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Leucodistrophy-Repositioning: Laquinimod for Zellweger-Syndrome

Zellweger Syndrome spectrum, an orphan disease, is a peroxisomal biogenesis disorder with no treatment currently available. We offer the use of the clinically known Laquinimod (developed for multiple sclerosis) for the therapy of Zellweger Syndrom, for which we achieved successfully an in vivo proof-of-concept.

Challenge

Leukodystrophies are metabolic and/or hereditary CNS disorders. Among them are peroxisomal disorders, characterized by failure of organelle formation (peroxisome biogenesis disorders) or a defect in a single peroxisomal protein or a distinct peroxisomal pathway. Zellweger Syndrome spectrum (ZSS) is a peroxisomal biogenesis disorder. ZSS can be caused by mutations of the proteins required for peroxiome biogenesis (Pex proteins/peroxins).

Characteristic features: neuropathologically, neuronal migration defects and progressive symmetric white matter abnormalities in the CNS.

No treatment is currently available for ZSS. Severely affected patients die within months.

Our Solution

We offer Laquinimod and other quinoline-3-carboxamide derivatives for the therapy of Zellweger Syndrome (ZSS) or similar Leukodystrophies. Laquinimod is a quinoline-3-carboxamide derivative having a strong background in modulating innate immunity, i.e. in animal model of multiple sclerosis (MS) and has been evaluated for the treatment of MS.

 

Experimental: Laquinimod might be a promising therapeutic approach for ZSS and similar untreatable CNS conditions

Results

 

Improved walking ability with laquinimod treatment at the age of 4 months. The highly significant clinical improvement in motor coordination was maintained throughout the experiment. Laquinimod reduces microglia activation, demyelination and axonal loss. (figure source: WO2017042274A1)

Method

Cnp-Cre Pex5fl/fl Rag1-/- mice of both sexes received 25 mg/kg Laquinimod (n=11) or water (n=18) by oral gavage 6 out 7 day/week and treatment was initiated at the age of 6 week up to month 6. Behavioral analysis: was assessed with a balanced beam test. Mice were put on a beam and alloed to run toward a hiding box. After a training period, the time to pass a distance of 0,6m was measured (three repeats per time point). Histological and morphological analysis: according to standard protocols. Staining: Demyelination was evaluated (luxol fast blue, LFB), macrophage staining (mouse anti-L1 antibody MAC387), axonal density (Bielschowsky silver).

Advantages

  • Successful in vivo proof of concept.
  • Improved walking ability with laquinimod treatment.
  • Laquinimod reduces microglia activation (less inflammation).
  • Laquinimod reduces demyelination and axonal loss.
  • Clinical and histopathological in vivo evidence.
  • Similar pathological findings as in ZSS also occur in other metabolic or hereditary CNS disorders (Leukodystrophies) and could be potentially treated.

Applications

To be used for the therapy of Zellweger Syndrome or similar Leukodystrophies.

Developmental Status

In preclinics for Zellweger Syndrom. Laquinimod has been in clinics already.

 

Patent Status

EP + US patent applications based on WO2017042274A1 in the name of the University Medical Center of Goettingen and of Teva Pharmaceutical Industries Ltd. We look for a partner to license, develop and commercialize our innovative technology. This innovation is currently been exploited by the Universitätsmedizin Göttingen, Germany, in agreement with Teva Pharmaceutical Industries Ltd. Israel.

Contact

Dr. Martin Andresen
Patent Manager LifeSciences
E-Mail: mandresen@sciencebridge.de
Tel.: +49-551-30724150
Reference: BioT-1895-UMG

 

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