in-vitro-enzyme-measurement-to-test-pharmacological-chaperone

<em>In Vitro</em> Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease

The use of personalized medicine to treat rare monogenic diseases like lysosomal storage disorders (LSDs) is challenged by complex clinical trial designs, ...

University Federico II

A promising strategy for the treatment of genetic diseases, pharmacological chaperone therapy, has been proposed recently. It exploits small molecules which can be administered orally, reach difficult tissues such as the brain and have low cost. This strategy has a vast field of application. In order to make drug development as fast as possible, it is important to exploit drug repositioning. We evaluated the impact and limitations of this approach for rare diseases and we provide a shortcut in finding drugs for off-target usage.

Drug repositioning can accelerate discovery of pharmacological chaperones.

Fabry disease is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable than the wild type protein. These mutants can be stabilized by small molecules which are defined as pharmacological chaperones. The first chaperone to reach clinical trial is 1-deoxygalactonojirimycin, but others have been tested in vitro. Residual activity of GLA mutants has been measured in the presence or absence of pharmacological chaperones by several authors. Data obtained from transfected cells correlate with those obtained in cells derived from patients, regardless of whether 1-deoxygalactonojirimycin was present or not. The extent to which missense mutations respond to 1-deoxygalactonojirimycin is variable and a reference table of the results obtained by independent groups that is provided with this paper can facilitate the choice of eligible patients. A review of other pharmacological chaperones is provided as well. Frequent mutations can have residual activity as low as one-fourth of normal enzyme in vitro. The reference table with residual activity of the mutants facilitates the identification of non-pathological variants.

The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations.

Rare diseases represent a challenge for physicians because patients are rarely seen, and they can manifest with symptoms similar to those of common diseases. In this work, genetic confirmation of diagnosis is derived from DNA sequencing. We present a tutorial for the molecular analysis of a rare disease using Fabry disease as an example.

Article	Year
Drug repositioning can accelerate discovery of pharmacological chaperones. Orphanet journal of rare diseases\| PubMed ID: 25947946	2015
The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations. International journal of molecular sciences\| PubMed ID: 27916943	2016
E-Learning for Rare Diseases: An Example Using Fabry Disease. International journal of molecular sciences\| PubMed ID: 28946642	2017

Valentina Citro

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