development, FOCUSSING & OPTIMISATION



To discover, patent and develop innovative treatments


ProGeLIFE develops two patented families of molecules, with administration routes fitting paediatric population and each targeted disease.

PGL201
The patented molecule PGL201 is in early development and aims to offer a treatment for Progeria patients.

PRECLINICAL PROOF OF CONCEPT:

> PGL201 degrades progerin
> blocks progerin synthesis
> slow down accelerated aging caused by the accumulation of progerin in cell nucleus

inhibits the secretion, by progerin-expressing cells, of proteins triggering senescence of neighboring cells

SYSTEMIC ADMINISTRATION ROUTE

PGL101
The patented molecule PGL101 is dedicated to patients with Xeroderma pigmentosum (« Children of the Moon » disease).

The galenic formulation (cream) is in the finalization phase, for a topical application of the drug to specifically target skin cells. 

PRECLINICAL PROOF OF CONCEPT:

 > PGL101 slows down the appearance of UV-induced precancerous lesions and skin cancers 
> decreases the number and volume of these tumors 
> decreases  the risk of recurrence of UV-induced skin lesions 

> facilitates surgical treatment, which reduces the size of the scars it causes
> improves the life of XP patients and their families

TOPICAL ADMINISTRATION MODE

Because of their mechanisms of action, these two families of compounds may benefit other diseases, whether rare or more common.




ProGeLife développe des médicaments pour deux maladies génétiques rares avec
                                    vieillissement accéléré et prématuré

PGL201 and PGL101
adapted and
effective strategies

PGL201, a proteasome inhibitor
PGL201, an innovative progerin-clearing drug

  • ProGeLife is developing an innovative strategy to clear Progerin through PGL201 drug, a proteasome inhibitor.
  • Two different tools are involved in degradation of normal or mutated proteinsProtein : Molecule made by several tens or thousands aminoacids. within cells : proteasomeproteasome : Macromolecular enzymatic complex, localised in cytosol and in nucleoplasm. Made of several subunits. Some of them are ATPases. Other are proteases whose activity required a neutral pH. Involved in protein degradation into peptides. Proteins to be degraded have to be tagged by ubiquitin. Proteasome and lysosome are the main two ways allowing protein degradation within cells., a macromolecular protease complex associating several subunitsSubunit : A protein from a macromolecular complex made of several different or identical proteins., and lysosomelysosome : Acidic pH cell compartment rich in enzymes digesting all types of biological molecules (sugars, lipids, proteins, nucleic acids) either originating from inside cell or from extracellular space., a membrane compartment.



Pre-clinical proofs of concept
from cultured Progeria patient cells
80%
DECREASE IN PROGERIN AMOUNT
in cultured cells from patients affected by Progeria or Progeria-like diseases
  • Proteasome inhibitor PGL201, as well as two other drugs belonging to the same family, PGL202 and PGL203, induced Progerin degradation in cultured dermal fibroblasts from Progeria patients.
  • Two FDA- and EMA-approved proteasome inhibitors, Bortezomib (BTZ), Carfilzomib (CFZ), for the treatment of lymphocytic leukemias failed to induce progerin degradation.
  • PGL201 also reduced the amount of protein of the same family than progerin in cultured cells from patients affected by rare diseases, exhibiting a similar physiopathological mechanism than Progeria.

Pre-clinical Proofs of concept
FROM PROGERIA MICE MODEL DESIGNED IN THE ACADEMIC LAB
80%

DECREASE IN PROGERIN AMOUNT

in Progeria mice model

 

  • Intramuscular injection of PGL201 in Progeria mice model resulted in the degradation of progerin and reduced progerin biosynthesis by muscle cells.
     

     

PRE-CLINICAL PROOF OF CONCEPT
FROM A MICE MODEL REPRODUCING XERODERMA PIGMENTOSUM DISEASE

50%
DECREASE IN BOTH NUMBER AND VOLUME OF SKIN CANCERS
in mice model reproducing human Xeroderma pigmentosum disease
PGL101
a successful strategy
to decrease both number and volume of
UV-induced skin cancers
NADPH oxidase type 1 ( NOX1NOX1 : Plasma membrane complex, associating 2 membrane (p67 and p22) and 3 cytosolic (Rac1, NOXA1, NOXO1) subunits. Activated NOX1 produces Reactive Oxygen Species (ROS) through the catalytic subunit p67. ) is activated by UV exposure
NOX1 inhibition by peptide PGL101 results in the slowing down of skin cancer development through the blocade of ROSROS : Acronym for Reactive Oxygen Species. Oxygen derivatives, produced among others by NADPH oxidase complexes, among them NOX1. Hydrogen peroxide (H2O2) is a ROS. In small amounts and for a short period of time, ROS are communication signals. Higher ROS concentrations are responsible of oxidative lesions of cell molecular components, particularly DNA. production by NOX1


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In control mice of in mice reproducing the human Xeroderma pigmentosum disease, the topical administration of PGL101 slows down skin cancer development or reduces UV-induced skin cancer volume.

  • Prevention of UV-induced skin cancers : a topical administration of PGL101 for 6 weeks before UV-irradiation (3 times a week) resulted in a 50% decrease in skin cancer number and volume both in control mice and in mice reproducing human XPXP : Acronym for Xeroderma Pigmentosum, a group of rare genetic diseases characterized by a defect in one of the DNA repair pathways. Depending on the mutated protein, eight XP diseases are known, XPA to XPG and XPV. disease.
  • Treatment of UV-induced skin cancers : when skin cancers have been established after UV-exposure, a topical administration of PGL101 for 6 weeks resulted in a 50% decrease in skin cancer volume both in control mice and in mice reproducing human XPXP : Acronym for Xeroderma Pigmentosum, a group of rare genetic diseases characterized by a defect in one of the DNA repair pathways. Depending on the mutated protein, eight XP diseases are known, XPA to XPG and XPV. disease.

PGL101 : a topical drug in order to prevent the development of UV-induced skin cancers in three other populations at risk. Skin tumors are characterized by a very high recurrence risk. 

  • Solid organ transplant recipients (SOTR) under immunosuppressive treatment to avoid organ transplant rejection : 130,000 new transplantations are completed each year worldwide. UV-induced non melanoma skin cancers developped in around 40% SOTR in the 5 years after transplantation.
  • More than 20 millions patients (USA + Europe) are under immunosuppressive treatment for other diseases (Crohn disease, rhumatoid arthritis…).
  • Il the general (elderly) population (USA + Europe), about 13 millions of new UV-induced non melanoma skin cancers develop each year as well as 130 millions of new lesions of actinic keratosis.

PGL101 : a topical solution to decrease UV-induced skin cancer volume, thus facilitating surgical excision, minimising scars and reducing the need for aesthetic repair often required (skin graft…).

A drug (PGL201) decreasing by
80%
progerin amount
A drug (PGL101) decreasing by
50%
both number and volume of UV-induced skin cancers