Introduction:
Description of the Problem:
Enzyme replacement therapy (ERT) makes a significant impact on the clinical manifestations and quality of life of patients with Gaucher disease (GD) . The goals of therapy focus mainly on platelets, hemoglobin, spleen, liver, bones and growth parameters for children.
ERT is mostly effective in patients with type 1 GD; still some patients don't achieve normalization or near normalization of the therapeutic targets . Glucosylsphingosine (LysoGb1) is the most specific and sensitive, and hence is probably the best currently available GD biomarker. A level of LysoGB1 \< 140 ng/ml is considered a marker for controlled GD (personal communication).
Patients with GD may also experience chronic fatigue that causes functional disability and adversely affects quality of life . The fatigue severity scale (FSS) is a 9-item tool; each item is scored on a scale from 1 to 7, with a mean score of 4 or higher considered to represent significant fatigue . Patients with GD have improvements in fatigue within 6 months of starting ERT, and that it may be among the first symptoms to show significant improvement. Using the FSS, no association was identified between fatigue and time on ERT (P = 0.57). In a survey of patients with Type 1 GD and physicians, patients ascribed greater importance to fatigue than other disease parameters, while physicians placed more emphasis on objective measures of visceral and hematologic disease manifestations.
B. Pharmacological chaperones:
The underlying pathology in GD is not only due to the lysosomal accumulation of glucosylceramide in the tissue macrophages. There is a broader spectrum of lysosomal dysfunction and various intracellular and molecular changes that could lead to additional disease manifestations that are not affected by ERT. In particular, the retention of the mutant glucocerebrosidase within the endoplasmic reticulum (ER) which causes ER stress, unfolding protein response (UPR) and early ER associated degradation (ERAD) . These ER related changes are the rationale behind the use of pharmacological chaperones which are capable of partially removing the misfolded proteins from the ER, thereby relieving ER stress, avoiding ERAD and preventing consequent complications . Pharmacological chaperones increase glucocerebrosidase activity by stabilizing the enzyme in the lysosome.
C. The Therapy to be Examined:
Ambroxol hydrochloride, an over-the-counter antitussive available in many markets, was identified as an interesting pharmacological chaperone. In addition to a mucolytic action, ambroxol has antioxidant and anti-inflammatory properties . Importantly, ambroxol therapy was found safe when given to pregnant women for prevention of neonatal respiratory distress syndrome. In skin fibroblasts derived from Type 1 and Type 2 GD patients, ambroxol increases both the lysosomal fraction and the enzymatic activity of several mutant glucocerebrosidase variants with low toxicity . Incubation of human induced pluripotent stem cell macrophages from patients with type I-III GD with ambroxol corrected the abnormal phenotypes of GD macrophages. Ambroxol, has a small molecule chaperone, has been shown in healthy nonhuman primates to cross the blood-brain barrier, and increase brain glucocerebrosidase activity . In Drosophila neuropathic model, ambroxol was show to alleviate the neuronopathic phenotype through reducing ER stress \].
The investigators have performed a pilot study to test the tolerability and efficacy of ambroxol as a pharmacological chaperone in patients with symptomatic, type 1 GD who present with measurable disease parameters but are not receiving ERT in order to provide proof of concept and/or ascertain the suitability of ambroxol for a larger clinical trial \[29\] . The Israeli Ministry of Health Form 29c was employed to prescribe ambroxol for off-label use. Twelve patients were dispensed 2 capsules of 75 mg of ambroxol daily for 6 months. One patient withdrew because of a hypersensitivity reaction, one because of elective splenectomy. No patient experienced clinically relevant deterioration in disease parameters measured. One patient achieved a robust response relative to baseline: +16.2% hemoglobin; +32.9% platelets; -2.8% liver volume; and -14.4% spleen volume. Three patients elected to continue on ambroxol for a further 6 months: hemoglobin levels and liver volumes were relatively stable, but platelet counts further increased in the above patient (+52.6% from baseline) and spleen volumes decreased further in all three patients (-6.4%, -18.6%, and -23.4% from baseline) . More recently, a pilot study of ambroxol was done in five patients with neuronopathic GD in combination with enzyme replacement therapy \[30\]. High-dose oral Ambroxol had good safety and tolerability with clinical and laboratory signs of activity.
Thus, ambroxol, an oral available drug on the market, may be a safe option for GD patients with potential disease-specific efficacy and should be expanded into a clinical trial using higher doses and placebo-controlled design \[31\]. The investigators propose to start with a phase II study for patients with type 1 GD and suboptimal response to ERT. In addition the investigators plan to open an international registry of patients with GD currently receiving ambroxol (off study).
