14 Mai The role of intestinal permeability

Posted at 13:59h in Pll Therapeutics by

The role of intestinal permeability in the development and chronicity of Amyotrophic Lateral Sclerosis (ALS)

ENCALS meeting 2021, 12 to 14 of May

More and more the Gut is highlighted in many diseases as playing a key role in Parkinson or ALS by being the open gate for many components as bacteria, fungal element, lipopolysaccharides (LPS), toxins and chemicals to move in the blood and in the brain which can have a role in the development of the disease and in its chronicity.

ALS is a multifactorial disease where around 5 to 10% of the cases have a genetic origin.

PLL THERAPEUTICS is developping a Drug product around the Neuro metabolism link to ALS tryptophan’s metabolites, reactive oxygen species, radical’s products … and to develop our formulation with the target to solve the gut leaking and avoid, due to some reasons in the change of microbiome for example, the increase of the intestinal permeability. In terms of effect, we will reduce the inflammatory process, decrease intestinal hyperpermeability, has an anti-oxidant effect, has an anti-free radical effect, has an antibacterial, antiviral and antifungal effect and rebalances neurological metabolisms causing degeneration of neurons and motor neurons.

Our first target was to validate the markers as circulating antibodies, which are the reflect of gut permeability and ALS disease, to create a companion diagnosis and to formulate our drug product with components able to decrease gut hyperpermeability and our ALS markers which will prove the stabilisation of the disease and improvement of the patient behaviour.

The way to transport our molecules is to use a dedicated GMP Grade Poly-L-Lysine (PLL) which :

  • will increase the half-life of the active molecules of the composition in the body,
  • will target the tissues or cells on which the composition molecules are active.
  • will allow the active ingredients to pass the blood-brain barrier and to penetrate into the cells, in particular into the neurons and the motor neurons.
  • will increase the stability and bioavailability of the active ingredient.

PLL-Butyric acid

PLL-Butyric acid

PLL conjugates in motoneurons and demonstrated that PLL conjugates are internalized in a chronic Experimental animal model.

Anti-conjugated methionine in motoneurons of the spinal cord (A,B).

Immunoreactivity disappeared in antibody preabsorption (C), antibody elimination (D),

Immunoreactivity was absent in vehicle animals (E) and in animals(F).

Methionine

The Drug product (DP) is divided in 2 DP :

  • DP1 dedicated to restore the function of intestinal permeability with for example the regulation of the mucus membranes in particular thanks to PLL-Acetate, PLL-Butyrate…
  • DP2 dedicated to be active in regulation of auto immune with PLL-retinoic for example and cell protector, in particular thanks of PLL-pantothenic acid and PLL-CoenzQ10 (protection at the level of mitochondrial chain)

RAT

In-vivo and ex-vivo permeability analysis in rats

After 3 days of DP1 on DSS ( Dextran Sulphate Sodium) 2% rats the gut permeability came back to normal (as on witness) and their behaviour became normal and the inflammation disappear.

rats

MICE

On Going trial with SOD1 mice with our DP1+DP2

First results after 15 weeks on Rotarod