Hunter Syndrome, MPS2
Mucopolysaccharidosis type II (MPSII) (or Hunter syndrome) is a disease which affects the function of a lysosomal enzyme called iduronate-2-sulfatase. This enzyme is able to digest glycosaminoglycans (long linear polysaccharides) and its deficiency leads to an accumulation of these polysaccharides in whole the body. This accumulation impairs the biological balance.
Apteeus commits to this project in order to test 2600 compounds from its library on cells from a patient affected by MPSII. Based on LC-MS technology, Apteeus investigates to restore the level of glycosaminoglycans. One candidate drug is currently under new investigation. It could be useful as an add-on of enzyme replacement therapy for adressing central symptoms.
Acid ceramidase deficiency
La céramidase (acide) est une enzyme lysosomale impliquée dans le recyclage et le catabolisme des céramides. Sa déficience entraîne une accumulation des céramides dans le lysosome et d’autres organites et perturbe le métabolisme des cellules (ORPHA:333 et 2590). Le syndrome d’amyotrophie spinale proximale-épilepsie myoclonique progressive ou SMA-PME est une manifestation de la déficience en céramidase n’affectant qu’une dizaine de patients. Il s’agit d’une maladie ultra-rare. La maladie de Farber, dont les symptômes sont plus sévères et précoces concernent elle un peu plus de patients.
Après plusieurs mois de recherche individualisée, Apteeus a identifié plusieurs candidats médicament. Plusieurs enfants atteints de cette maladie reçoivent actuellement notre candidat médicament TEE1482. Apteeus reste pleinement impliqué dans le suivi biochimique des enfants et collecte des éléments qui pourraient démontrer l’effet du traitement et limiter l’aggravation des symptômes.
Fumarase is an enzyme mainly involved in the krebs cycle, essential for the production of energy by the mitochondria. Its deficiency leads to fumaric aciduria (ORPHA:24), a disease that disrupts the normal development of the child. It is an ultra-rare disease with about 100 cases reported to date. Fumarate hydratase deficiency is principally known to predispose to certain cancer.
Apteeus is looking for a relevant in vitro model based on the use of Lino cells. We also established a collaboration with Dr. Frezza in Cologne.
The peroxisome is a cellular organelle involved in the metabolism of fatty acids and amino acids, the reduction of reactive oxygen derivatives and the synthesis of plasmalogens. The proteins necessary for peroxisomes are synthesized outside of the latter, in the cytosol. Peroxins are responsible for proteins import into the peroxisome and are encoded by the PEX genes. Deficiency in one of those peroxins causes peroxisomopathy.
We developed an original screening assay based on the use of patient primary cells to follow the biogenesis of peroxisomes. We have teste more than 2500 drugs and confirmed some of the results published in the litterature. We have also identified a new family of molecules able to improve the biogenesis of the peroxisomes in the patient cells. We are currently caracterizing those new promising candidate drugs.
The ACOX1 protein, for Acyl-CoEnzymeA oxidase type 1, is a peroxisomal protein involved in the beta-oxidation of very long chain fatty acids in the peroxisome (ORPHA:2971). Peroxisomal acyl-CoA oxidase deficiency is an ultra-rare disorder. Its prevalence is unknown. Only a few dozen cases have been described in the medical literature.
Thanks to our technology based on liquid chromatography coupled with mass spectrometry, we identified TEE886, a drug candidate that restores a normal level of very long fatty acids in the cells of an ACOX1 deficient child. The child was compassionately treated with the candidate drug and monitored to evaluate the progress of his pathology under treatment. A case report is currently produced and will be published soon.
Krabbe disease (or globoid cell leukodystrophy) is a lysosomal disorder affecting the white matter of the central (CNS) and peripheral nervous systems (PNS) (ORPHA:487). It is a deficiency of the enzyme galactocerebrosidase (GALC) that causes the accumulation of psychosine toxic to oligodendrocytes and consequently demyelination of the CNS and PNS.
We developped an brand new in vitro assay using primary patient cells and we tested more than 2500 active pharmaceutical ingredient. We are currently analysing the results.
d-bifonctionnal protein deficiency
Bi-functional protein D is a peroxisomal enzyme involved in the beta-oxidation of very long fatty acids. Its deficiency leads to an accumulation of very long fatty acids and disrupts the other functions of the cell (ORPHA:300). D-bifunctional protein deficiency is estimated to affect 1 in 100,000 newborns. The prevalence is very low, it is an ultra-rare disorder.
Apteeus used liquid chromatography coupled with mass spectrometry to highlight the accumulation of very long chain fatty acids in Noé’s cells in culture. Miniaturized and automated, the test has made it possible to identify several drugs. Unfortunately time and disease have been against us. We were unable to assess the benefit-risk balance of its use on Noé. This program will benefit to other patients suffering from the same disorder.
PLAN, or PLA2G6-Associated Neurodegeneration, one of the NBIA (Neurodegeneration with Brain Iron Accumulation) disorders is caused by mutation in PLA2G6 Gene. PLA2G6 is coding a phospholipase A2 that is implicated in the metabolism of lipids. It is essential to maintain membrane integrity and functionality of the cells.
We are currently developping a screening assay using patient cells.