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. These are in particular the peroxins, responsible for the protein import system and encoded by the PEX genes. Deficiency in any of the peroxins causes peroxisomopathy.
We have developed a screening test allowing, by LCMS-MS, to assay the specific lipid derivatives of peroxisomes. Several children will participate in this research program aimed at identifying drugs capable of limiting the impact of a peroxin deficiency.
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.
Apteeus is still looking for a relevant in vitro model of Lino disease.
repositioning TEE703 - 1482
Acid ceramidase deficiency
Ceramidase (acid) is a lysosomal enzyme involved in the recycling and catabolism of ceramides. Its deficiency results in the accumulation of ceramides in the lysosome and other organelles and disrupts the metabolism of cells (ORPHA: 333 and 2590). Proximal spinal muscular atrophy-progressive myoclonic epilepsy or SMA-PME syndrome is a manifestation of ceramidase deficiency affecting only about ten patients. This is an ultra-rare disease. Farber’s disease, whose symptoms are more severe and early, affect a few more patients.
After several months of individualized research, Apteeus identified several drug candidates. A child with this disease is currently receiving some of them. Apteeus remains involved in the biological monitoring of the child in order to obtain evidence proving the effectiveness of the treatment in limiting the worsening of symptoms. Other children with the same disease are also in the study.
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. A drug could eventually be useful as an add-on of enzyme replacement therapy.
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.
It is our technology based on liquid chromatography coupled with mass spectrometry that has enabled us to identify TEE886, a drug candidate that restores a normal level of very long fatty acids in the cells of an ACOX1 deficient child. The child is currently monitored to evaluate the progress of his pathology under treatment.
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 are currently working on the development of an in vitro model that would allow us to identify drugs capable of limiting the impact of this disease.
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.