Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

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Re: Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

Postby HeatherLst » Sat Apr 14, 2018 8:45 pm

A friend of mine got me the entire study. I’m going to have to spend some time reading it, and then re-reading a few more times.


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Re: Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

Postby PBW » Sun Apr 15, 2018 5:26 am

I definitely will follow Dr Huang's research...maybe more for those who follow. At 66 not sure I will see his work come to fruition of actual treatment protocol for 4/4 in my lifetime. Never say never!

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Re: Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

Postby MichaelR » Thu Dec 13, 2018 4:03 pm

In terms of the worries about apoE production in neurons vs. astrocytes and CNS vs. periphery, and therefore benign functions of apoEε4 that might be buggered up by structure correctors or other approaches: this doesn't seem to have been posted:
A 40-year-old African American man was referred to the Lipid Clinic, University of California, San Francisco, with severe hyperlipidemia relatively unresponsive to statin and fibrate treatment. He had large tuberous xanthomas ... His diet, generally low in fat, contained little saturated and no trans fats and was low in rapidly absorbed carbohydrates. He had no signs or symptoms of neurological deficit, ophthalmological disease, or cardiovascular disease (CVD). He did not start talking until age 3 years. At school, he performed better in mathematics than reading, finishing 11th grade with a C+/B− average. ... [He underwent] Whole-exome sequencing, lipoprotein analysis, and neurocognitive function.

Results The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). [That is: the mutation caused him to produce zero APOE, of any flavor -M]. ... Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high [serum] cholesterol content [and various unusual lipid characteristics] ...

Conclusions and Relevance Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled.
JAMA Neurol. 2014;71(10):1228-1236. doi:10.1001/jamaneurol.2014.2011

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Re: Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

Postby Julie G » Thu Dec 13, 2018 6:36 pm

Thank you, MichaelR! We've previously discussed this when it was initially published... though I'd be hard pressed to find it.

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Re: Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

Postby Brian4 » Thu Feb 13, 2020 7:00 pm

Do you know why PH002 itself isn't a therapy?
Good question!

It would not be that hard to 1) order some:

https://www.emdmillipore.com/US/en/prod ... BIO-178477

2) do a rodent safety and dose discovery study, then 3) do a Phase I trial in humans.

Last I checked, E-Scape Bio was not focusing on their AD program (and at the moment their website is down).

http://www.e-scapebio.com/

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Re: Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

Postby ApropoE4 » Sun Feb 16, 2020 12:23 pm

I wouldn't give mice PH002 unless I want to kill them. (actually most of my interactions with mice involved killing them so that might not be a bad thing)

The molecules in e-scape bio's queue and several others are supposedly functional analogs but without the toxic effects that I assume PH002 would have on mice and men.

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Re: Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

Postby floramaria » Sun Feb 16, 2020 2:13 pm

ApropoE4 wrote:I wouldn't give mice PH002 unless I want to kill them. (actually most of my interactions with mice involved killing them so that might not be a bad thing).
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Re: Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

Postby Brian4 » Sun Feb 16, 2020 2:33 pm

but without the toxic effects that I assume PH002 would have on mice and men
Why do you assume that?

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Re: Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

Postby ApropoE4 » Sun Feb 16, 2020 3:02 pm

I thought this was presented in the original paper by Mahley and Huang.

https://doi.org/10.1021/jm3008618

However, to date, the most potent phthalazinone apoE4SCs caused significant toxicity in mice. Therefore, we have expanded our validation studies to other apoE4SCs. A series of pyrazoline analogues were prepared by Merck Research Laboratories and used to establish SARs. This series was highly effective in blocking apoE4 domain interaction, as determined by FRET, and demonstrated parallel effects in enhancing COX1 levels and reducing mitochondrial toxicity in apoE4-expressing neuronal cells.

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Re: Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

Postby Brian4 » Sun Feb 16, 2020 3:05 pm

Ah, thanks! I'd missed that!


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