Viewing 4 reply threads
  • Author
    Posts
    • #15504
      Igor
      Participant

      Disclaimer:
      a) All ideas below are only my opinion
      b) All information was taken from public Internet. There is not any spoiler here
      c) I am well qualified IT specialist (project manager, analytic) and don’t have any medical education
      d) I can be mistaken as any ordinary people
      e) English is my second language. So, be patient if you notice some mistakes

      I think I found a big gulf between university researchers and commercials companies.

      The first ones are interested in research process and local result, the seconds ones are very interested in finding something new, creating new drug or therapy and receive rights to sell it alone for some years. It means that some university researches results won’t be tested on humans and won’t be followed to new drug.

      One surprise for me. Researchers use clear substances, but at the end of their research why they don’t test certified drugs (Cilostazol – Pletal, Myriocin – Fingolimod – Gylinya). They have ready environment so it will take less time, less resources and less expenses, according my project manager experience. It is very strange.

      I try to show two examples.

      1) Cilostazol (Pletal)

      It is strange but a lot of tests linked to Alzheimer disease (AD) and not tested for ALS.

      Nov 2017 Ari W. Schaler, Natura Myeku “Cilostazol,a phosphodiesterase 3 inhibitor, activates proteasome-mediated proteolysis and attenuates tauopathy and cognitive decline”

      They received grant in NY and tested on mice Roflumilast and Cilostazol and found that they activate proteasome and it reduces TDP-43 aggregates. It was Ad research, but on site with result I read that it is similar to ALS disease.

      I found next research (it was at 2018 I think, I lost link unfortunately. It is my fault.) They tested rolipram, roflumilast and cilostazol on mice too. As a result, rolipram works short time, roflumilast works with dangerous high doze for humans and cilostazol works enough long time and doze is suitable for humans.

      So Cilostazol is approved by FDA long ago. I think somebody had to start clinical tests on ALS patients, but I couldn’t find any. I found tests for AD
      Article: Apr 2017 https://www.tandfonline.com/doi/full/10.1080/13543784.2017.1364360

      I think we lost a chance from 2018 to today to test Pletal on ALS patients and  it was a very fast way to receive new drug for ALS patients, if it works of cause.

      2) USP14
      2018, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766829/
      Researches received new generation of equipment and GPCR drugs should be developed faster.
      I met a lot of times USP14 target when I read articles about proteasome activation.
      So I found a good article Nov. 2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702663/

      Result:
      “Discussion:
      Toxic misfolded proteins, often of mutant origin, are etiological agents in neurodegenerative diseases and in many other disorders. Given the prevalence of diseases of this type, collectively known as proteopathies, methods for reducing the levels of such damaging proteins are of potential interest. The elimination of misfolded proteins is a key function of the ubiquitin-proteasome pathway, and it is plausible that a significant fraction of proteopathic proteins are proteasome substrates although not necessarily preferred substrates. Thus, small molecules that enhance proteasome activity could have therapeutic value. Proteasome activity is held under negative control by deubiquitinating enzymes in that they remove the ubiquitin signal needed for effective targeting to the proteasome. Small-molecule inhibitors of USP14 and other deubiquitinating enzymes have accordingly been found to stimulate the degradation of proteasome substrates (8, 10, 18, 20,–22, 26, 58,–62).

      Almost 100 deubiquitinating enzymes are encoded in the human genome, providing myriad opportunities for modulating the output of the ubiquitin pathway (63,–65), although it remains unclear what fraction of deubiquitinating enzymes play significant roles in negative regulation and how substrate-specific such effects may be. In some cases, potential applications of DUB inhibitors in cancer chemotherapy are under investigation (66, 67).

      One deubiquitinating enzyme that has been validated as a negative regulator of the proteasome is USP14. Its importance was highlighted first by studies of its yeast ortholog, Ubp6, which was discovered to be a potent endogenous inhibitor of the proteasome as well as a major proteasome component (7, 9, 15, 68). An unusual feature of this enzyme, as compared with other DUBs, is that its capacity to inhibit protein degradation requires a domain on Ubp6 that targets it to the proteasome (the Ubl domain) (7). Thus, Ubp6 is thought to remove ubiquitin from substrates that have already docked at the proteasome. The identification of a specific inhibitor of USP14, IU1, allowed for this paradigm to be extended to mammalian cells (8). IU1 has also been used to identify new functions of USP14’s deubiquitinating activity (13, 28, 62, 69, 70), which in most cases remain to be elucidated in detail.

      To better probe USP14 function in cells, we have developed a significantly improved derivative of IU1. The new compound, IU1-47, is 10-fold more potent. IU1-47 should prove to be an effective research tool. The improved properties of this compound may facilitate the identification of new functions of USP14 while helping to minimize off-target effects.”

      It shows that potentially this target can reduce protein aggregates and they found a very effective substance IU1-47.

      It was 2017, now it is 2020.

      Do you hear about new drug for USP14?

      I couldn’t find any, but IU1-47 is possible to buy for research proposes very ease.

      Main question: Why did nobody take this result and try to create new drug?

      P.S. I can be mistaken of cause and some companies private are creating it, but I think it is unreal situation. Companies like creating press releases as soon as possible.

      I’ll come back to UPS14 later.

    • #15546
      Chad Smith
      Participant

      Interesting read.  Thanks for sharing

    • #15551
      Danielle Uskovic
      Participant

      I agree with Chad. Igor this is an interesting and great read.

      Not sure if you’ve read “Chasing my Cure” by David Fajgenbaum? It’s a remarkable story of a young doctor diagnosed with a rare and terminal illness that decided to spearhead finding a cure to his disease.

      He found a drug already available on the market, for something completely different, that helped.

      It’s going to take courageous people like you, me and other ALS patients to look for alternative solutions.

    • #15561
      Owen
      Participant

      Here’s my thought on this subject. From what I’ve read, and what my wife’s doctor at Johns Hopkins said, mouse models are really of minimal use. I think they’re typically used to justify moving on the human trials, but they’re of such little use that it’s an unnecessary delay more than anything else. We still know so little about ALS, but we know enough that we should be able to make some educated guesses about drugs or types of drugs with plausible mechanisms. From there, they should do a safety study and then quickly move to Phase 2. The one thing ALS patients don’t have is time, and they have very little to lose by trying something new.

      I personally think more research needs to be done on trying drugs in combination. I think it’s fairly unlikely we’ll ever discover a miracle drug that cures ALS. I think it’s much more likely we could find a cocktail of drugs that either a) slows the progression way down, or b) turns the illness from terminal to chronic, but manageable.

    • #15562
      Igor
      Participant

      @Owen, I agree with you. Please read my next topic

Viewing 4 reply threads
  • You must be logged in to reply to this topic.

©2021 KLEO Template a premium and multipurpose theme from Seventh Queen

CONTACT US

We're not around right now. But you can send us an email and we'll get back to you, asap.

Sending

Log in with your credentials

or    

Forgot your details?

Create Account