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Rational Design of Novel Therapies for Pantothenate <scp>Kinase–Associated</scp> Neurodegeneration
Rational Design of Novel Therapies for Pantothenate <scp>Kinase–Associated</scp> Neurodegeneration
- Source :
- Movement disorders 36(9), 2005-2016 (2021). doi:10.1002/mds.28642
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- Background This review highlights the recent scientific advances that have enabled rational design of novel clinical trials for pantothenate kinase-associated neurodegeneration (PKAN), a rare autosomal recessive neurogenetic disorder associated with progressive neurodegenerative changes and functional impairment. PKAN is caused by genetic variants in the PANK2 gene that result in dysfunction in pantothenate kinase 2 (PANK2) enzyme activity, with consequent disruption of coenzyme A (CoA) synthesis, and subsequent accumulation of brain iron. The clinical phenotype is varied and may include dystonia, rigidity, bradykinesia, postural instability, spasticity, loss of ambulation and ability to communicate, feeding difficulties, psychiatric issues, and cognitive and visual impairment. There are several symptom-targeted treatments, but these do not provide sustained benefit as the disorder progresses. Objectives A detailed understanding of the molecular and biochemical pathogenesis of PKAN has opened the door for the design of novel rationally designed therapeutics that target the underlying mechanisms. Methods Two large double-blind phase 3 clinical trials have been completed for deferiprone (an iron chelation treatment) and fosmetpantotenate (precursor replacement therapy). A pilot open-label trial of pantethine as a potential precursor replacement strategy has also been completed, and a trial of 4-phosphopantetheine has begun enrollment. Several other compounds have been evaluated in pre-clinical studies, and additional clinical trials may be anticipated. Conclusions Experience with these trials has encouraged a critical evaluation of optimal trial designs, as well as the development of PKAN-specific measures to monitor outcomes. PKAN provides a valuable example for understanding targeted drug development and clinical trial design for rare disorders. © 2021 International Parkinson and Movement Disorder Society.
- Subjects :
- genetics [Pantothenate Kinase-Associated Neurodegeneration]
0301 basic medicine
drug therapy [Pantothenate Kinase-Associated Neurodegeneration]
Neurodegeneration with brain iron accumulation
Iron
translational therapy
Bioinformatics
Pantothenate kinase-associated neurodegeneration
03 medical and health sciences
0302 clinical medicine
pantothenate kinase-associated neurodegeneration
genetics [Phosphotransferases (Alcohol Group Acceptor)]
medicine
Humans
ddc:610
Pantothenate Kinase-Associated Neurodegeneration
Randomized Controlled Trials as Topic
clinical rating scale
neurodegeneration with brain iron accumulation
Dystonia
treatment
business.industry
Clinical study design
Neurodegeneration
Brain
medicine.disease
PANK2
Clinical trial
Phosphotransferases (Alcohol Group Acceptor)
Phenotype
030104 developmental biology
Neurology
Drug development
metabolism [Brain]
Neurology (clinical)
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15318257 and 08853185
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Movement Disorders
- Accession number :
- edsair.doi.dedup.....30fd8d417742f96cbee4da291cfe4dd9
- Full Text :
- https://doi.org/10.1002/mds.28642