A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease.

OBJECTIVE: Gaucher disease (GD) is a rare disorder linked to the absence/deficiency of glucocerebrosidase. GD can be treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The aim of this systematic review (SR) is to assess the effectiveness of drugs used for GD treatment. DATA SOURCES: Searches were conducted in PubMed and Scopus, in April 2021. The search strategies encompassed the name of the disease and of the drug treatments. Manual search was also conducted. STUDY SELECTION AND DATA EXTRACTION: Observational and interventional longitudinal studies evaluating ERT and SRT for GD were included. Single mean meta-analyses were conducted for each drug using R. DATA SYNTHESIS: The initial search retrieved 2246 articles after duplicates were removed. Following screening and eligibility assessment, 68 reports were included. The studies evaluated imiglucerase, velaglucerase alfa, taliglucerase alfa, miglustat, and eliglustat. The results showed that ERT is effective as a treatment in both naïve and experienced patients. Miglustat did not significantly improve blood outcomes in naïve patients and resulted in a decrease in the platelet levels of experienced patients. Eliglustat was mainly assessed for experienced patients and resulted in stable outcome values. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This extensive SR confirms the effectiveness of GD treatments in short- and long-term follow-ups. CONCLUSIONS: The results were favorable for all ERTs and for eliglustat. Based on the assessed evidence, miglustat did not achieved expressive results. However, all evidence should be interpreted considering its limitations and does not replace well-conducted randomized trials.

Characteristics of 26 patients with type 3 Gaucher disease: A descriptive analysis from the Gaucher Outcome Survey.

The Gaucher Outcome Survey (GOS) is an international disease-specific registry established in 2010 for patients with a confirmed diagnosis of Gaucher disease (GD), regardless of GD type or treatment status. Historically, there has been a limited understanding of type 3 GD (GD3) and its natural history in patients irrespective of their treatment status. Here, we describe the disease characteristics of patients with GD3 enrolled in GOS. As of October 2015, 1002 patients had been enrolled, 26 of whom were reported as GD3. The majority of patients with GD3 were from the US (13; 50.0%), seven (26.9%) were from the UK, three (11.5%) from Israel, and three (11.5%) from Brazil. No patients were of Ashkenazi Jewish origin. Median age of symptom onset was 1.4 (interquartile range: 0.5-2.0) years. The most common GBA1 mutation genotype was L444P/L444P, occurring in 16 (69.6%) of 23 patients who had genotyping information available. Nine patients reported a family history of GD (any type). Of 21 patients with treatment status information, 20 (95.2%) had received GD-specific treatment at any time, primarily imiglucerase (14 patients) and/or velaglucerase alfa (13 patients). Hemoglobin concentrations and platelet counts at GOS entry were within normal ranges for most patients, and there were no reports of severe hepatomegaly or of splenomegaly in non-splenectomized patients, most likely indicative of the effects of treatment received prior to GOS entry. This analysis provides information on the characteristics of patients with GD3 that could be used as the baseline for longitudinal follow-up of these patients.

Phase I and II clinical trials for the mucopolysaccharidoses.

INTRODUCTION: The mucopolysaccharidoses are lysosomal diseases characterized by deficient activity of one of the enzymes that degrades glycosaminoglycans. Treatment options are limited; therefore, new treatments are under investigation. Areas covered: We review the medicinal products for the treatment of mucopolysaccharidoses that are currently being investigated in phase I and phase II clinical trials. Expert opinion: The number of alternatives to treat MPS diseases increased dramatically in an attempt to provide therapy options for orphan MPS diseases and to address the unmet needs of the MPS that already have a treatment available. Intravenous enzyme replacement therapy (ERT) with fusion proteins, intrathecal/intracerebroventricular (ICV) ERT and gene therapy are the most promising strategies addressing the CNS manifestations. Stop-codon read-through, although proposed only for patients with nonsense mutations, might be useful in all MPS types. Substrate reduction therapy could also play a role in any MPS type, as anti-inflammatory drugs are also being tested. This new generation of therapies is now in clinical development and should bring new hope to MPS patients. As cost and logistics remain major challenges, especially for low- and middle-income countries, the possibility of having a one-time treatment such as gene therapy is anxiously awaited by affected families and healthcare systems.

Small Molecules: Substrate Inhibitors, Chaperones, Stop-Codon Read Through, and Beyond

Abstract Lysosomal storage disorders are rare genetic disorders due to deficient lysosomal activity, which leads to progressive accumulation of nonmetabolized substrates. Patient's clinical outcomes have significantly improved since the advent of enzyme replacement therapy, even though this therapeutic approach presents important limitations, such as immune reactions, low bioavailability of recombinant enzymes, and incapability to reach the central nervous system. New strategies based on gene therapy or small molecules have been proposed and tested as an alternative to enzyme replacement therapy or to complement it. Small molecules are orally administrated, no antigenic compound that can diffuse across cell membranes and distribute in steady-state concentrations, also reaching the central nervous system. Substrate reduction therapy, pharmacological chaperones, and stop-codon read-through enhancers are small molecules currently available for the treatment of lysosomal storage disorders. This article describes the characteristics of this class of compounds and the possible strategies to improve their efficiency in future development.

Neurological and cardiac responses after treatment with miglustat and a ketogenic diet in a patient with Sandhoff disease.

Sandhoff disease is a progressive neurodegenerative disorder characterized by accumulation of GM2 gangliosides. We describe a 6-year-old male with coarse facial features, developmental delay, refractory seizures, hypertrophic cardiomyopathy, who was later found to have Sandhoff disease. Previous studies have revealed that caloric restriction in combination with miglustat increased survival and motor behavior in mouse model of Sandhoff disease. These findings suggest that combination therapy may result in improved outcomes for patients with Sandhoff. Initiation of treatment with miglustat and a ketogenic diet was followed by improvement of the patient's seizure control and cardiac function. Further clinical investigation is required to better determine the benefit of management in late-onset forms of Sandhoff disease.