From IHUB's falconner66a, Fletch Histone Dea

From IHUB's falconner66a,
Fletch


Histone Deacetylases Not Comparable to Anavex

A complex subject; upon which I will only touch the surface.

HDACs are histone deacetylases, enzymes (properly-folded proteins, as it happens) that remove acetyl groups from chromatin, thereby exposing naked DNA (genes) to make enzymes.

Chromatin is a DNA/RNA/protein complex that folds and encloses DNA. DNA molecules are lengthy, and if allowed to float independently in the chromosomes would become tangled and subject to breakage (among other untoward biochemical outcomes).

DNA is condensed in the chromatin complex in chromosomes, where its genetic integrity is protected.

But while thoroughly enclosed in the chromatin sheath, the genetic information of the DNA, the genes, cannot be read or expressed by the cell. For genetic expression, the DNA information must first be transferred to ribonucleic acid, RNA, a process called transcription (“writing across”). The genetic information, which codes for the eventual production of a specific reaction-controlling enzyme (a folded protein), creates a new RNA sequence.

Then, the RNA is enzymatically split off from the HDAC-exposed DNA strand, and the genetic info is taken by the mRNA (messenger RNA) to an extremely complex organelle, the ribosome. Here, the mRNA strand is fed through the ribosome, and specific amino acids are connected in exact sequence, thereby making exact, precise amino acid sequences. Genetic info goes from DNA to RNA to a specific amino acid sequence.

The amino acid sequences, finally, are processed in the rough endoplasmic reticulum, where they get properly folded into bio-active enzymes. The exquisitely-formed enzymes control cellular chemical reactions, and the cell functions normally. There is a continuing stimulus/response interaction turning on and turning off proper enzyme production. Specifically, that’s the “homeostasis” so often spoken of in reference to Anavex 2-73.

Back, now, to HDACs.

In the case of Rodin Therapeutics (as best I can determine), the company apparently has a chemical that can inhibit HDAC activity, apparently targeting the chromatin of specific Alzheimer’s genes. Prevent those genes from being transcribed, by inhibiting the HDACs that expose the Alzheimer’s genes, and although a person has Alzheimer’s genes, they can’t be transcribed. They remain obscured in the protective chromatin.

Sounds good, in theory, at least. Several problems might arise. First, would be the creation of a specific HDAC inhibitor, one that locks only specific Alzheimer’s genes. If it inadvertently locks up other genes in the enclosing chromatin, all sorts of adverse events would occur.

Getting this molecule inside neurons might be problematic. Cells wall themselves off from external chemistries, and should any extraneous chemical entities gain entrance, pierce the plasma membrane, a host of mechanisms bind to and actively excrete the intruders. This is a common cause of bacterial antibiotic resistance. The bugs expel the antibiotics before they kill the bacteria.

I can’t discount the Rodin Therapeutics technology. It might work. But it’s far more complex, with multiple molecular targeting complications. It will need a lot of work to demonstrate efficacy on both lab rodents and humans.

I’m not impelled to check the stock price of Rodin Therapeutics. I don’t see it as Anavex competition in any regard. Two very different Alzheimer’s therapies (neither of which attempt to remove waste proteins—the universally unsuccessful treatment modality.