Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis

Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

show abstract

“…α-Mannosidosis could possibly be treated by bone marrow transplantation or enzyme replacement therapy (Lamzede) [153,154].…”

Section: α-Mannosidosismentioning

confidence: 99%

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…LSDs are a group of about 50 inborn errors of metabolism (IEM) characterized by the lysosomal accumulation of partially or non-degraded molecules. Therapies for LSDs treatment may include: (1) to promote the storage clearance by administering an exogenous functional enzyme, (i.e., ERT); (2) to prevent the lysosomal accumulation of substrates by inhibiting their synthesis (i.e., substrate reduction therapy); (3) to enhance the enzyme activity of a mutated protein (i.e., PC therapy); and (4) to perform a bone marrow or stem cell transplantation, especially in those diseases with central nervous system (CNS) involvement [30][31][32][33][34][35][36]. Molecular characterization of LSDs has shown that in most of the cases the disease is caused by missense mutations [37,38].…”

Section: Use Of Pharmacological Chaperones In Lsdsmentioning

confidence: 99%

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Diaz

Castillo

Rodríguez-López

et al. 2019

IJMS

View full text Add to dashboard Cite

The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. It this sense, it has been proposed that the use of small molecules, called pharmacological chaperones (PCs), can restore the folding, trafficking, and biological activity of mutated enzymes. PCs have the advantages of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity than enzyme replacement therapy. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

show abstract

“…The compound was granted marketing authorization in the European Union in April 2018 at a dose of 1 mg/kg body weight per week and is intended to be used “for patients with mild to moderate alpha‐mannosidosis for treating effects of the disease that do not involve the brain (non‐neurological effects)” (https://www.ema.europa.eu/en/medicines/human/EPAR/lamzede). In the United States, recombinant human alpha‐mannosidase received oprhan drug designation in 2006, in addition, “adeno‐associated virus serotype 6 containing human LAMAN cDNA,” an investigational gene therapy, was granted orphan drug designation in February 2018. Both compounds did not yet receive formal approval by the FDA for the treatment of alpha‐mannosidosis .…”

Section: Introductionmentioning

confidence: 99%

“…The clinical development program for velmanase alfa was reviewed by Harmatz et al, which included a post‐hoc multiple variable responder analysis for efficacy on pharmacodynamic, functional, and quality of life domains . Long‐term survival was not assessed in the clinical trials of velmanase alfa.…”

Section: Introductionmentioning

confidence: 99%

Ultra‐orphan lysosomal storage diseases: A cross‐sectional quantitative analysis of the natural history of alpha‐mannosidosis

Zielonka

Garbade

Kölker

et al. 2019

J of Inher Metab Disea

View full text Add to dashboard Cite

Alpha‐mannosidosis (OMIM 248500) is a rare lysosomal storage disorder caused by a deficiency of the enzyme alpha‐mannosidase. Recently, enzyme replacement therapy was approved in the European Union for the treatment of alpha‐mannosidosis, but evaluation regarding long‐term efficacy and safety is hard to assess due to missing quantitative natural history data, in particular survival. We performed a quantitative analysis of published cases (N = 111) with alpha‐mannosidosis. Main outcome measures were age of disease onset, diagnostic delay and survival (overall and by subgroup exploration). Residual alpha‐mannosidase activity and age of onset were explored as potential predictors of survival. STROBE criteria were respected. Median age of onset was 12 months. Median diagnostic delay was 6 years. At the age of 41 years 72.3% of patients were alive (N = 111). Residual alpha‐mannosidase activity (N = 34) predicted survival: Patients with a residual alpha‐mannosidase activity below or equal to 4.5% of normal in fibroblasts had a median survival of 3.5 years, whereas patients with alpha‐mannosidase activity above this threshold all survived during the observation period reported. Patients with age of onset above 7 years survived significantly longer than patients with age of onset below or equal to 7 years. Patient distribution was panethnic with hotspots in the United States and Germany. We defined age of onset, diagnostic delay, and survival characteristics in a global cohort of 111 patients with alpha‐mannosidosis by retrospective quantitative natural history modeling. These data expand the quantitative understanding of the clinical phenotype.

show abstract

Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis

Cited by 34 publications

References 28 publications

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Ultra‐orphan lysosomal storage diseases: A cross‐sectional quantitative analysis of the natural history of alpha‐mannosidosis

Contact Info

Product

Resources

About