Institute of Biomolecular Chemistry-National Research Council of Italy (ICB-CNR)
Title: Therapy of rare diseases with small molecules: Fabry disease and PMM2-CDG
Host: Paula Videira
A large fraction of missense mutations associated with human diseases causes the destabilization of the affected proteins. Small molecules (SM) can enhance the activity of mutant proteins in the cell. Therapy with small molecules (SMT) represents a transversal approach that can be applied to unrelated rare diseases. SMs is used as a general term to indicate low molecular weight chemicals.
SMs can act directly, by binding and stabilizing the target mutant, or indirectly, enhancing the synthesis of the protein, inhibiting its degradation, favouring folding etc. We use the term pharmacological chaperone (PC) for the SM that act directly. SMT requires stratification of patients. In fact for any given disease, some genotypes are treatable, some are not. Large deletions, non-sense mutations are certainly non amenable, as well as missense mutations affecting the active site or preventing protein folding. In general, proteins that are intrinsically active and foldable, but are destabilized by a mutation, can be targets of SMT. Such proteins are cleared by the quality control system of the cell. Their stationary state concentration is lower than normal and, as a consequence of this, their activity in the cell is insufficient.
We are studying Fabry disease and PMM2-CDG.
Farbry disease is caused by mutations in lysosomal α-galactosidase , and a large proportion of mutations destabilize the enzyme and cause the accumulation of globotriaosylceramide. A pharmacological chaperone has already been approved but, regrettably, it is an inhibitor of the enzyme. The therapy is limited to a group of patients and needs a precise dosage and regimen to balance the stabilizing effect of the drug, which is required, versus the inhibitory effect, which is detrimental.
The therapeutic approach with small molecules can be extended to diseases without a cure such as PMM2-CDG. Since complete absence of PMM2 activity is not compatible with life, all genotypes associated to PMM2-CDG retain residual activity and are in principle amenable of treatment with SM and even a slight increase in PMM2 activity could alleviate symptoms.
Although phenotypically different, Fabry disease and PMM2-CDG are caused by protein instability which makes it plausible utilizing a common experimental approach for drug development.
Our ultimate goal in both cases are drugs that stabilize pathogenic instable mutants. In addition to drug repositioning, that should be considered as the first option in the development of pharmacological therapies for rare diseases, we are also interested in the search for new molecules among the natural products.
Researcher since 2001 at the Institute of Biomolecular Chemistry-Pozzuoli (Naples-Italy), National Research Council of Italy
Degree in Chemistry and PhD in Biochemistry from the University of Naples Federico II.
Keywords: Protein chemistry, enzymology, rare diseases, drug discovery, pharmacological chaperone, NMR spectroscopy, metabolomics
- 1989-95: Enzymes from thermophilic bacteria: Purification and characterization of aminotransferases from the thermophilic archaebacterium Sulfolobus solfataricus, from the hyperthermophilic archaebacteria Pyrococcus furiosus and Thermococcus litoralis. Cloning and expression in E. coli of thermostable indole-3-glycerol-phosphate synthase from Sulfolobus solfataricus and study on the main features that confer thermal stability.
- Recent interests:
i) Pharmacological chaperones: identification of targets and development of drugs. Fabry disease and PMM2-CDG (congenital disorder of glycosylation Ia or Jaken disease)
ii) Purification and characterization of proteins/enzymes for biotechnological applications: Glycosyl hydrolases from marine organisms and exploitation of their potential for biotechnological applications (fine and pharmaceutical chemistry, agrochemistry, and so on). Biomolecules (proteins, lipids, ect.) from biomaterials.
iii) Application of NMR spectroscopy to metabolomic studies (aiming to characterize and distinguish milks and dairy products) and to structural characterization of proteins and peptides.
SCIENCE OUTREACH (selected activities)
- from 2017: Coordinator of DidaLab@ICB (Laboratory for didactic activities).
- from 2015. Scientific coordinator of “Piccolo Museo della Scienza”. http://collection.na.icb.cnr.it/
- from 2015: Projects of working training for students according to the Italian law 107/2015
- from 2016: Divulgation and formation activities concerning biomolecular chemistry, aimed to support the social/scholastic/employment inclusion of children with autism – collaboration agreement between AutismAid Onlus and ICB-CNR
- October 2016-May 2017. "Together in the real and in the virtual worlds for a sustainable chemistry". Project committed to the divulgation of Science dedicated to teachers of intermediate schools, MIUR
- from 2015: Events within the European Biotech Week (2015, 2016, 2017, 2018).