Gene Therapy Trial for ApoE4 Homozygotes

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HopefulCaroline
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Re: Gene Therapy Trial for ApoE4 Homozygotes

Postby HopefulCaroline » Tue Dec 10, 2019 4:08 pm

Fredsbrain wrote:Is this trial still opened? I was diagnosed with mild cognitive impairment by a neurologist after an evaluation by a psychologist several months ago. But I didn't have any scans. Would I have to get a scan thru my neurologist or how can I get one ordered?


Fredsbrain,

Welcome to the APOE4 community. We are so glad you found us! You will find this is a very supportive community full of terrific information and likely great hope regarding improving symptoms of MCI. There is so much we can do to keep our brains functioning well. You have come to the right place!

You may want to review the Wiki page which has many helpful links about diet, lifestyle, supplement discussions and much more.

The Primer is another great resource as it may also be helpful in answering questions now or in the future. It is an introduction to ApoE4, biochemistry and possible prevention strategies. This is written by Dr. Stavia, a member, in layman's terms.

The search tool is also quite helpful in finding discussions on more specific topics. I hope this is helpful for you.

Once again welcome. We are so glad you are here!


Sincerely,
Caroline
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Re: Gene Therapy Trial for ApoE4 Homozygotes

Postby Sara » Tue Dec 10, 2019 6:19 pm

Greetings Fredsbrain and welcome to the apoe4.info site. So glad you found us! This supportive community offers many opportunities to learn and share insights, as you have already found out. We would love to learn more about you and what led you to our site... if you are so inclined please consider sharing your journey via "Our Stories". If you haven't found it already, please feel free to use the Primer, which is a valuable educationtional resource for our members. Warm Regard.
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Re: Gene Therapy Trial for ApoE4 Homozygotes

Postby Fc1345linville » Fri Dec 20, 2019 10:37 am

I too have spoken with Cornell and received a 13 page consent form. As it has already been pointed out in prior posts, this trial is truly pioneer work and the risks need to be very seriously considered. If they do not evaluate you as at least MCI, you will not be invited to participate. Only if I were to be diagnosed with Alzheimer's would I consider participating. Not there yet!

Fc

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Re: Gene Therapy Trial for ApoE4 Homozygotes

Postby TheBrain » Fri Dec 20, 2019 12:24 pm

Fc1345linville wrote:I too have spoken with Cornell and received a 13 page consent form. As it has already been pointed out in prior posts, this trial is truly pioneer work and the risks need to be very seriously considered. If they do not evaluate you as at least MCI, you will not be invited to participate. Only if I were to be diagnosed with Alzheimer's would I consider participating. Not there yet.


I had the same experience and feel the same way.
ApoE 4/4 - When I was in 7th grade, my fellow students in history class called me "The Brain" because I had such a memory for detail. I excelled at memorization and aced tests. This childhood memory helps me cope!

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Re: Gene Therapy Trial for ApoE4 Homozygotes

Postby ApropoE4 » Thu Apr 29, 2021 6:26 am

Results from a second generation investigational gene therapy program show effective delivery of APOE2, the gene associated with protection against the development of Alzheimer’s disease, while also targeting and silencing APOE4, the gene that increases risk of developing the disease. A 40% reduction was observed in APOE4 expression, while APOE2 expression was maintained, suggesting APOE2 was resistant to microRNAs (miRNAs) silencing. The efficacy of gene silencing by miRNAs targeting APOE4 was evaluated by inserting miRNA into the AAV vector expression cassette.

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Re: Gene Therapy Trial for ApoE4 Homozygotes

Postby Jlhughette » Thu Apr 29, 2021 3:03 pm

This study is confusing to me. My sister, grandmother and great grandmother all died from AD with ApoE2/4. My mother had AD with ApoE 3/4 and had AD as well. You could say it was because of their lifestyles and diets, which could be true with my grandmother and great grandmother, meat and potato and dessert eaters, but not my sister, a practicing naturopath and acupuncturist, very sick with AD now who still eats a stellar diet mostly organic veg with small amounts of fish and supplement regime. Is the study replacing one of the 4s with a 2? Is it the same as having ApoE2/4 from birth or does silencing just one 4 make more of an impact?
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Re: Gene Therapy Trial for ApoE4 Homozygotes

Postby NF52 » Thu Apr 29, 2021 4:36 pm

Jlhughette wrote:This study is confusing to me. My sister, grandmother and great grandmother all died from AD with ApoE2/4. My mother had AD with ApoE 3/4 and had AD as well. You could say it was because of their lifestyles and diets, which could be true with my grandmother and great grandmother, meat and potato and dessert eaters, but not my sister, a practicing naturopath and acupuncturist, very sick with AD now who still eats a stellar diet mostly organic veg with small amounts of fish and supplement regime. Is the study replacing one of the 4s with a 2? Is it the same as having ApoE2/4 from birth or does silencing just one 4 make more of an impact?
Hi again jlhughette,

Please accept my deep sympathy for the recent death of your father, mentioned in another post. He went way past the average lifespan for a man born about the start of the Depression, and sounds like he raised wonderful kids. You've mentioned earlier that both he and your sister tested as ApoE 2/4 and people in his family all died earlier of heart disease or diabetes. That sounds like the ApoE 2 gene that he passed down to your sister had an outsize effect in previous generations in his family, given the association of ApoE 2 and risk of diabetes, which can then cause heart disease. So you sister presumably inherited her ApoE2 from him and her ApoE 4 from your mother.

Since you have ApoE 3/4, and your dad could only pass on ApoE 2 or ApoE 4, I have to assume you inherited ApoE 4 from him and a "neutral" copy of ApoE 3 from your mom. That would seem to mean that your dad was ApoE 2/4 and your mom was ApoE 3/4. It may be that the early changes you saw in her 40's and 50's were more from Lewy body dementia, since that is most commonly diagnosed in people over the age of 50, according to the Lewby Body Association. https://www.lbda.org/about-lbd/

If I'm interpreting this correctly, the incidence of Alzheimer's which you mentioned earlier occurred in the 80's in your mother and her mother and grandmother, was likely to due to late-life Alzheimer's from that one copy of ApOE 4, along with likely vascular issues, which are the norm, not the exception, in people who are diagnosed in their 80's. Especially among women your mother's generations and older, no one worried about blood pressure in the 120-160 range, and no one referred women to cardiologists, and much of what happens to blood vessels in aging brains may not be visible except in things like hearing loss or changes in vision.

As for the fascinating study in NYC, it's still at the very early stages of looking at safety of three different doses by studying adverse events and maximum tolerated doses. And of course they hope to show that this therapy changes ApoE 4 to ApoE 2. It wouldn't likely be as effective as having ApoE 2/4 from birth, because initially they would only try this on people who had already experienced confirmed amyloid plaques and tau tangles due to Alzheimer's pathology. Having ApoE 2 since birth is usually (but not always, as your sister's fate shows) linked to resistance to developing Alzheimer's pathology.

Only if this study proves there is a safe dose and the drug hits its target will they move to a larger study to see if it also slows or reverses the cognitive and behavioral of people with AD. Here's an excerpt from Clinical Trials.gov:

The [NCT03634007] study will establish a maximum tolerable dose and generate preliminary evidence regarding whether direct administration of AAVrh.10hAPOE2 to the CNS of those Alzheimer's patients will lead to conversion of the APOE protein isoforms in the CSF of APOE4 homozygotes from APOE4 to APOE2-APOE4.
. Gene Therapy for APOE4 Homozygote of Alzheimer's Disease

Your support for your sister is a great gift to her; one I'm sure she appreciates each day.
4/4 and still an optimist!

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Re: Gene Therapy Trial for ApoE4 Homozygotes

Postby Jlhughette » Thu Apr 29, 2021 5:57 pm

Thank you NF52 for responding so quickly. It really is remarkable that the Cornell study has had early success in 40 percent of people so far. And you are likely correct in pointing to undiagnosed diabetes and heart disease as setting the stage for AD in my relatives as well. Lately I am considering the idea that perhaps depression plays the largest part in the development of AD in some people. Both my mother and my sister suffered from bouts of depression, both treated and untreated medically. Thank you for putting so much consideration into your responses to so many of us.
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Re: Gene Therapy Trial for ApoE4 Homozygotes

Postby ApropoE4 » Sat May 01, 2021 2:37 pm

Jlhughette wrote:Thank you NF52 for responding so quickly. It really is remarkable that the Cornell study has had early success in 40 percent of people so far. And you are likely correct in pointing to undiagnosed diabetes and heart disease as setting the stage for AD in my relatives as well. Lately I am considering the idea that perhaps depression plays the largest part in the development of AD in some people. Both my mother and my sister suffered from bouts of depression, both treated and untreated medically. Thank you for putting so much consideration into your responses to so many of us.


To add to NF52's great summary - the trial hasn't shown success in 40% of participants - rather it's shown APOE4 expression was down by 40% on average among participants, while APOE2 expression was maintained at least over the months that have passed. We know that in APOE4 equivalent mice this is sufficient to reverse AD symptoms, but we also know that many (all, so far) treatments work in mice but not humans, so we should be cautiously optimistic. Of course having E2/4 doesn't guarantee old age free of dementia, but it should greatly improve the odds.

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Re: Gene Therapy Trial for ApoE4 Homozygotes

Postby Julie G » Tue May 04, 2021 2:01 pm

Just to add a bit to all of the great information, I've stayed in touch with the folks working on this and the intervention has been generally well tolerated. Baby steps, and certainly, one to follow.


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