Hi Quiltman, ( nice find) I emailed MT a day after his tenure...

Hi Quiltman, ( nice find)

I emailed MT a day after his tenure started. Here is a precis of what my thoughts were. There was other scientific data that I mentioned that is not relevant to your question, so I have redacted that to simplify this post.

Good morning Dr Thurn,

Welcome to Pharmaust and I do hope it's a enjoyable juncture in your career.

I have a science based background and though retired I still research to my content.

The absolute key to a successful treatment to MND/ALS , is can Monepantel reduce TDP-43 , if it can I can nearly guarantee that this drug ( owned by whoever) will be used in the future.


What is TDP-43 in MND?

One of the key features in almost all cases of MND ( 97%) , including the most common genetic form related to changes to the C9orf72 gene, is the accumulation of a protein called TDP-43 in the nerve cells of the brain and the spinal cord.

Mandrioli in the 2018 study states,

Rapamycin treatment for Amyotrophic lateral sclerosis :noted that rapamycin combined with riluzole, a glutamate blocker, can clear the cytoplasmic TDP-43 aggregates through induced autophagy.

One key to this pathway is MEK 5 , mTOR inhibitors reduce MEK5 expression which suppresses TDP-43 toxicity via the mTOR-independent activation of the autophagy-lysosome pathway. ( It's complex to explain and all I can say is that both drugs are synergising the excess protein removal)

The science stacks up , we may make a huge difference.Monepantel induces autophagy in human ovarian cancer cells through disruption of the mTOR/p70S6K signalling pathway.

Farnaz Bahrami, 2014 states ,

"On the other hand, accumulation of acidic vacuoles with distinct chromatin morphology and an increase in punctuate localization of green fluorescent protein-LC3B, and MPL-induced changes in the expression of SQSTM1/p62 were all indicative of MPL-induced autophagy".

So in relation to above, if SQSTM1/p62 ratio affects TDP-43 it creates a ratio imbalance on TDP-43 to create misfolded proteins. Thus reduces MND.


Dr MT answered thus ,

" I tend to agree with your summation on the importance of TDP-43 and likely positive effect MPL with have on reversing TDP-43 accumulation".

So your question Quiltman, is highly significant.

Kpax