ProMIS Neurosciences introduces intrabodies against misfolded TDP-43 - Padirac Innovations' blog

ProMIS Neurosciences introduces intrabodies against misfolded TDP-43

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ProMIS Neurosciences is a biotechnology company focused on the discovery and development of antibody therapeutics intended for neurodegenerative diseases. This biotech has just released an update on several new programs including using intrabodies.

Until now their vaccine platform could rapidly and cost-effectively identify peptide antigens (MHC) and create specifically tailored antibody drugs, diagnostic tools and vaccines. They had work on such a vaccine for SOD1 ALS on the premise that ALS is a prion like disease where a prion like protein moves from cell to cell.

A vaccine is not really applicable to neurons as it would accelerate the progression of the disease, by making the immune system kill any defective neuron. Indeed from birth to death we use the same neurons. As most neurons do not reproduce, if they die, the host would die. So such a vaccine could only apply to the glial cells which are cells that reproduce every few hours.

We can see that making a vaccine for ALS is even more difficult than designing a molecular drug that targets a cell receptor.

Clearly any vaccine designer that wants to address the ALS has to experience a paradigm shift. The problem then is no more to kill the defective cell, but how to heal it.

Intrabodies are somewhat similar to antibodies.

An intrabody (from intracellular and antibody) works within the cell to bind to an intracellular protein. The antibody then activates some cellular mechanism, for example moving the binded protein from one place in the cell to another place, operating some transformation upon it or signaling it as to be recycled.

Intrabodies could be designed to promote degradation of toxic species of TDP-43 while preserving normal forms of the protein. Normal TDP-43 is essential for proper cell function.

One problem is how to introduce the intrabody in the cell. An intrabody is too huge to enter a cell via one cellular pore. A classical solution is to modify the DNA of cells to make the cell produce the intrabodies themselves. Many articles have described the use of gene therapy vectors to introduce intrabodies in a cell and at least two have described this technology for ALS.

An alternative solution is to use a cell penetrating peptide that, when inside the cell, has similar properties to intrabodies.

We have proposed a gene therapy against misfolded TDP-43 early in 2019, following articles by several teams in this area.

This therapy is also presented in our book on ALS research. An alternative with Cell Penetrating Peptides has been presented by the end of 2019.

We had the chance to discuss briefly such mechanisms in a few emails exchanged with Dr. Neil Cashman, ProMIS Neurosciences’ Co-Founder and Chief Science Officer in late November 2019.

ProMIS has now generated several highly selective intrabodies that bind to toxic TDP-43 protein aggregates within cells and promote their degradation without affecting normal TDP-43. This represent a promising first step in the eventual development of a safe and effective therapy for ALS, FTD and other TDP-43-driven disorders. Indeed those intrabodies still need to be introduced in the target cell with some gene therapy vector.

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