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  1. Article: Favorable outcomes following early onset oral miglustat in early infantile Niemann Pick Type C.

    Curelaru, Shiri / Zehavi, Yoav / Almagor, Tal / Spiegel, Ronen

    Molecular genetics and metabolism reports

    2021  Volume 27, Page(s) 100739

    Abstract: Niemann-Pick disease Type C (NPC) is a rare autosomal recessive neurovisceral lysosomal disorder. Perinatal and early infantile onset NPC are the most severe types of the disease. Early infantile type is characterized by a rapidly progressive ... ...

    Abstract Niemann-Pick disease Type C (NPC) is a rare autosomal recessive neurovisceral lysosomal disorder. Perinatal and early infantile onset NPC are the most severe types of the disease. Early infantile type is characterized by a rapidly progressive neurodegenerative course, which entails significant morbidity and usually results in death within 5 years. Miglustat, an iminosugar that selectively inhibits the glycosylceramide synthase enzyme, is known to stabilize or delay neurological progression in individuals with NPC, but its impact on affected infants is yet to be elucidated. We present two siblings with early infantile NPC due to the previously reported devastating homozygous mutation c.2279_2281delTCT in
    Language English
    Publishing date 2021-03-06
    Publishing country United States
    Document type Case Reports
    ZDB-ID 2821908-9
    ISSN 2214-4269
    ISSN 2214-4269
    DOI 10.1016/j.ymgmr.2021.100739
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  2. Article ; Online: Lack of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile-onset brainstem neurodegenerative disease with early lethality.

    Abu Hanna, Firas / Zehavi, Yoav / Cohen-Barak, Eran / Khayat, Morad / Warwar, Nasim / Shreter, Roni / Rodenburg, Richard J / Spiegel, Ronen

    Orphanet journal of rare diseases

    2024  Volume 19, Issue 1, Page(s) 92

    Abstract: Background: Congenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among them, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Biallelic pathogenic variants in ... ...

    Abstract Background: Congenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among them, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Biallelic pathogenic variants in NDUFAF2, encoding the nuclear assembly CI factor NDUFAF2, were initially reported to cause progressive encephalopathy beginning in infancy. Since the initial report in 2005, less than a dozen patients with NDUFAF2-related disease have been reported.
    Methods: Clinical, biochemical, and neuroradiological features of four new patients residing in Northern Israel were collected during 2016-2022 at Emek Medical Center. Enzymatic activities of the five respiratory-chain complexes were determined in isolated fibroblast mitochondria by spectrophotometric methods. Western blot analyses were conducted with anti-human NDUFAF2 antibody; antibody against the mitochondrial marker VDAC1 was used as a loading control. Genetic studies were performed by chromosome microarray analysis using Affymetrix CytoScan 750 K arrays.
    Results: All four patients presented with infantile-onset growth retardation, ophthalmological impairments with nystagmus, strabismus (starting between 5 and 9 months), and further progressed to life-threatening episodes of apnea usually triggered by trivial febrile illnesses (between 10 and 18 months) with gradual loss of acquired developmental milestones (3 of 4 patients). Serial magnetic-resonance imaging studies in two of the four patients showed a progressive pattern of abnormal T2-weighted hyperintense signals involving primarily the brainstem, the upper cervical cord, and later, the basal ganglia and thalami. Magnetic-resonance spectroscopy in one patient showed an increased lactate peak. Disease progression was marked by ventilatory dependency and early lethality. 3 of the 4 patients tested, harbored a homozygous 142-kb partial interstitial deletion that omits exons 2-4 of NDUFAF2. Mitochondrial CI activity was significantly decreased in the only patient tested. Western blot analysis disclosed the absence of NDUFAF2 protein compared to normal controls. In addition, we reviewed all 10 previously reported NDUFAF2-deficient cases to better characterize the disease.
    Conclusions: Biallelic loss-of-function mutations in NDUFAF2 result in a distinctive phenotype in the spectrum of Leigh syndrome with clinical and neuroradiological features that are primarily attributed to progressive brainstem damage.
    MeSH term(s) Humans ; Neurodegenerative Diseases ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Leigh Disease/genetics ; Leigh Disease/metabolism ; Electron Transport Complex I/metabolism ; Brain Stem/pathology ; Mutation/genetics ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism
    Chemical Substances Mitochondrial Proteins ; Electron Transport Complex I (EC 7.1.1.2) ; NDUFAF2 protein, human ; Molecular Chaperones
    Language English
    Publishing date 2024-02-28
    Publishing country England
    Document type Review ; Journal Article
    ZDB-ID 2225857-7
    ISSN 1750-1172 ; 1750-1172
    ISSN (online) 1750-1172
    ISSN 1750-1172
    DOI 10.1186/s13023-024-03094-0
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  3. Article ; Online: Molybdenum cofactor deficiency: A natural history.

    Spiegel, Ronen / Schwahn, Bernd C / Squires, Liza / Confer, Nils

    Journal of inherited metabolic disease

    2022  Volume 45, Issue 3, Page(s) 456–469

    Abstract: Molybdenum cofactor deficiency (MoCD) includes three ultrarare autosomal recessive inborn errors of metabolism (MoCD type A [MoCD-A], MoCD-B, and MoCD-C) that cause sulfite intoxication disorders. This natural history study analyzed retrospective data ... ...

    Abstract Molybdenum cofactor deficiency (MoCD) includes three ultrarare autosomal recessive inborn errors of metabolism (MoCD type A [MoCD-A], MoCD-B, and MoCD-C) that cause sulfite intoxication disorders. This natural history study analyzed retrospective data for 58 living or deceased patients (MoCD-A, n = 41; MoCD-B, n = 17). MoCD genotype, survival, neuroimaging, and medical history were assessed retrospectively. Prospective biomarker data were collected for 21 living MoCD patients. The primary endpoint was survival to 1 year of age in MoCD-A patients. Of the 58 MoCD patients, 49 (MoCD-A, n = 36; MoCD-B, n = 13) had first presenting symptoms by Day 28 (neonatal onset; median: 2 and 4 days, respectively). One-year survival rates were 77.4% (overall), 71.8% (neonatal onset MoCD-A), and 76.9% (neonatal onset MoCD-B); median ages at death were 2.4, 2.4, and 2.2 years, respectively. The most common presenting symptoms in the overall population were seizures (60.3%) and feeding difficulties (53.4%). Sequelae included profound developmental delay, truncal hypotonia, limb hypertonia that evolved to spastic quadriplegia or diplegia, dysmorphic features, and acquired microcephaly. In MoCD-A and MoCD-B, plasma and urinary xanthine and S-sulfocysteine concentrations were high; urate remained below the normal reference range. MOCS1 mutation homozygosity was common. Six novel mutations were identified. MoCD is a severe neurodegenerative disorder that often manifests during the neonatal period with intractable seizures and feeding difficulties, with rapidly progressive significant neurologic disabilities and high 1-year mortality rates. Delineation of MoCD natural history supports evaluations of emerging replacement therapy with cPMP for MoCD-A, which may modify disease course for affected individuals.
    MeSH term(s) Coenzymes ; Humans ; Infant, Newborn ; Metal Metabolism, Inborn Errors/diagnosis ; Metalloproteins ; Prospective Studies ; Pteridines ; Retrospective Studies ; Seizures/complications
    Chemical Substances Coenzymes ; Metalloproteins ; Pteridines
    Language English
    Publishing date 2022-03-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 438341-2
    ISSN 1573-2665 ; 0141-8955
    ISSN (online) 1573-2665
    ISSN 0141-8955
    DOI 10.1002/jimd.12488
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  4. Article: A favorable outcome in an infantile-onset Pompe patient with cross reactive immunological material (CRIM) negative disease with high dose enzyme replacement therapy and adjusted immunomodulation.

    Curelaru, Shiri / Desai, Ankit K / Fink, Daniel / Zehavi, Yoav / Kishnani, Priya S / Spiegel, Ronen

    Molecular genetics and metabolism reports

    2022  Volume 32, Page(s) 100893

    Abstract: Infantile onset Pompe disease (IOPD) is a rare devastating disease that presents in early infancy with rapidly progressive hypertrophic cardiomyopathy, severe generalized myopathy and death within the first year of life. The emergence of enzyme ... ...

    Abstract Infantile onset Pompe disease (IOPD) is a rare devastating disease that presents in early infancy with rapidly progressive hypertrophic cardiomyopathy, severe generalized myopathy and death within the first year of life. The emergence of enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has improved the natural course of IOPD with a significant impact on cardiomyopathy but has a more limited effect on the progression of myopathy and consequently the later deterioration of the disease. Possible reasons for reduced ERT efficacy include insufficient enzyme, partial targeting of skeletal muscle and the development of IgG rhGAA antibodies especially in patients who are cross-reactive immunological material (CRIM) negative. We report a CRIM-negative IOPD female patient who started treatment upon diagnosis at 4.5 months with ERT at 20 mg/kg every other week and a course of combined immunomodulation with rituximab, methotrexate and IVIG according to the published Duke protocol and increased ERT within a month to 40 mg/kg/week. Despite initial good clinical response to ERT and immunomodulation, monthly monitoring identified a gradual increase of serum antibody titers to rhGAA necessitating a second course of immunomodulation with bortezomib and maintenance rituximab and methotrexate. A gradual reduction in frequency of immunotherapy was instituted and over a period of 14 months was discontinued. Serum anti-rhGAA antibody titers remained negative for 5 months since cessation of immunomodulation and the patient is now immune tolerant with recovery of CD19. At the age of 30 months the patient is walking independently and has normal cardiac function and anatomy. We recommend initiating ERT at 40 mg/kg/week in CRIM-negative IOPD patients, concomitant with immunomodulation and monthly monitoring of serum anti-rhGAA IgG titers upon confirmation of the diagnosis.
    Language English
    Publishing date 2022-07-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2821908-9
    ISSN 2214-4269
    ISSN 2214-4269
    DOI 10.1016/j.ymgmr.2022.100893
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  5. Article ; Online: Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria.

    Al Rawi, Sara / Simpson, Lorna / Agnarsdóttir, Guðrún / McDonald, Neil Q / Chernuha, Veronika / Elpeleg, Orly / Zeviani, Massimo / Barker, Roger A / Spiegel, Ronen / Laman, Heike

    The FEBS journal

    2024  

    Abstract: Mutations in FBXO7 have been discovered to be associated with an atypical parkinsonism. We report here a new homozygous missense mutation in a paediatric patient that causes an L250P substitution in the dimerisation domain of Fbxo7. This alteration ... ...

    Abstract Mutations in FBXO7 have been discovered to be associated with an atypical parkinsonism. We report here a new homozygous missense mutation in a paediatric patient that causes an L250P substitution in the dimerisation domain of Fbxo7. This alteration selectively ablates the Fbxo7-PI31 interaction and causes a significant reduction in Fbxo7 and PI31 levels in patient cells. Consistent with their association with proteasomes, patient fibroblasts have reduced proteasome activity and proteasome subunits. We also show PI31 interacts with the MiD49/51 fission adaptor proteins, and unexpectedly, PI31 acts to facilitate SCF
    Language English
    Publishing date 2024-03-11
    Publishing country England
    Document type Journal Article
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.17114
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 260: Show issues Location:
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  6. Article ; Online: Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies.

    Schwahn, Bernd C / van Spronsen, Francjan / Misko, Albert / Pavaine, Julija / Holmes, Victoria / Spiegel, Ronen / Schwarz, Guenter / Wong, Flora / Horman, Alistair / Pitt, James / Sass, Jörn Oliver / Lubout, Charlotte

    Journal of inherited metabolic disease

    2024  

    Abstract: Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these ...

    Abstract Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD-A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search.
    Language English
    Publishing date 2024-04-16
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 438341-2
    ISSN 1573-2665 ; 0141-8955
    ISSN (online) 1573-2665
    ISSN 0141-8955
    DOI 10.1002/jimd.12730
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  7. Article: Favorable outcome of empagliflozin treatment in two pediatric glycogen storage disease type 1b patients.

    Hexner-Erlichman, Zufit / Veiga-da-Cunha, Maria / Zehavi, Yoav / Vadasz, Zahava / Sabag, Adi D / Tatour, Sameh / Spiegel, Ronen

    Frontiers in pediatrics

    2022  Volume 10, Page(s) 1071464

    Abstract: Background: Glycogen storage disease type 1b (GSD1b) is an ultra-rare autosomal recessive disorder, caused by mutations in : Methods: Off-label treatment with EMPA was established in two GSD1b patients after signed informed consent. The patients were ...

    Abstract Background: Glycogen storage disease type 1b (GSD1b) is an ultra-rare autosomal recessive disorder, caused by mutations in
    Methods: Off-label treatment with EMPA was established in two GSD1b patients after signed informed consent. The patients were followed clinically. We monitored neutrophil counts and function, 1,5-AG levels in plasma and its renal clearance before and during EMPA treatment.
    Results: A 17 year-old girl who had long standing oral ulcers and developed IBD, requiring systemic steroid and regular granulocyte colony-stimulating factor (GCSF) therapy and an 8 year-old boy who had steady non healing oral lesions were treated with empagliflozin during 18-24 months. Treatment led to increase of neutrophil counts and function with substantial clinical improvement. This included remission of IBD in the first patient which allowed to discontinue both GCSF and steroid therapy and resolution of oral lesions in both patients. The concentration of 1,5-AG in blood was greatly decreased within two weeks of treatment and remained stable thereafter.
    Conclusions: Repurposing of empagliflozin to treat neutropenia in two GSD1b patients was safe and resulted in the urinary excretion of 1,5-AG, the normalization of neutrophil function, and a remarkable improvement of neutropenia-related clinical traits. We showed for the first time that empagliflozin increases concomitantly the renal clearance of both 1,5-anhydroglucitol and glucose in GSD1b patients.
    Language English
    Publishing date 2022-11-23
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2711999-3
    ISSN 2296-2360
    ISSN 2296-2360
    DOI 10.3389/fped.2022.1071464
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  8. Article ; Online: Campylobacter gastroenteritis in children in north-eastern Israel comparison with other common pathogens.

    Sakran, Waheeb / Hexner-Erlichman, Zufit / Spiegel, Ronen / Batheesh, Hamed / Halevy, Raphael / Koren, Ariel

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 5823

    Abstract: Gastroenteritis is common among children. Campylobacter jejuni is one of the main causative bacterial pathogens, together with Shigella, Salmonella and invasive Escherichia coli. Campylobacteriosis is a zoonotic, usually self-limited disease that does ... ...

    Abstract Gastroenteritis is common among children. Campylobacter jejuni is one of the main causative bacterial pathogens, together with Shigella, Salmonella and invasive Escherichia coli. Campylobacteriosis is a zoonotic, usually self-limited disease that does not always require antibiotic treatment. In cases of protracted diarrhoea in healthy children or immunocompromised patients, antibiotic treatment is recommended, and the drug of choice is still macrolides, with very low resistance rates in Campylobacter species. However, it is crucial to isolate the causative organism, because some cases, such as Shigella encephalitis, call for initiation of empiric antibiotic treatment. In this study, we compared the incidence, epidemiology, clinical findings and laboratory results of gastroenteritis with dysentery caused by these organisms in children in our area. C. jejuni was found to be the leading pathogen in children hospitalized with bacterial gastroenteritis, followed by Shigella and Salmonella. Macrolides were the drug of choice for Campylobacter, and ceftriaxone and ciprofloxacin were the best empiric treatments for Shigella and Salmonella, respectively.
    MeSH term(s) Anti-Bacterial Agents/therapeutic use ; Campylobacter Infections/drug therapy ; Campylobacter Infections/epidemiology ; Campylobacter Infections/microbiology ; Campylobacter jejuni/drug effects ; Child ; Child, Preschool ; Female ; Gastroenteritis/drug therapy ; Gastroenteritis/epidemiology ; Gastroenteritis/microbiology ; Humans ; Infant ; Israel/epidemiology ; Male
    Chemical Substances Anti-Bacterial Agents
    Language English
    Publishing date 2020-04-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-62744-y
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  9. Article: Intrafamilial Phenotypic Variability in Two Siblings with Primary Ciliary Dyskinesia Due to Homozygous Loss of Function Mutation in the CCDC151 Gene.

    Abu Hanna, Firas / Prais, Dario / Zehavi, Yoav / Sakran, Waheeb / Spiegel, Ronen

    The Israel Medical Association journal : IMAJ

    2020  Volume 22, Issue 4, Page(s) 260–262

    MeSH term(s) Carrier Proteins/genetics ; Child ; Child, Preschool ; Ciliary Motility Disorders/genetics ; Ciliary Motility Disorders/physiopathology ; Ciliary Motility Disorders/therapy ; Diagnosis, Differential ; Female ; Hearing Loss/diagnosis ; Hearing Loss/etiology ; Humans ; Loss of Function Mutation ; Lung Diseases/diagnosis ; Lung Diseases/etiology ; Lung Diseases/physiopathology ; Otitis/diagnosis ; Otitis/etiology ; Otitis/physiopathology ; Patient Care Management ; Siblings ; Situs Inversus/diagnostic imaging ; Situs Inversus/genetics
    Chemical Substances Carrier Proteins ; ODAD3 protein, human
    Language English
    Publishing date 2020-07-05
    Publishing country Israel
    Document type Case Reports ; Journal Article
    ZDB-ID 2008291-5
    ISSN 1565-1088 ; 0021-2180
    ISSN 1565-1088 ; 0021-2180
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    Zs.A 5470: Show issues Location:
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  10. Article: Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial.

    Sharma, Reena / Hastings, Caroline / Staretz-Chacham, Orna / Raiman, Julian / Paucar, Martin / Spiegel, Ronen / Murray, Bryan / Hurst, Bryan / Liu, Benny / Kjems, Lise / Hrynkow, Sharon

    Molecular genetics and metabolism reports

    2023  Volume 36, Page(s) 100988

    Abstract: Background: Niemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed a critical role of ... ...

    Abstract Background: Niemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed a critical role of systemically administered hydroxypropyl-β-cyclodextrin (HP-β-CD; Trappsol
    Methods: This was a multicenter, Phase I/II, randomized, double-blind, parallel-group, 48-week study (ClinicalTrials.gov identifier NCT02912793) to compare the PK of three different single intravenous (IV) doses of HP-β-CD in pediatric and adult patients with NPC1 and to evaluate the efficacy and tolerability of three different dosages of HP-β-CD in patients with NPC1 after long-term treatment. Twelve patients aged at least 2 years (2-39 years of age) with a confirmed diagnosis of NPC1 were randomized to receive one of three IV doses of HP-β-CD (1500 mg/kg, 2000 mg/kg, or 2500 mg/kg) every 2 weeks for 48 weeks. All patients received HP-β-CD; there was no placebo or other control. PK testing of plasma and cerebrospinal fluid (CSF) was at set times after the first infusion. Pharmacodynamic assessments included biomarkers of cholesterol metabolism (synthesis and breakdown products),
    Results: Nine patients completed the study, 2 in the 1500 mg/kg group, 4 in the 2000 mg/kg group and 3 in the 2500 mg/kg group. Three patients (all in the 1500 mg/kg group) discontinued the study because of either physician decision/site Principal Investigator (PI) discretion, withdrawal by subject/patient/parent/guardian, or other non-safety reasons. In 5 patients who underwent serial lumbar punctures, HP-β-CD was detected in the CSF. Of the 9 patients who completed the study, 8 (88.9%) improved in at least two domains of the 17-Domain Niemann-Pick disease Type C-Clinical Severity Scale (17D-NPC-CSS), and 6 of these patients improved in at least one domain viewed by patients and their caregivers to be key to quality of life, namely, speech, swallow, fine and gross motor skills, and cognition. Of the 9 patients who completed the study, 7 were viewed by their treating physicians as having improved to some degree at the end of the study, and 2 remained stable; both outcomes are highly relevant in a progressive neurodegenerative disease. Some patients and families reported improvement in quality of life.All three doses of HP-β-CD were well tolerated overall, with most treatment-emergent adverse events transient, mild-to-moderate in nature, and considered by the site PIs to be not related to study drug.
    Interpretation: This 48-week trial is the longest to date to evaluate the safety, tolerability, and efficacy across multiple clinical endpoints of IV administration of Trappsol
    Language English
    Publishing date 2023-06-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2821908-9
    ISSN 2214-4269
    ISSN 2214-4269
    DOI 10.1016/j.ymgmr.2023.100988
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