# Gaucher Disease in Internal Medicine and Dentistry
## 5 Pharmacological Treatment  
There are two different therapeutic approaches to the GD: the ERT and the substrate reduction therapy (SRT) [115].  
ERT consists in an intravenous infusion of the enzyme glucocerebrosidase. The Food and Drug Administration (FDA), in 2022, approved three ERTs: imglucerase, valglucerase alfa and tali glucterase alfa [116]. Their use was approved for GD type 1 and type 3 without brain involvement, but they are not suitable for GD type 2 and type 3 with brain involvement, because they do not pass through the blood-brain barrier [115]. The purpose of ERT is to slow down the accumulation of the metabolites and prevent further organ damages. ERT acts on the symptoms, but not on the underlying genetic cause. Furthermore, antibodies against the ERT can be developed and, therefore, the treatment could result ineffective [115; 116].  
Instead, SRT consists in the oral administration of the substrates involved in the glycosphingolipid biosynthesis. The purpose of this therapy is to inhibit the accumulation of toxins and metabolites that can cause organs and tissues damages. The FDA approved two different SRT drugs, namely eliglustat and miglustat. Eliglustat does not pass through the blood-brain barrier, so it is mostly used for the treatment of GD type 1 [117]. The efficacy of eliglustat was considered similar to ERT and greater than miglustat [118]. On the other hand, miglustat can effectively be used for GD type 2 and 3, but, currently, its use is approved only for mild or moderate forms of GD type 1 in adults [115]. The main drawback induced by SRT is the inhibition of other metabolic pathways, such as intestinal disaccharidases, which leads to gastrointestinal disorders [119; 120].  
Other new therapeutic strategies are represented by chaperone therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) and gene therapy [116].  
Chaperone therapy restores GCase activity and corrects the misfolding of enzymes. Ambroxol, an inhibitor of GCase, is considered one of the potential candidates to the chaperone therapy [121]; it seems to have positive effects on adult neurological manifestations [122] and on pediatric skeletal and hematological alterations [123]. Unfortunately, it is a specific mutation-therapy [116].  
Allo-HSCT is a therapeutic strategy in which hematopoietic stem cells are transferred from a healthy donor to an affected recipient, in order to restore the physiological enzyme activity [116]. Allo-HSCT seems to operate either the improvement of visceral and skeletal alterations and the stabilization of neurological manifestations [124; 125; 126; 127].  
Another therapeutic approach is represented by gene therapy (GT), in which the gene is modified in order to treat the disease. It is distinguished into in vivo and ex vivo. In the first technique, the vector is injected into the patient; however, in the second one the vector is injected into the patient's cells and then they are retransplanted [116]. Over the years in the ex vivo technique, the gammaretroviral and the lentiviral vectors were tested [128; 129]. The most promising clinical trial is represented by GuardOne, based on a lentiviral vector [130; 131]. Currently, there is no clinical trial in which is tested in vivo GT for the GD treatment [116].