Vilazodone Hydrochloride br Current therapies for metabolic

Current therapies for metabolic diseases Inborn errors of metabolism caused by deficiency of particular enzymes due to loss of function mutations or deletions have been treated by decreasing the intake of the enzymatic substrate, supplementation with an essential cofactor or vitamin, increasing metabolism by enzyme replacement therapy (ERT), or more recently, by gene therapeutic approaches [90]. For some diseases, substrate intake can be decreased by dietary modification. The most advanced example of this approach has been phenylketonuria, which is managed by newborn diagnosis and institution of a restricted diet that avoids food proteins and dietary supplements, e.g., the artificial sweetener aspartame, which are rich in toxic phenylalanine. In some metabolic diseases of defective carboxylation, e.g., biotinidase deficiency, or holocarboxylase synthetase deficiency, defects in the biotinylation of protein substrates can be treated by lifelong supplementation with biotin. Enzyme replacement therapy in which purified or recombinant enzyme has been used to replace adenosine deaminase (ADA) in some types of severe combined immunodeficiency syndrome (SCIDS), glucocerebrosidase in Gaucher disease, Vilazodone Hydrochloride alpha-glucosidase in Pompe disease, and alpha-galactosidase A in Fabry disease have all been used [91]. Efforts to increase enzymatic activity by gene therapy are still experimental, but offer the promise of permanent correction of metabolic defects. Early strategies have focused on the use of viral or non-viral vectors to introduce wild-type copies of a defective enzyme into affected cells, either by transplantation of a patient's own cells after in vitro gene transduction or by in vivo injection. The recent discovery and rapid development of the CRISPR/Cas9 system as a method to modify the mutant gene sequence, thereby normalizing it, make gene editing a real possibility.
ALDH activators—a new strategy for treatment of metabolic disease The Mochly-Rosen laboratory has developed a series of small molecule activators for several members of the ALDH family of enzymes. These small molecules, called Aldas, were designed to increase enzymatic activity of specific ALDH isoforms. One such activator of ALDH2 enzymatic activity, is Alda-1 [N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide], a chemical chaperone which corrects the disturbed helix in the mutant enzyme (Fig. 3). Alda-1 increases the stability of both the wild-type and mutant ALDH2 tetramer. In addition, Alda-1 prevents ALDH inactivation by reactive aldehydes and acts as an allosteric agonist, increasing the catalytic activity of the enzyme [66]. Alda-1 appears to be safe, as it has been used in many animal studies and shows no toxicity [36,39,92] and one Alda was found to be safe in a small phase 1 clinical study (unpublished data). A strategy that can be used as an alternative to or complementary to Alda-1 treatment is to recruit other members of the ALDH family of enzymes to take over the role of ineffective or mutant ALDH2 to increase the detoxification of genotoxic aldehydes, like acetaldehyde. Alda-89 was developed by the Mochly-Rosen lab to direct ALDH3A1 (another member of the ALDH family of enzymes) to metabolize acetaldehyde, which is not normally a substrate for ALDH3A1 [93]. Using computer simulated docking, Alda-89 was found to bind in the catalytic pocket of ALDH3A1, near catalytic cysteine 243, where it is available to direct acetaldehyde to the active site [93]. Using enzyme activation and recruitment strategies like these may increase the number of targets available to treat genetic metabolic diseases. Potential clinical application of ALDH2 activators, in FA include both delaying or preventing marrow failure or AML as well as preventing post-BMT incidence of secondary malignancies. Because ALDH3A1 levels are high in the airways, mouth and upper digestive system, which is where FA patients tend to have high incidence of solid tumors as secondary malignancies, Alda-89 or other ALDH3A1 activating compounds may be a cancer chemopreventive in these patients.