-
Considering a proposal for CERF medical prize
Hello all,
I would like to make a proposal to the CERF medical prize 2020.
What I search (and the reason why I post this) is that I need to be backed by a CRO to be credible. CRO are research organizations that could conduct tests on animal models. ALS TDI is an example of CRO that is specialized in ALS.
The key goal of the CERF Medical Prize initiative is to find a successful approach to improve usable muscle strength in MND/ALS patients. Smaller laboratories and individual entrants may apply for support from CERF to develop their projects.
For a few years several academic laboratories in Japan, Canada and USA [1-3] have demonstrated that removing mis-localized TDP-43 aggregates from motor neurons’ cytosol is helpful in ALS animal models.
To my knowledge, no efforts have been made in biotechs to further study those results, so I think it is helpful for ALS patients to raise attention to what those academic laboratories did. One could think that this kind of therapy would nicely complement Nurown or Arimoclomol therapies. One therapy would clean cells, while the other would restore its health.
My proposal to the CERF prize would not use a viral vector to carry a peptide inside cells, as did the academic labs. While this could be done easily, viral vectors have a bad reputation, for example, only a few percent of cells are converted. Their administration mode requires intrathecal injection, something that needs rare medical resources. And there is no way to reverse the effects of the therapy once it is administrated.
Therefore my proposal will use Cell-Penetrating Peptides (CPP). CPPs are not the most efficient mechanism either, but it could be used as much as needed and if there are side effects, it is simple to stop administration. CPPs costs are also much lower than genetic therapy costs.
CPPs could reach the brain via nasal administration, where upper motor neurons have their bodies. They could reach lower motor neurons bodies via Retrograde transport.They are designed in order to bind to the TDP-43 specific domain on one end and bind to an importin protein [4] at the other end.
CPPs could be designed with online tools and tailored to target the cytosol, while not being toxic to the body. There are many free academic prediction servers [5] that could help.
There are many questions to solve: Efficiency, specificity, the toxicity of the proposed therapy.
So if you know someone working in a CRO and if you could advocate for them to join this proposal, a great step toward a way to clean motor neuron cells would be accomplished.
Many thanks for your attention.
Best regards,
Jean-Pierre Le Rouzic
Retired R&D engineer
https://padiracinnovation.org/News/
[1] The Inhibition of TDP-43 Mitochondrial Localization Blocks Its Neuronal Toxicity
Article in Nature medicine · June 2016
DOI: 10.1038/nm.4130
[2] TDP-43 inhibitory peptide alleviates neurodegeneration and memory loss in an APP transgenic
mouse model for Alzheimer’s disease
Ju Gao, Luwen Wang, Chao Gao, Hiroyuki Arakawa, George Perry, Xinglong Wang
DOI: https://doi.org/10.1016/j.bbadis.2019.165580
[3] Elimination of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfolding-
specific intrabody with dual proteolytic signals
Yoshitaka Tamaki , Akemi Shodai , Toshifumi Morimura , Ryota Hikiami , Sumio
Minamiyama , Takashi Ayaki , Ikuo Tooyama , Yoshiaki Furukawa , Ryosuke Takahashi & Makoto
Urushitani
[4] http://pdb101.rcsb.org/motm/85
[5] An example: http://tox.charite.de/protox_II/
-
1 Reply
-
Some news:
The CERF prize received groundbreaking innovations from the foremost medical scientists and engineers in the world, not to mention some incredible submissions of work from teams previously unknown from them.There are both engineering solutions to improve function, and medical/biological solutions to improve function and survival. So they have decided to offer two separate prizes; one for engineering solutions to improve function, and one for medical approaches to improve both function and survival.
The applications should be sent by March 31st 2020.
Please, if you are a stakeholder in a laboratory interested in a therapy for ALS based on CPP or similar technologies such as PROTAC, ask them to join my initiative.
People can email me at [email protected].
Best regards from France,
Jean-Pierre
-
Something related to my CERF possible proposal, as in both cases the goal is to destroy molecular aggregates (misfolded aggregates TDP-43 in my case):
Faze Medicines, a biotechnology company pioneering therapeutics based on biomolecular condensates, announced its launch and Series A financing of $81 million. Faze is founded by leading experts in the emerging field of biomolecular condensates with the mission of leveraging this fundamentally new understanding of cell biology to develop therapies to slow, halt or reverse disease pathology.
The Series A will support Faze’s preclinical research in two initial therapeutic focus areas – ALS and myotonic dystrophy type 1 (DM1) – as well as research to explore condensate biology in other disease areas. In ALS and DM1, a robust body of literature points to a causative role for condensate dysregulation. Leveraging state-of-the-art screening and proteomics techniques, Faze will identify proteins that are key components or regulators of disease-causing condensates, and then employ proprietary assays to discover small molecule drugs targeting these proteins.
I wrote a longer article about Faze Medicines on my web site.
Jean-Pierre
-
I am really excited!
Scientists, including one with which I corresponded last year have develop a peptide to target and degrade α-synuclein in Parkinson disease.
The peptide is assembled with the TAT sequence, a sequence specific to α-synuclein, and a sequence signaling degradation to the proteasome. See the previous discussion for more info.This time it is the seventh study on the topic of using peptides to remove a misfolded protein in a neurodegenerative disease (ALS, Alzheimer, Parkinson).
I know that another scientist in Australia is working on using a PROTAC (a very similar technology) to target TDP-43.It’s very easy to imagine that the same technology would apply to TDP-43, so it is probably a matter of months before it is done.
You can find a summary of Nature biology’s article on my website.
Log in to reply.