Scaffolds for Sustained Release of Ambroxol Hydrochloride, a Pharmacological Chaperone That Increases the Activity of Misfolded β‐Glucocerebrosidase

To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat lysosomal storage disorders (LSDs). Methods Assessment of the drug pipeline through analysis of the FDA database for orphan drug designations with descriptive and comparative statistics. Results Between 1983 and 2019, 124 orphan drug designations were granted by the FDA for compounds intended to treat 28 lysosomal storage diseases. Orphan drug designations focused on Gaucher disease (N = 16), Pompe disease (N = 16), Fabry disease (N = 10), MPS II (N = 10), MPS I (N = 9), and MPS IIIA (N = 9), and included enzyme replacement therapies, gene therapies, and small molecules, and others. Twenty-three orphan drugs were approved for the treatment of 11 LSDs. Gaucher disease (N = 6), cystinosis (N = 5), Pompe disease (N = 3), and Fabry disease (N = 2) had multiple approvals, CLN2, LAL-D, MPS I, II, IVA, VI, and VII one approval each. This is an increase of nine more approved drugs and four more treatable LSDs (CLN2, MPS VII, LAL-D, and MPS IVA) since 2013. Mean time between orphan drug designation and FDA approval was 89.7 SD 55.00 (range 8-203, N = 23) months. Conclusions The drug development pipeline for LSDs is growing and evolving, with increased focus on diverse small-molecule targets and gene therapy. CLN2 was the first and only LSD with an approved therapy directly targeted to the brain. Newly approved products included "metoo"-enzymes and innovative compounds such as the first pharmacological chaperone for the treatment of Fabry disease.

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“…Targeting the affected enzyme: TPP1 enhancer, chaperone, enzyme/ chaperone co-administration [37][38][39][40][41][42] Gemfibrozil…”

Section: Mps I Cystinosismentioning

confidence: 99%

FDA orphan drug designations for lysosomal storage disorders – a cross-sectional analysis

et al. 2020

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“…Recently, a group demonstrated a slow release system for ambroxol (Enshaei et al, 2019). Another, interesting recent finding is that Arimoclomol, a heat shock protein amplifier has been shown to increase levels of GCase and GCase activity in GD models (Fog et al, 2018).…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

GBA RNAi but not catalytic inhibition of glucocerebrosidase with Conduritol-β-epoxide increases levels of total α-synuclein in SH-SY5Y cells

Zurbruegg

Chan

Svenningsson

2019

Neuroscience Letters

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“…Although many materials have been employed as therapeutic platforms for drug delivery, polymers have received special attention because of their properties and versatility. [1] Over the last years, drug delivery using polymeric platforms based on (nano)particles, [2] (nano)fibers, [3,4] (nano)films, [4,5] and hydrogels [6] have been extensively investigated. Among polyesters, poly--caprolactone (PCL) has attracted great interest for drug release due to its biodegradable and biocompatible nature, [7] as well as by the approval of PCL-based devices by the U.S. Food and Drug Administration (FDA) for many medical applications, including drug delivery devices, in the human body.…”

Section: Introductionmentioning

confidence: 99%

Semi‐Interpenetrated Hydrogels‐Microfibers Electroactive Assemblies for Release and Real‐Time Monitoring of Drugs

Moghimiardekani

Molina

Enshaei

et al. 2020

Macromolecular Bioscience

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Simultaneous drug release and monitoring using a single polymeric platform represents a significant advance in the utilization of biomaterials for therapeutic use. Tracking drug release by real-time electrochemical detection using the same platform is a simple way to guide the dosage of the drug, improve the desired therapeutic effect, and reduce the adverse side effects. The platform developed in this work takes advantage of the flexibility and loading capacity of hydrogels, the mechanical strength of microfibers, and the capacity of conducting polymers to detect the redox properties of drugs. The engineered platform is prepared by assembling two spin-coated layers of poly--glutamic acid hydrogel, loaded with poly(3,4-ethylenedioxythiophene) (PEDOT) microparticles, and separated by a electrospun layer of poly--caprolactone microfibers. Loaded PEDOT microparticles are used as reaction nuclei for the polymerization of poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PHMeDOT), that semi-interpenetrate the whole three layered system while forming a dense network of electrical conduction paths. After demonstrating its properties, the platform has been loaded with levofloxacin and its release monitored externally by UV-Vis spectroscopy and in situ by using the PHMeDOT network. In situ real-time electrochemical monitoring of Authors acknowledge MINECO-FEDER (RTI2018-098951-B-I00) and Agència de Gestió d'Ajuts Universitaris i de Recerca (2017SGR359). Support for the research of C.A. was received through the prize "ICREA Academia" for excellence in research funded by the Generalitat de Catalunya.

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Scaffolds for Sustained Release of Ambroxol Hydrochloride, a Pharmacological Chaperone That Increases the Activity of Misfolded β‐Glucocerebrosidase

Cited by 5 publications

References 44 publications

FDA orphan drug designations for lysosomal storage disorders – a cross-sectional analysis

FDA orphan drug designations for lysosomal storage disorders – a cross-sectional analysis

GBA RNAi but not catalytic inhibition of glucocerebrosidase with Conduritol-β-epoxide increases levels of total α-synuclein in SH-SY5Y cells

Semi‐Interpenetrated Hydrogels‐Microfibers Electroactive Assemblies for Release and Real‐Time Monitoring of Drugs

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