Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C.
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ABSTRACT: Objective
To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann-Pick disease type C (NPC) patients.Methods
In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments.Results
33 subjects aged 7-64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred.Conclusions
NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. CLINICALTRIALS.Gov identifier
NCT03759639.
SUBMITTER: Bremova-Ertl T
PROVIDER: S-EPMC8361244 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNiemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC.MethodsThis multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.DiscussionPre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.Trial registrationsThe trial (IB1001-301) has been registered at www.Clinicaltrialsgov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.
| S-EPMC10226221 | biostudies-literature
Project description:OBJECTIVES:The aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ß-cyclodextrin) may be more appropriately monitored and understood. DESIGN:Fifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients. RESULTS:Over half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4 kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function. CONCLUSIONS:This is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype.
| S-EPMC3895917 | biostudies-literature
Project description:Lysosomal storage disorders are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. 573C10 is a Schwann cell line derived from a mouse model of Niemann-Pick type C disease-1, NPC (-/-). Under serum-starved conditions, NPC (-/-) cells manifested impaired autophagy accompanied by an increase in the amount of p62 and lysosome enlargement. Addition of L-leucine to serum-starved NPC (-/-) cells ameliorated the enlargement of lysosomes and the p62 accumulation. Similar autophagy defects were observed in NPC (-/-) cells even without serum starvation upon the knockdown of Spinster-like 1 (SPNS1), a putative transporter protein thought to function in lysosomal recycling. Conversely, SPNS1 overexpression impeded the enlargement of lysosomes, p62 accumulation and mislocalization of the phosphorylated form of the mechanistic Target of rapamycin in NPC (-/-) cells. In addition, we found a reduction in endogenous SPNS1 expression in fibroblasts derived from NPC-1 patients compared with normal fibroblasts. We propose that SPNS1-dependent L-leucine export across the lysosomal membrane is a key step for triggering autophagy, and that this mechanism is impaired in NPC-1.
| S-EPMC5698481 | biostudies-literature
Project description:Primary skin fibroblasts from four Niemann-Pick type C patients homozygous for the I1061T mutation and four control individuals were cultured under identical conditions in DMEM containing 10% fetal bovine serum. Cells were harvested at 50-70% confluency. mRNA was isolated with the FastTrack 2.0 mRNA isolation kit according to the manufacturer's instructions (Invitrogen, Carlsbad, CA). A reference RNA comprised of 10 cell lines was used as the control for each hybridized sample (Stratagene, La Jolla, CA). Both sample and reference RNAs were amplified using the MessageAmp II aRNA amplification kit (Ambion, Austin, TX). Set of arrays that are part of repeated experiments Keywords: Biological Replicate
2007-08-15 | GSE8770 | GEO
Project description:Primary skin fibroblasts from four Niemann-Pick type C patients homozygous for the I1061T mutation and four control individuals were cultured under identical conditions in DMEM containing 10% fetal bovine serum. Cells were harvested at 50-70% confluency. mRNA was isolated with the FastTrack 2.0 mRNA isolation kit according to the manufacturer's instructions (Invitrogen, Carlsbad, CA). A reference RNA comprised of 10 cell lines was used as the control for each hybridized sample (Stratagene, La Jolla, CA). Both sample and reference RNAs were amplified using the MessageAmp II aRNA amplification kit (Ambion, Austin, TX). Set of arrays that are part of repeated experiments Biological Replicate Complex
2007-08-15 | E-GEOD-8770 | biostudies-arrayexpress
Project description:Niemann-Pick disease type C (NPC) is a model for inborn errors of metabolism whose gene product mediates molecular trafficking rather than catabolizing macromolecules, as in classic lipidoses. We report the case of an infant who presented with hepatosplenomegaly without neurological abnormalities. Decreased activity of acid ?-glucosidase and elevated serum chitotriosidase and tartrate-resistant acid phosphatase on repeated measurements led to initial diagnosis of Gaucher disease (GD). Failure to respond to enzyme replacement therapy after one year, however, put the diagnosis in question. Cholesterol esterification assays in cultured skin fibroblasts and NPC gene analysis led to the correct diagnosis of NPC. The patient had markedly reduced cholesterol esterification and was a compound heterozygote for a known and a novel mutation in the NPC gene (395delC and 2068insTCCC), which are both predicted to lead to protein truncation. Although the full phenotype of NPC involves hepatosplenomegaly and neurodegenerative disease, the initial presentation in a pediatric patient may be restricted to visceral disease. Of interest, this patient had decreased activity of leukocyte acid ?-glucosidase activity and elevated serum chitotriosidase to levels often seen in GD. Although acid ?-glucosidase activity in leukocytes was low, it was in the normal range in skin fibroblasts. Therefore, diagnostic delay may occur in NPC due to false positive testing for GD. Diagnosis of NPC requires a high index of suspicion and should be considered in a patient with hepatosplenomegaly even in the absence of neurodevelopmental signs. Prompt diagnosis will become increasingly important as effective therapies are developed for NPC.
| S-EPMC3053412 | biostudies-literature
Project description:Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive, neurodegenerative disease associated with a wide variety of progressive neurological manifestations. Miglustat is indicated for the treatment of progressive neurological manifestations in both adults and children. Since approval in 2009 there has been a vast growth in clinical experience with miglustat. The effectiveness of miglustat has been assessed using a range of measures.Comprehensive review of published data from studies of cellular neuropathological markers and structural neurological indices in the brain, clinical impairment/disability, specific clinical neurological manifestations, and patient survival.Cranial diffusion tensor imaging and magnetic resonance spectroscopy studies have shown reduced levels of choline (a neurodegeneration marker), and choline/N-acetyl aspartate ratio (indicating increased neuronal viability) in the brain during up to 5 years of miglustat therapy, as well as a slowing of reductions in fractional anisotropy (an axonal/myelin integrity marker). A 2-year immunoassay study showed significant reductions in CSF-calbindin during treatment, indicating reduced cerebellar Purkinje cell loss. Magnetic resonance imaging studies have demonstrated a protective effect of miglustat on cerebellar and subcortical structure that correlated with clinical symptom severity. Numerous cohort studies assessing core neurological manifestations (impaired ambulation, manipulation, speech, swallowing, other) using NP-C disability scales indicate neurological stabilization over 2-8 years, with a trend for greater benefits in patients with older (non-infantile) age at neurological onset. A randomized controlled trial and several cohort studies have reported improvements or stabilization of saccadic eye movements during 1-5 years of therapy. Swallowing was also shown to improve/remain stable during the randomized trial (up to 2 years), as well as in long-term observational cohorts (up to 6 years). A meta-analysis of dysphagia - a potent risk factor for aspiration pneumonia and premature death in NP-C - demonstrated a survival benefit with miglustat due to improved/stabilized swallowing function.The effects of miglustat on neurological NP-C manifestations has been assessed using a range of approaches, with benefits ranging from cellular changes in the brain through to visible clinical improvements and improved survival.
| S-EPMC6094874 | biostudies-other
Project description:BACKGROUND: Niemann-Pick type C disease (NPC) is a rare autosomal recessive lipid storage disease characterized by progressive neurodegeneration. As only a few studies have been conducted on the impact of NPC on sensory systems, we used a mutant mouse model (NPC1(-/-)) to examine the effects of this disorder to morphologically distinct regions of the olfactory system, namely the olfactory epithelium (OE) and olfactory bulb (OB). METHODOLOGY/PRINCIPAL FINDINGS: For structural and functional analysis immunohistochemistry, electron microscopy, western blotting, and electrophysiology have been applied. For histochemistry and western blotting, we used antibodies against a series of neuronal and glia marker proteins, as well as macrophage markers. NPC1(-/-) animals present myelin-like lysosomal deposits in virtually all types of cells of the peripheral and central olfactory system. Especially supporting cells of the OE and central glia cells are affected, resulting in pronounced astrocytosis and microgliosis in the OB and other olfactory cortices. Up-regulation of Galectin-3, Cathepsin D and GFAP in the cortical layers of the OB underlines the critical role and location of the OB as a possible entrance gate for noxious substances. Unmyelinated olfactory afferents of the lamina propria seem less affected than ensheathing cells. Supporting the structural findings, electro-olfactometry of the olfactory mucosa suggests that NPC1(-/-) animals exhibit olfactory and trigeminal deficits. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a pronounced neurodegeneration and glia activation in the olfactory system of NPC1(-/-), which is accompanied by sensory deficits.
| S-EPMC3877006 | biostudies-literature
Project description:Niemann-Pick type C disease (NPC) is a fatal, autosomal recessive disorder, which causes excessive accumulation of free cholesterol in endolysosomes, resulting in progressive hepatomegaly and neurodegeneration. Currently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) is used at a high dose for the treatment of NPC, risking lung toxicity and hearing loss during treatment. One method to reduce the required dose of HP-β-CyD for the treatment of hepatomegaly is to actively deliver β-cyclodextrin (β-CyD) to hepatocytes. Previously, we synthesized lactosyl-β-CyD (Lac-β-CyD) and demonstrated that it lowers cholesterol in NPC model liver cells. In the present study, we studied the efficacy and safety of Lac-β-CyD treatment of hepatomegaly in Npc1-/- mice. After subcutaneous administration, Lac-β-CyD accumulated in the liver and reduced hepatomegaly with greater efficacy than HP-β-CyD. In addition, subcutaneous administration of a very high dose of Lac-β-CyD was less toxic to the lungs than HP-β-CyD. Notably, the accumulation of intracellular free cholesterol in endolysosomes of NPC-like liver cells was significantly lower after administration of Lac-β-CyD than after treatment with HP-β-CyD. In conclusion, these results suggest that Lac-β-CyD is a candidate for the effective treatment of hepatomegaly in NPC.
| S-EPMC6566927 | biostudies-literature
Project description:Niemann-Pick C1-like 1 (NPC1L1) and Niemann-Pick C2 (NPC2) is a critical mediator of cholesterol absorption. The aim of the present study was to investigate the prognostic value of NPC1L1 and NPC2 in human primary hepatocellular carcinoma (HCC). The expression level of NPC1L1 and NPC2 were evaluated by Immunohistochemistry, Westen blot and Real-time Quantitative PCR. Protein expression level in tissue was represented by integral optic density (IOD). For prognosis analyses, outcome-based cut-point was calculated by X-tile software. Kaplan-Meier analysis, Cox regression analysis were used evaluate prognostic value of NPC1L1 and NPC2 and NPC1L1/NPC2 combination. Both of NPC1L1 and NPC2 were significantly decreased in HCC tissues than peritumoral liver tissues (61 pairs of tissue for Immunohistochemistry and 10 pairs of tissues for Western blot and Real-time Quantitative PCR), respectively. (n=61: p=0.0005 for NPC1L1 and p=0.0001 for NPC2; n=10: p=0.0002 for NPC1L1 and p=0.0489 for NPC2). Kaplan-Meier analyses in 265 HCC cases were showed that the low expression level of NPC1L1 and NPC2 and NPC1L1/NPC2 combination were significantly correlated with poor overall survival (OS) and shorter time to recurrence (TTR). In addition, univariate and multivariate Cox analyses showed that the expression level of NPC1L1/NPC2 combination in HCC was an independent prognostic factor for OS and TTR. Conclusion: NPC1L1 and NPC2 were lowly expressed in HCC compared with peritumoral liver tissues, and low expression of NPC1L1 and NPC2 in HCC tissues may indicate poor outcome of HCC patients after surgery. NPC1L1/NPC2 combination is an independent prognostic factor for OS and TTR in postoperative HCC patients.
| S-EPMC5820923 | biostudies-literature