From Dr. Robert Mahley

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
User avatar
Julie G
Mod
Mod
Posts: 6597
Joined: Sat Oct 26, 2013 6:36 pm

From Dr. Robert Mahley

Postby Julie G » Sat May 30, 2015 1:15 pm

I quickly wanted to share a note I received from Dr. Mahley:

It was a great pleasure to meet with the ApoE4 Info group. Thank you for visiting the Gladstone.

For us it was humbling, inspiring and motiving to have the opportunity to discuss what we doing in our attempt to make a difference in the lives of millions of people. It can assure you that we are committed and will not stop our work until we contribute to treating, curing, or preventing the devastation that can be caused by apoE4. As we said, we believe that we have a way forward for a new therapeutic approach to apoE4-associated neuropathology, but it will take time. Please maintain your faith in the potential for a treatment, sooner rather than later.

With appreciation.

Bob

G has previously shared that Dr. Mahley is his "hero." I totally agree for many reasons; especially his offer to write us prescriptions for cabernet...resveratrol and all ;) I'm sure it was completely tongue-in-cheek: don't go CRAZY.

Online
circular
Contributor
Contributor
Posts: 3645
Joined: Sun Nov 03, 2013 10:43 am

Re: From Dr. Robert Mahley

Postby circular » Mon Jun 22, 2015 6:27 pm

I found his note very touching. I think we tap into the heart of these researchers. It must be very easy for them to be caught up in the scientific fascination of it, and the passion for research itself, and we provide a living, breathing, appreciative reminder of the lives on the line. Not that they'd forget what it's about, but seeing the beneficiaries of future treatments up close and personal and waiting for results must touch them in some way, I imagine. Thanks for sharing the note.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

User avatar
Gilgamesh
Mod
Mod
Posts: 1662
Joined: Sat Oct 26, 2013 11:31 am
Location: Northeast US mostly
Contact:

Re: From Dr. Robert Mahley

Postby Gilgamesh » Tue Jun 23, 2015 12:38 am

APOE is his life.

It's fascinating to see how the story of APOE unfolded. An article worth reading, as are the older referenced papers:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458626/

I remain immensely grateful for his efforts. I don't (simply) want a cure for Alzheimer's, nor even for dementia in general, but for all APOE-ε4-related pathology. That's what he and his team are working on.

GB

User avatar
Julie G
Mod
Mod
Posts: 6597
Joined: Sat Oct 26, 2013 6:36 pm

Re: From Dr. Robert Mahley

Postby Julie G » Tue Jun 23, 2015 12:28 pm

Thank you for sharing, G. I didn't think it was possible to admire Dr. Mahley any more, but I do :D Coincidentally, family members from my father's side also hail from Shelbyville, IN. I'm going to explore how far back & compare notes with Dr. Mahley.

User avatar
Julie G
Mod
Mod
Posts: 6597
Joined: Sat Oct 26, 2013 6:36 pm

Re: From Dr. Robert Mahley

Postby Julie G » Thu Oct 01, 2015 2:22 pm

After recently spending time musing about ways to improve our mitochondrial function, I just received this timely update from Dr. Mahley and wanted to share it with all. Apparently, he's musing about the same and looking beyond the structure corrector:

Dear Julie,

I would like to keep you and the apoE4 community updated on the progress that we have made in advancing our apoE studies towards a therapy. Over the past year our research has demonstrated that our compounds that convert the "abnormal" apoE4 to the "normal" apoE3-like form, and in so doing prevent the apoE4-assocaited neuropathology in animal models, have the potential to be candidates for a structure corrector drug. These results attracted attention of Venture Capitalists who were willing to invest to advance our small-molecules (potential drugs) to a treatment. Thus, in July we launched a biotech company, E-scape Bio, Inc., to move the apoE4 structure correctors to the clinic. E-scape Bio will expand the development of our chemical series of structure correctors and provide significant resources for both synthesis and biological characterization beyond the current focus with the expectation of moving these structure correctors towards a treatment of apoE4 subjects to prevent, slow and/or reverse the pathology.

While I am a co-founder of the company, I will remain at the Gladstone Institutes and continue my research. That is also true for my colleague Dr. Yadong Huang. Personally I will explore mechanisms designed to complement the structure corrector program by focusing on how apoE4 actually kills nerve cells and investigating another way besides the structure corrector approach to prevent that killing. I know that apoE4 is toxic to nerve cells by poisoning the activity of an organelle, called mitochondria--the powerhouse of the cell. ApoE4 starves the cells of energy by interacting with mitochondria. I will explore ways to prevent this "starvation" of the cells that is involved in the apoE4-associated neuropathology. Such a complex disease as Alzheimer's disease will undoubtedly require multiple approaches to defeat its detrimental effects on the brain. This represents another way forward.

Now that the company is formed to focus on the development of apoE4 structure correctors, I will seek ways to advance ancillary and complementary approaches by protecting the mitochondria. To that end, I must now seek to advance these new studies as well as the structure corrector program. Your interest, encouragement and support are appreciated.

I will keep you informed.

Bob
__________________________________
Robert W. Mahley, M.D. Ph.D.
President Emeritus/Senior Scientist
The J. David Gladstone Institutes
Professor of Pathology and Medicine
University of California, San Francisco

Online
circular
Contributor
Contributor
Posts: 3645
Joined: Sun Nov 03, 2013 10:43 am

Re: From Dr. Robert Mahley

Postby circular » Thu Oct 01, 2015 2:42 pm

How generous of him to take the time to update us through you! What a gem.

ApoE4 starves the cells of energy by interacting with mitochondria. I will explore ways to prevent this "starvation" of the cells that is involved in the apoE4-associated neuropathology. Such a complex disease as Alzheimer's disease will undoubtedly require multiple approaches to defeat its detrimental effects on the brain. This represents another way forward.


It's very interesting that while he believes in the structure corrector, he's not confident at this time that it alone is an answer. I would hope that babies could be genotyped and their e4 safely corrected at a early age to prevent the e4 vulnerabilities, but I guess that doesn't address the fact that non-e4s get AD too. I'm guessing that other processes also interact with the mitos and lead through mito dysfunction to neuronal cell starvation, such that his research going forward might help non-e4s as well, but he's saying he's looking for additional ways to target the cell starvation by e4 specifically, so he must feel the correctors won't be sufficient for us.

Sorry for that circuitous para … gotta run ...
ApoE 3/4 > Thanks in advance for any responses made to my posts.

ApropoE4
Contributor
Contributor
Posts: 332
Joined: Sun Feb 02, 2014 10:43 pm

Re: From Dr. Robert Mahley

Postby ApropoE4 » Thu Oct 01, 2015 8:36 pm

I'm not a biologist but as I understand it, part of the issue is that apoe is synthesized inside neuronal cells, and therefore correcting its structure outside those cells will not correct its intracellular detrimental interactions. So the structure corrector helps with Ab and tau, and probably with vascular issues, but not with mitochondrial interactions.

Online
circular
Contributor
Contributor
Posts: 3645
Joined: Sun Nov 03, 2013 10:43 am

Re: From Dr. Robert Mahley

Postby circular » Fri Oct 02, 2015 10:36 am

Oh thanks, ApropoE4 … it all makes more sense now.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

Online
Tincup
Contributor
Contributor
Posts: 1653
Joined: Fri Aug 08, 2014 2:57 pm
Location: Front Range, CO

Re: From Dr. Robert Mahley

Postby Tincup » Fri Oct 02, 2015 1:54 pm

I'm wondering how "feeding the mitochondria" as per Dr. Bruce Ames and Dr. Terry Wahls might help mitigate this mitochondrial issue. In her lactate podcast with Dr. George Brooks, Dr. Rhonda Patrick said she viewed AD as a traumatic brain injury in "slow motion." The thrust of this podcast was lactate as an alternative brain fuel. 12/2/14 in this list: https://itunes.apple.com/us/podcast/foundmyfitness/id818198322 She also addresses this in her interview with Terry Walhs 7/21/14 in the same list.
Tincup
E3,E4

User avatar
Gilgamesh
Mod
Mod
Posts: 1662
Joined: Sat Oct 26, 2013 11:31 am
Location: Northeast US mostly
Contact:

Re: From Dr. Robert Mahley

Postby Gilgamesh » Fri Oct 02, 2015 3:01 pm

ApropoE4 wrote:I'm not a biologist but as I understand it, part of the issue is that apoe is synthesized inside neuronal cells, and therefore correcting its structure outside those cells will not correct its intracellular detrimental interactions. So the structure corrector helps with Ab and tau, and probably with vascular issues, but not with mitochondrial interactions.
But are we certain the correction would only take place outside neurons? (1) suggests possibly not, but I read the paper two years ago and I don't have the original with me right now.

Quote from my notes:

"In vivo data, established using 4, demonstrate that it achieves excellent brain penetration following 10 consecutive days of daily intraperitoneal dosing of NSE-apoE4 mice (30 mg/kg: 7.9 ± 1.7 μM plasma; 35.1 ± 7.5 μM brain) and no in vivo toxicity during this treatment period. Furthermore, there was a 20−25% decrease in the levels of apoE4 fragments in the brain and hippocampus. In addition, COX1 levels increased in the hippocampi by about 55% (unpublished data). These data demonstrate that potent apoE4SCs have therapeutic effects in vivo, at least in mice with the human apoE4 isoform, and suggest that apoE4 is a promising drug target in patients with neuropathology associated with this apoE isoform."

(1) Small-molecule structure correctors target abnormal protein structure and function: structure corrector rescue of apolipoprotein E4-associated neuropathology.

GB


Return to “Science and Research”

Who is online

Users browsing this forum: No registered users and 3 guests