"Substrate reduction therapy "

Substrate reduction therapy (SRT) has been proposed as a new gene therapy for Fabry disease (FD) to prevent the formation of globotriaosylceramide (Gb3). Nanomedicines containing different siRNA targeted to Gb3 synthase (Gb3S) were designed. Formulation factors, such as the composition, solid lipid nanoparticles (SLNs) preparation method and the incorporation of different ligands, such as gold nanoparticles (GNs), protamine (P) and polysaccharides, were evaluated. The new siRNA-golden LNPs were efficiently internalized in an FD cell model (IMFE-1), with GNs detected in the cytoplasm and in the nucleus...

OBJECTIVES: To estimate the economic burden of patients diagnosed with Gaucher disease at a public hospital from a societal perspective. METHODS: Data from 30 Gaucher patients visiting the Genetic Clinic of the Department of Pediatrics at the study site in Mumbai was analyzed between January 2019 and January 2021. A cost of illness analysis was undertaken to estimate direct, indirect and intangible costs. Costs in treated and treatment naive groups were compared...

Most rare diseases(orphan diseases) still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to expedite the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs...

Thank you for allowing us the opportunity to respond to the commentary from Mistry and colleagues (Comment: The two substrate reduction therapies for type 1 Gaucher disease are not equivalent) [...].

Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA), and methylmalonic aciduria (MMA). Isobutyryl-CoA dehydrogenase (ACAD8) and short/branched-chain acyl-CoA dehydrogenase (SBCAD, ACADSB) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences...

Background: A salutary effect of treatments for Gaucher disease (GD) has been reduction in the incidence of avascular osteonecrosis (AVN). However, there are reports of AVN in patients receiving enzyme replacement therapy (ERT), and it is not known whether it is related to individual treatments, GBA genotypes, phenotypes, biomarkers of residual disease activity or anti-drug antibodies. Objective: Prompted by development of AVN in several patients receiving ERT, we aimed to delineate the determinants of AVN in patients receiving ERT or eliglustat substrate reduction therapy (SRT) during 20 years in a tertiary referral center...

BACKGROUND: Since the results of previous studies regarding the safety and efficacy of miglustat in GM2 gangliosidosis (GM2g) were inconsistent, we aimed to assess miglustat therapy in GM2g patients. METHODS: This study followed the latest version of PRISMA. We included the observational or interventional studies reporting GM2g patients under miglustat therapy by searching PubMed, Web of Science, and Scopus. Data extracted included the natural history of individual patient data, as well as the safety and efficacy of miglustat in GM2g patients...

CONTEXT: Gaucher's disease (GD) is a rare inherited metabolic disorder caused by the defective activity of glucocerebrosidase. Enzyme replacement therapy (ERT) and substrate reduction therapy are the treatment of choice. Total splenectomy has a role when the child develops complications of massive splenomegaly. There are only a few case series of partial splenectomy in GD in the pediatric age group. AIMS: To study the role, technical feasibility, and challenges of partial splenectomy in children with GD with hypersplenism...

In their paper, Hughes et al. [...].

The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. Biallelic variants in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder characterised by loss of GCase activity and aberrant intracellular accumulation of GCase substrates. Carriers of GBA1 variants have an increased risk of developing Parkinson disease (PD), with odds ratio ranging from 2.2 to 30 according to variant severity. GBA1 variants which do not cause GD in homozygosis can also increase PD risk...

Ambroxol hydrochloride (ABX), an oral mucolytic drug available over the counter for many years, acts as a pharmacological chaperone for mutant glucocerebrosidase, albeit at higher doses. Proof-of-concept reports have been published over the past decade on all three types of Gaucher disease (GD). Here, we assess the safety and efficacy of 12 months of 600 mg ambroxol per day in three groups of Type 1 GD patients with a suboptimal response to enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), defined as platelet count < 100 × 103 /L, lumbar spine bone density T-score < -2...

BACKGROUND: Continuation of standard management of Gaucher disease (GD) has been challenging during the COVID-19 pandemic, resulting in infrequent/missed infusions and follow-up appointments. Little data are available on the consequences of these changes and on the SARS-CoV-2 vaccinations in German GD patients. METHODS: A survey with 22 questions about GD management during the pandemic was sent to 19 German Gaucher centres. It was answered by 11/19 centres caring for 257 GD patients (almost ¾ of the German GD population); 245 patients had type 1 and 12 had type 3 GD; 240 were ≥ 18 years old...

Gaucher disease (GD) causes the accumulation of glucocerebrosides in various organs, resulting in hepatosplenomegaly, anemia, decreased platelet counts, and bone disorders. Glucosylsphingosine accumulates in the brain and causes central nervous system (CNS) disorders. GD can be classified into type I (without CNS disorders), II, and III. Substrate reduction therapy (SRT) is an oral therapy that improves patients' quality of life; however, its effect on type III GD is unknown. We administered SRT to GD type I and III patients and found it effective...

Glucosylsphingosine (lyso-Gb1), the deacylated form of glucocerebroside, was shown to be the most specific and sensitive biomarker for diagnosing Gaucher disease (GD). The aim of this study is to assess the contribution of lyso-Gb1 at the time of diagnosis for treatment decisions in naïve patients with GD. Newly diagnosed patients from July 2014 to November 2022 were included in this retrospective cohort study. The diagnosis was done by sending a dry blood spot (DBS) sample for GBA1 molecular sequencing and lyso-Gb1 quantification...

Lysosomal storage diseases (LSDs) are a group of metabolic inborn errors caused by defective enzymes in the lysosome, resulting in the accumulation of undegraded substrates. LSDs are progressive diseases that exhibit variable rates of progression depending on the disease and the patient. The availability of effective treatment options, including substrate reduction therapy, pharmacological chaperone therapy, enzyme replacement therapy, and bone marrow transplantation, has increased survival time and improved the quality of life in many patients with LSDs...

Eliglustat is an orphan medicine used for long-term treatment of Gaucher disease type 1 (GD1) in adults. GD1 is a genetic condition, in which glucosylceramide builds up in the body, typically in liver, spleen, and bone. Clinical signs and symptoms of the disease are anemia, tiredness, easy bruising, hepatosplenomegaly, bone pain, and fractures. Eliglustat works by blocking glucosylceramide synthase (substrate reduction therapy). This medicine is subject to additional safety monitoring by regulatory authorities in the European Union...

Mucopolysaccharidosis type I (MPS I) is a metabolic genetic disease caused by the deficiency of a lysosomal enzyme involved in glycosaminoglycans (GAGs) degradation. MPS I cells have a constant level of GAG synthesis, but disturbed degradation means that GAGs accumulate progressively, impairing cell metabolism. GAG metabolism can be modulated by flavonoids, and these are being studied as therapeutics for MPS. We have optimised the protocol for obtaining fibroblasts and hepatocytes from the MPS I murine model and characterised the cells for their suitability as an in vitro model for testing compounds with therapeutic potential...

Late-onset Pompe disease (LOPD) is a genetic myopathy causing skeletal muscle weakness and severe respiratory impairment, due to the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) leading to lysosomal glycogen accumulation along with other complex pathophysiological processes. A major step for treatment of Pompe disease was reached in 2006 with the marketing of alglucosidase alfa, a first enzyme replacement therapy (ERT) that showed a significant motor and respiratory benefit. However, efficacy of alglucosidase alfa is limited in LOPD with a loss of efficacy over time, promoting research on new treatments...

Historically, disease burden and treatment responses in patients with Gaucher disease (GD) was assessed by monitoring clinical data, laboratory, imaging, chitotriosidase (CHITO), and other biomarkers; however, these biomarkers lack specificity and CHITO is uninformative in patients heterozygous or homozygous for the CHIT1 c.1049_1072dup24 variant. Recently, glucosylsphingosine (lyso-Gb1 ), a sensitive and specific GD biomarker, has been recommended for patient monitoring. Furthermore, studies measuring lyso-Gb1 and CHITO in patients on long-term treatment with enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT) reported as group data show a reduction in both analytes, yet individualized patient data are generally unavailable...

Gaucher disease (GD) is a rare inherited lysosomal metabolism disorder, characterized by an accumulation into lysosomes of reticuloendothelial cells, especially in the bone marrow, spleen, and liver of β-glucosylceramide and glucosyl sphingosine, which is its deacylated product. Impaired storage is responsible for a chronic inflammatory state at the sites of accumulation and together represents the pathophysiological cause of GD. GD is a progressive, multi-organ chronic disorder. Type 1 GD is the most prevalent form, with heterogeneous multisystem involvement and different severity of symptoms at any age...