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Pilot trial on the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration: a single-arm, open-label study.

ABSTRACT: OBJECTIVE:This study aimed to explore the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration (PKAN). METHODS:A single-arm, open-label study was conducted. All subjects received pantethine during the 24-week period of treatment. The primary endpoints were change of the Unified Parkinson's Disease Rating Scale (UPDRS) I-III and Fahn-Marsden (FM) score from baseline to week 24 after treatment. RESULTS:Fifteen children with PKAN were enrolled, and all patients completed the study. After 24?weeks of treatment with pantethine at 60?mg/kg per day, there was no difference in either UPDRS I-III (t?=?0.516, P?=?0.614) or FM score (t?=?0.353, P?=?0.729) between the baseline and W24. Whereas the rates of increase in UPDRS I-III (Z?=?2.614, p?=?0.009) and FM scores (Z?=?2.643, p?=?0.008) were slowed. Four patients (26.7%) were evaluated as "slightly improved" by doctors through blinded video assessment. Patients with lower baseline UPDRS I-III or FM scores were more likely to be improved. The quality of life of family members improved after pantethine treatment, evaluated by PedsQL TM 2.0 FIM scores, whereas the quality of life of the patients was unchanged at W24, evaluated by PedsQL TM 4.0 and PedsQL TM 3.0 NMM. Serum level of CoA was comparable between baseline and W24. There was no drug related adverse event during the study. CONCLUSIONS:Pantethine could not significantly improve motor function in children with PKAN after 24?weeks treatment, but it may delay the progression of motor dysfunction in our study. Pantethine was well-tolerated at 60?mg/kg per day. TRIAL REGISTRATION:Clinical trial registration number at www.chictr.org.cn :ChiCTR1900021076, Registered 27 January2019, the first participant was enrolled 30 September 2018, and other 14 participants were enrolled after the trial was registered.

SUBMITTER: Chang X

PROVIDER: S-EPMC7491170 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Pilot trial on the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration: a single-arm, open-label study.

Chang Xuting X Zhang Jie J Jiang Yuwu Y Yao Bufan B Wang Jingmin J Wu Ye Y

Orphanet journal of rare diseases 20200914 1

<h4>Objective</h4>This study aimed to explore the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration (PKAN).<h4>Methods</h4>A single-arm, open-label study was conducted. All subjects received pantethine during the 24-week period of treatment. The primary endpoints were change of the Unified Parkinson's Disease Rating Scale (UPDRS) I-III and Fahn-Marsden (FM) score from baseline to week 24 after treatment.<h4>Results</h4>Fifteen children with PKAN ...[more]

PMID: 32928263

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Project description:Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas, mainly the basal ganglia. The predominant clinical symptoms include spasticity, progressive dystonia, Parkinson's disease-like symptoms, neuropsychiatric alterations, and retinal degeneration. Among the neurodegeneration with brain iron accumulation disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2 (PANK2) which catalyzed the first reaction of the coenzyme A biosynthesis pathway. Currently there is no effective treatment to prevent the inexorable course of these disorders. The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN. Recently, we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction and a pronounced increase of markers of oxidative stress. In addition, PKAN fibroblasts showed a morphological senescence-like phenotype. Interestingly, pantothenate supplementation, the substrate of the PANK2 enzyme, corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression. However, pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein. The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts. Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations. Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment. The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate. The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available, and monitoring its effect on the pathophysiological changes, can help for a better therapeutic strategy. In addition, these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.

Dataset Information

Pilot trial on the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration: a single-arm, open-label study.

Publications

Pilot trial on the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration: a single-arm, open-label study.

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