the disease looks like a butterfly (photo to the right is a fundus photograph of butterfly pattern).

Vitelliform 2 is called Best disease. This is not because it is the best disease to have nor is it because Dr. Best hijacked the disease and named it for himself. It is because the disease comes as a result of a mutation on the BEST1 gene. (Apparently that means we all have BEST genes and there are at least two of them. How about that.)

Best disease is a pattern dystrophy because – all together now! – it makes a PATTERN on your retina. The pattern is a sunny-side-up egg. The yolk is centered on the fovea.

One of the nice things about Best disease is you may never know you have it.  According to the Hereditary Ocular Disease site 7 to 9 percent of those with Best disease are asymptomatic. Others may experience vision loss but recover most of their function. A much smaller percentage may proceed to neovascularization and serious loss. Of course, the older we get the better chance we have of having some really serious problems. And by the way, children can have this one.

That is because, once again, it is genetic. Best disease is an autosomal dominant condition. That means it is on a body-forming chromosome – not the chromosome that has the x or the y and makes you a boy or a girl.  It is also dominant and can express itself whether or not its partner gene wants it to. You only need one of these babies to be in trouble.

Of course there are all sorts of things that may or will affect whether or not this gene does actually express. However, this is not a place to discuss epigenetics. Nor am I the one to explain THAT baby! Suffice it to say, you should warn everyone you are related to by blood that it has expressed in the family and they need to have regular eye exams.

Like AMD there is absolutely no treatment and no cure. (I get so tired of typing that). If you have Best disease and progress to CNV you may profit from shots.

And that, my dears, is that. Continue reading “Not Created Equal”

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Sisters Are Doin’ It For Themselves

I have paid a lot of attention to the male movers and shakers in vision research. Perhaps it is time to note the contributes of the women. Recently I have come upon short articles about the research of two.

Sally Temple, SUNY-Albany, and her colleagues recently published a paper on how nicotinamide can suppress the progression of AMD. Nicotinamide is a vitamin B3 derivative.

Dr. Temple took pluripotent cells, that is stem cells, from people who had AMD and those who did not. She manipulated the stem cells to become retinal pigmentation epithelial cells and grew them in her lab.

One of the first things Temple and her team noted was the cells from the AMD people acted differently from the RPEs grown from healthy subjects’ cells. The cells from people with AMD produced different chemicals. The chemicals were the same ones that figure in the production of drusen and contribute to inflammation.

These were RPEs growing on a culture medium in a glass dish. There was nothing else to contribute to the formation of the chemicals. The chemicals had to be coming from the RPEs. And, with no other possible influences, the cause for the production of these chemicals pretty much had to be genetic.

The fault, dear readers, is not in ourselves but in our genes. One more tally in the genes are destiny column.

But the good news is, when they squirted (or whatever) nicotinamide on the offending RPEs, things improved. Chemicals that are responsible for the bad things were less and the RPEs survived longer.

Perhaps if we find a way to get nicotinamide directly into eyes, we will get the same results in vivo as in vitro. Worth a try.

Masayo Takahashi is a Japanese researcher. Takahashi has been experimenting using pluripotent cells taken from the same people they are going back into. No embryonic cells required.

There is excitement about this new procedure not only because of ethical issues. There are indications this procedure will be cheaper and faster to implement. In additional, they are thinking people can ‘bank’ their stem cells. These can be used either for ‘repairs’ in the original cell ‘owner’ or they can be given to other people who are immune matched. (Sort of like blood type matching. Don’t want the body getting up in arms over the ‘invading’ materials.)

Bottom line is the ladies are out there rocking it just like the men. They continue to come up with great new findings and each one takes us a little bit closer to effective treatments and maybe – just maybe – even a cure.

To copy Lin’s use of old song titles, “sisters are doing’ it for themselves”. And they are doing it for us, too! Continue reading “Sisters Are Doin’ It For Themselves”

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