Niemann-Pick disease, type C is an autosomal recessive, fatal, neurodegenerative disorder caused by pathological variants in NPC1 or NPC2 . Dysfunction of either NPC1 or NPC2 results in impaired intracellular cholesterol transport and subsequent storage of unesterified cholesterol in endolysosomal compartments. Earlier cell-based studies utilized patient fibroblasts to study this disease; however, neuronal cells allow for investigation of the neurodegenerative aspect of NPC1. Expression of neurogenin in induced pluripotent stem cells leads to the generation of i 3 Neurons (integrated, isogenic, and inducible), allowing for rapid, synchronized growth of homogenous neurons. In this study, we report the development and characterization of a human iPSC-derived NPC1 I1061T/I1061T i 3 Neuronal model system. NPC1 I1061T is a missense variant resulting in a misfolded protein targeted for proteasomal degradation in the ER. NPC1 I1061T/I1061T i 3 Neurons phenocopied the cellular pathological features of NPC1 disease including endolysosomal cholesterol accumulation, lysosomal morphological changes, and response to the proteostasis modulator, mo56HC. The NPC1 phenotype was alleviated by 2-hydroxypropyl-β-cyclodextrin treatment, a drug demonstrating efficacy both in vitro and in vivo . This NPC1 I1061T/I1061T i 3 Neuronal cell line can facilitate future high-throughput drug and genomic screens, particularly those aimed at identifying proteostasis regulators that improve the expression/stability of the mutant NPC1 protein.

Niemann-Pick disease, type C1 (NPC1), is a rare, fatal neurodegenerative disorder caused by pathological variants in NPC1, which encodes a lysosomal cholesterol transporter. FDA-approved treatments are limited and do not target the underlying genetic defect. Both systemic and central nervous system delivery of AAV9-hNPC1 have shown significant disease amelioration in NPC1 murine models. To assess the impact of dose in null Npc1m1N/m1N mice, we systemically administered three different doses of AAV9-hNPC1 at 4 wk old. Then, to assess the impact of age, we administered the medium dose before phenotypic onset or at early or late stage of disease progression (4, 6, or 8 wk old, respectively). Higher vector doses and earlier treatment were associated with significantly increased lifespan, slower disease progression, and enhanced central nervous system transduction. In Npc1I1061T/I1061T mice, a model recapitulating a common human hypomorphic variant, similar benefits ensued. Our findings help define dose ranges, treatment ages, and efficacy in hypomorphic models of NPC1 deficiency and suggest that higher doses of AAV9-hNPC1 in presymptomatic disease states are likely to yield better outcomes in NPC1 individuals.

In 2018, the International Niemann-Pick Disease Alliance (INPDA) and the International Niemann-Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann-Pick disease type C (NPC)-an ultra-rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease-modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high-quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re-evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up-to-date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital-based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.

Abstract Background Niemann–Pick disease type C1 (NPC1) is a rare neurodegenerative disorder in which dysphagia is common and aspiration pneumonia is a leading cause of mortality. Aspiration may be clinically apparent or silent, reflecting impaired airway sensation and protective reflexes. We aimed to characterize aspiration and silent aspiration in the National Institutes of Health (NIH) NPC1 Natural History Study (NCT00344331). We analyzed 130 participants with NPC1 enrolled between 2006 and 2024 who underwent speech-language pathology swallowing evaluations, including clinically indicated videofluoroscopic swallow studies (VFSS). Aspiration risk was rated using the NIH Penetration–Aspiration Scale (NIH-PAS). Silent aspiration was defined as aspiration on VFSS without cough, throat clearing, or wet vocal quality. Longitudinal models examined the presence of silent aspiration alone or (2) a NIH-PAS score > 1 (moderate–profound aspiration) or silent aspiration. Covariates included demographics, neurologic disease onset and duration, body weight/BMI, reflux and seizure medications, miglustat use, NPC Neurological Severity Score (NSS) 5-domain total and subscores (including swallow and respiratory), and the Annualized Severity Increment Score (ASIS). Results Silent aspiration occurred in 24/130 (18.4%) participants. Among these, 50% demonstrated recurrent silent aspiration at subsequent visits, and 58.3% exhibited intermittent silent aspiration on follow-up. Considering aspiration risk, 27/130 (20.8%) had NIH-PAS > 1, including all silent aspirators. Silent aspiratiors alone had worse NIH-PAS, higher total NSS with poorer swallow, speech, ambulation, and fine-motor subscores, and higher ASIS. Patients with silent aspiration or NIH-PAS > 1 had an increased aspiration risk with longer neurologic symptom duration, seizure history, higher NSS, higher ASIS, and in children with lower weight percentile. Miglustat use was protective in the overall cohort, but not in the pediatric subgroup (< 20 years-old). Mean time to silent aspiration was ~ 10 years from neurologic symptom onset, with no difference by neurological disease onset. Conclusion Silent aspiration is common in NPC1 and closely linked to advancing neurologic disease severity than to age-of-onset phenotype. Bedside clinical evaluations may underestimate silent aspiration; proactive longitudinal swallowing surveillance is warranted in individuals with higher NSS/ASIS scores, seizure history, pediatric weight decline, or evolving motor-speech impairment. These findings support incorporating overt and silent aspiration alongside swallowing function, into routine care and therapeutic trials.

Neurodegeneration is a hallmark of Niemann-Pick disease type C1 (NPC1). One component in the pathology of neurodegeneration is increased lysosomal membrane permeability, especially in microglia. Leakage of lysosomal proteases, such as cathepsin B, into the cytoplasm and ultimately into the interstitial space can lead to activation of apoptosis and neuroinflammation. In line with previous reports showing the involvement of cathepsin B in neurodegeneration and the benefit of inhibiting cathepsin B to prevent neurodegeneration, we tested whether disease severity would be reduced in NPC1 mutant mice devoid of cathepsin B. Contrary to our expectation, the double mutant mice exhibited a more severe disease phenotype as measured by disease severity phenotypic scoring, beam walk latency test and a reduction in life expectancy. This highlights the importance of cathepsin B during postnatal development in the context of NPC1.

Background:Niemann-Pick disease, type C1 (NPC1), is a rare, fatal, neurodegenerative lysosomal disorder caused by pathological variants in NPC1. Defects in lysosomal cholesterol transport result in the accumulation of unesterified cholesterol within the endo-lysosomal compartments. Delayed diagnosis, limited treatment options, and phenotypic heterogeneity characterized by a broad range of signs/symptoms underscore the urgent need for effective biomarkers to facilitate diagnosis, monitor disease progression and assess therapeutic response. The goal of this study was to identify serum protein biomarkers for NPC1. Methods:Proximal Extension Assays (PEA) were used to determine relative protein expression levels from 68 serum samples from NPC1 individuals and 20 age-appropriate control serum samples. Statistical models identified NPC1 disease-specific effects after adjusting for covariates. Selected proteins were orthogonally validated by ELISA and correlated with assessments of both disease severity (Age of Neurological Onset (ANO) and Annual Severity Increment Score (ASIS)) and disease burden (NPC Neurological Severity Score (NSS). Results:Quantifiable data was obtained on 2888 proteins, revealing 186 increased (adjusted log2FC ≥ 1) and 286 decreased (adjusted log2FC ≤ -1) proteins with adj. p-value < 0.1 when comparing NPC1 individuals not being treated with miglustat versus control serum samples. Using orthogonal assays, we confirmed significant elevations for seven proteins: TREM2, AgRP, CCL18, Cathepsin L, GPNMB, NPY, and HSD17B14, and a significant decrease of BDNF. We further identified 100 proteins whose abundance levels were significantly altered towards normal by miglustat treatment. We found the 17-domain NPC NSS to be correlated with protein levels in the PEA data. Orthogonally validated data correlated with the age of neurological onset. We also identified 25 differentially abundant serum proteins in NPC1 baseline samples which are predominantly expressed in brain regions. Conclusions:The statistical analysis pipeline developed in this study is flexible and scalable and supports application to high-dimensional proteomic datasets. This study identified and validated serum proteins with altered expression in individuals with NPC1, responded to miglustat therapy, and correlated with disease severity or burden. These proteins may have clinical utility as biomarkers and provide insights into cellular mechanisms contributing to NPC1 disease pathology. Trial Registrations:NCT00344331 (Registration on 2006-06-23).

GM1 gangliosidosis is a progressive lysosomal storage disorder caused by β-galactosidase deficiency, resulting in accumulation of GM1 ganglioside and related glycoconjugates. Current diagnostic approaches rely on enzymatic and genetic testing but do not provide dynamic measures of substrate accumulation or therapeutic response. The oligosaccharide H3N2b has previously been identified as a potential biomarker of impaired β-galactosidase activity. In this study, H3N2b was quantified in plasma, urine, and cerebrospinal fluid (CSF) from patients with GM1 gangliosidosis (n = 47 plasma/urine; n = 34 CSF) and age- and sex-matched controls using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. A limited set of comparator lysosomal storage disorder samples was also analyzed to provide preliminary assessment of biomarker specificity. Longitudinal H3N2b measurements were obtained from participants receiving intravenous adeno-associated virus serotype 9 (AAV9)-mediated GLB1 gene therapy. H3N2b concentrations were significantly elevated in GM1 gangliosidosis compared with controls in plasma (cutoff 6.2 ng/mL; 100% sensitivity and specificity), urine (0.65 ng/μg creatinine; 99.3% sensitivity, 100% specificity), and CSF (5.1 ng/mL; 98.9% sensitivity, 100% specificity). H3N2b levels correlated with disease severity and were not influenced by age or sex. Among the comparator disorders analyzed, H3N2b values were generally below GM1 diagnostic cutoffs, although the comparator analysis was limited by sample availability and did not include several relevant disorders and CSF. In gene therapy recipients, plasma, urine, and CSF H3N2b concentrations decreased following treatment and closely paralleled changes in β-galactosidase activity, indicating pharmacodynamic responsiveness. These findings provide a cross-matrix clinical evaluation of H3N2b as a diagnostic and therapeutic biomarker for GM1 gangliosidosis and support its utility as a candidate biochemical biomarker to aid diagnosis and monitor treatment-associated biochemical changes.

Niemann-Pick disease, type C1 (NPC1) is a lysosomal disease that results in progressive loss of Purkinje neurons. Previous work has implicated dysregulation of glutamate signaling as a potential pathogenic mechanism. In this study, we explore the efficacy of AMPA receptor inhibition and the role of SLC1A6, a Purkinje neuron glutamate transporter, in NPC1 cerebellar pathology.

Niemann-Pick disease, type C1 (NPC1), is a rare, fatal neurodegenerative disorder caused by pathological variations in NPC1. We and others have previously demonstrated the efficacy of systemic adeno-associated virus (AAV) gene therapy with AAV9 in murine models of NPC1. The presence of neutralizing antibodies (NAbs) caused by natural exposure to wildtype AAVs may impair AAV transduction efficacy and reduce or negate the benefit of gene therapy. In addition, there remains the question of whether individuals seroconvert with age and whether seroconversion limits the window of therapeutic efficacy. Thus, we assessed the prevalence of anti-AAV9 and anti-AAV2 NAbs in serum samples from 22 individuals with NPC1 at two different time points: one closer to diagnosis (0.9-17 years old) and another collected between 4 and 15 years later during follow-up (6-28 years old). At a titer of <1:5, we found that more than half of the cohort lacked NAbs against either AAV2 (68.2%) or AAV9 (59.1% at time 1, 63.6% at time 2). Notably, only 3 out of 22 individuals showed a transition from undetectable to detectable NAb titers, and most participants maintained stable titers over time, unaffected by age. These data support the feasibility of systemic or direct CNS AAV9 gene therapy in this patient population.

Niemann-Pick Type C1 (NPC1) disease is a rare, autosomal recessive, neurovisceral lysosomal storage disorder caused by mutations in the NPC1. This condition leads to defective intracellular cholesterol and lipid trafficking, resulting in the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes. Clinically, NPC1 manifests with a heterogeneous spectrum of progressive neurological symptoms, including ataxia, vertical supranuclear gaze palsy, dysarthria, cognitive decline, and dystonia, often accompanied by systemic signs such as hepatosplenomegaly and neonatal cholestasis. The age of neurological symptom onset, rather than age at diagnosis, better reflects disease severity and progression, as delays in diagnosis are common due to phenotypic variability and lack of awareness. Therapeutic development for NPC1 has been historically limited, with miglustat approved in some regions for off-label use and 2-hydroxypropyl-β-cyclodextrin currently under clinical investigation. Recent advances in disease understanding have prompted the development of pharmacodynamic, diagnostic, and prognostic biomarkers to support earlier diagnosis and monitor therapeutic efficacy. Dysregulation of cholesterol homeostasis, neuroinflammation, and neuronal loss have guided biomarker discovery, with promising candidates including 24(S)-hydroxycholesterol, neurofilament light chain, and bile acid derivatives such as 3β,5α,6β-trihydroxycholanic acid. Novel lipid biomarkers including N-palmitoyl-O-phosphocholine-serine and oxysterols such as 7-ketocholesterol and cholestane-3β,5α,6β-triol also show diagnostic value. Despite growing mechanistic insight and a robust pipeline of candidate biomarkers and therapies, NPC1 remains a life-limiting disease with significant diagnostic and therapeutic gaps. Ongoing clinical trials and translational research are essential to accelerate biomarker qualification and regulatory approval of disease-modifying treatments. A comprehensive, mechanistically driven approach that integrates molecular, biochemical, and clinical endpoints is key to advancing precision medicine for NPC1.

The 5-Domain Niemann Pick Type C Clinical Severity Scale (5DNPCCSS) is used in clinical practice and trials. Although psychometric data support the clinical meaningfulness of the concepts and the scale's interrater reliability, more information is needed to support its construct validity. Here, we evaluated the convergent validity of the Cognition, Speech, and Fine Motor domains. Data from 121 individuals with Niemann-Pick disease type C were drawn from several studies conducted at 2 US sites. Direct standardized assessments included the Nine-Hole pegboard or Purdue pegboard, a portion of the Clinical Evaluation of Language Fundamentals, and the age-appropriate Wechsler IQ test or the Mullen Scales of Early Learning. The 5DNPCCSS domains were significantly related in the expected directions to their respective direct assessments, supporting their construct validity. In combination with previous evidence presented for the Ambulation and Swallow domains, these results support the fitness of purpose of the (5DNPCCSS for clinical studies in Niemann-Pick disease type C. ClinicalTrials.gov: NCT00344331, NCT01747135, NCT02534844.

Background:In the 12-month, randomized, double-blind, placebo-controlled Phase 2/3 NPC-002 study (NCT02612129), arimoclomol significantly reduced annual disease progression versus placebo, measured by the 5-domain NPC Clinical Severity Scale (5DNPCCSS). Arimoclomol has been approved in the US for treatment of Niemann-Pick disease type C (NPC) in combination with miglustat. This paper introduces the rescored 4-domain NPCCSS (R4DNPCCSS) as a post-hoc primary endpoint in NPC-002, discusses its validation, and presents the results of the post-hoc primary analysis. Methods:To more accurately assess changes in disease course over a 12-month time period in a heterogeneous group of patients, the Cognition domain was removed from the 5DNPCCSS and the Swallow domain was rescored to reflect linearity in disease progression. Rescoring of the Swallow domain was based on input from clinical NPC and swallow experts from a qualitative interview-based study (N = 12), resulting in the R4DNPCCSS. To supplement prior validation analyses, data supporting the overall validity and reliability of the R4DNPCCSS was gathered through additional analyses of construct and convergent validity. The NPC-002 prespecified primary efficacy endpoint analysis based on the 5DNPCCSS score change from baseline to 12 months was repeated with R4DNPCCSS. Results:Construct validity analysis demonstrated high agreement between the R4DNPCCSS domain scores and the Clinical Global Impression Scale of Severity (CGI-S) and NPC Clinical Database (NPC-cdb) scores. Convergent validity was confirmed by strong correlations between the R4DNPCCSS domains and corresponding items on the Scale for Assessment and Rating of Ataxia (SARA), 9-hole peg test (9-HPT), and Video Fluoroscopic Swallowing Study (VFSS) performance tests. The NPC-002 post-hoc primary analysis showed a mean standard error (SE) change in R4DNPCCSS score of 0.35 (0.40) with arimoclomol (N = 34) versus 2.05 (0.54) with placebo (N = 16), and a treatment effect in favor of arimoclomol over placebo of -1.70 (p = 0.0155). In the miglustat subgroup analysis, mean (SE) change in R4DNPCCSS score was -0.23 (1.02) with arimoclomol (N = 22) versus 1.92 (3.37) with placebo (N = 12), representing a treatment effect of -2.21 (p = 0.0077). Conclusion:The R4DNPCCSS is a valid and reliable measure of disease progression demonstrating consistent outcomes with the prespecified 5DNPCCSS endpoint. Arimoclomol significantly slowed disease progression through 12 months as measured by the R4DNPCCSS versus placebo.

BACKGROUND:The purpose of the Vigilan observational study (ClinicalTrials.gov, NCT02931682) was to prospectively assess the natural history and developmental course of creatine transporter deficiency (CTD). METHODS:Males with CTD aged 6 months to 65 years were evaluated at 6-month intervals for up to 4 years. Evaluations included neurodevelopmental assessments of intellectual functioning, adaptive functioning, challenging behaviors and the onset and progression of medical comorbidities. RESULTS:Fifty participants (median age, 7.6 years) were enrolled. The predominant CTD phenotype consisted of significant intellectual disabilities and limited skill development over time. Most participants had a history of febrile or nonfebrile seizures, gastrointestinal symptoms, and growth failure. All participants learned how to walk, 78% developed at least some verbal speech, and 34% communicated using phrases or sentences. Norm-referenced neurodevelopment assessments indicated declining standardized scores over time; however, absolute scores (i.e., age equivalent person ability scores) indicated that developmental gains were slower than average, particularly among older participants. Between-person differences in neurodevelopmental skills as a function of age did not match within-person change, suggesting a cohort effect. CONCLUSIONS:In this cohort, CTD was associated with significant and persistent intellectual disability. The use of absolute metrics from neurodevelopmental tests (e.g., person ability scores) allowed for the quantification of slow, but present, skill development.

Smith-Lemli-Opitz Syndrome (SLOS) is a rare, autosomal recessive, neurocognitive disorder caused by pathological variants in the 7-dehydrocholesterol reductase gene (DHCR7), leading to impaired cholesterol biosynthesis. The biochemical results of these defects include the accumulation of the cholesterol precursor, 7-dehydrocholesterol (7-DHC), and typically reduced cholesterol. Individuals with SLOS present with a spectrum of developmental anomalies and neurocognitive impairments. Despite various therapeutic approaches being explored, there is no curative treatment, highlighting the need for reliable biomarkers to better understand the disease's pathophysiology, allowing for important therapeutic intervention studies. Here, we utilized discovery-based mass spectrometry to perform quantitative proteomic profiling of cerebrospinal fluid (CSF) from SLOS individuals compared to unaffected controls. Our analyses identified several differentially expressed proteins that could serve as potential biomarkers for assessing therapeutic efficacy and advancing our understanding of SLOS. Notably, we observed previously unrecognized alterations in the reelin signaling pathway and a decrease in dopamine excretion, implicating these processes in the development and progression of the SLOS.

Purpose:Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disease caused by pathological variants in NPC1. Analysis of serum neurofilament light (NfL), a marker of neuronal damage, could be useful as a biomarker for patient monitoring and clinical trial design. Methods:We measured NfL levels in serum samples from 118 well-characterized individuals with NPC1 and analyzed them with respect to clinical measures and treatment status. Results:The results show a 6.1-fold increase in serum NfL in individuals with NPC1 compared with age-appropriate controls. Moreover, serum NfL levels showed a significant positive correlation with age of neurological symptom onset and the annual severity increment score. Serum NfL levels were also positively correlated with the 17- and 5-domain NPC Neurological Severity Scores. Longitudinal analyses reveal a 26% reduction in serum NfL levels in individuals on miglustat, a therapeutic drug used off-label for the treatment of NPC1 in the United States of America. Effectiveness of intrathecal hydroxypropyl-β-cyclodextrin treatment may be more beneficial in younger individuals. To help inform clinical trial design, our modeling predicts that a measurable reduction of serum NfL levels might be observed after 8 months of treatment with a potential drug exhibiting 10% to 20% efficacy. Conclusion:Our data suggest that NfL may be a useful serum biomarker for NPC1.