scholarly journals Expanded access with intravenous hydroxypropyl-β-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Caroline Hastings ◽  
Camilo Vieira ◽  
Benny Liu ◽  
Cyrus Bascon ◽  
Claire Gao ◽  
...  
Keyword(s):  
Disease Type ◽  
Lysosomal Storage ◽  
Safety Issues ◽  
Expanded Access ◽  
Niemann Pick Disease ◽  
The Us ◽  
Progression Of Disease ◽  
Report Analysis ◽  
Niemann Pick ◽  
Pick Disease

Abstract Background Niemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPβPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPβCD has been administered to NPC patients with approved INDs globally since 2009. Results Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPβCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPβCD following on average 13 months of IV HPβCD. Several patients transitioned to an alternate HPβCD. Moderately affected NPC patients treated with HPβCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer. Conclusions These expanded access data support the safety and potential benefit of systemic IV administration of HPβCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPβCD in NPC patients.

scholarly journals Invariant natural killer T cells are not affected by lysosomal storage in patients with Niemann-Pick disease type C

2012 ◽  
Vol 42 (7) ◽  
pp. 1886-1892 ◽  
Author(s):  
Anneliese O. Speak ◽  
Nicholas Platt ◽  
Mariolina Salio ◽  
Danielle te Vruchte ◽  
David A. Smith ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer T Cells ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Killer T Cells ◽  
Invariant Natural Killer ◽  
Pick Disease

scholarly journals Human iNSC-derived brain organoid model of lysosomal storage disorder in Niemann–Pick disease type C

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Seung-Eun Lee ◽  
Nari Shin ◽  
Myung Geun Kook ◽  
Dasom Kong ◽  
Nam Gyo Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Lysosomal Storage Disorder ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Storage Disorder ◽  
Niemann Pick ◽  
Pick Disease

AbstractRecent studies on developing three-dimensional (3D) brain organoids from stem cells have allowed the generation of in vitro models of neural disease and have enabled the screening of drugs because these organoids mimic the complexity of neural tissue. Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in the NPC1 or NPC2. The pathological features underlying NPC are characterized by the abnormal accumulation of cholesterol in acidic compartments, including late endosomes and lysosomes. Due to the inaccessibility of brain tissues from human NPC patients, we developed NPC brain organoids with induced neural stem cells from NPC patient-derived fibroblasts. NPC organoids exhibit significantly reduced size and proliferative ability, which are accompanied by accumulation of cholesterol, impairment in neuronal differentiation, and autophagic flux and dysfunction of lysosomes; therefore, NPC organoids can recapitulate the main phenotypes of NPC patients. Furthermore, these pathological phenotypes observed in NPC organoids were reversed by treatment with valproic acid and HPBCD, which are known to be an effective treatment for several neurodegenerative diseases. Our data present patient-specific phenotypes in 3D organoid-based models of NPC and highlight the application of this model to drug screening in vitro.

scholarly journals Altered distribution and function of natural killer cells in murine and human Niemann-Pick disease type C1

Blood ◽  
2014 ◽  
Vol 123 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Anneliese O. Speak ◽  
Danielle te Vruchte ◽  
Lianne C. Davis ◽  
Anthony J. Morgan ◽  
David A. Smith ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Nk Cell ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Cell Frequency ◽  
Niemann Pick Disease ◽  
Key Points ◽  
Niemann Pick ◽  
And Function ◽  
Pick Disease

Key Points Lysosomal storage affects NK-cell frequency, development, and function. Lysosomal calcium is important for NK-cell degranulation.

scholarly journals Adeno-associated viral vector serotype 9–based gene therapy for Niemann-Pick disease type A

2019 ◽  
Vol 11 (506) ◽  
pp. eaat3738 ◽  
Author(s):  
Lluis Samaranch ◽  
Azucena Pérez-Cañamás ◽  
Beatriz Soto-Huelin ◽  
Vivek Sudhakar ◽  
Jerónimo Jurado-Arjona ◽  
...  
Keyword(s):  
Mouse Model ◽  
Viral Vector ◽  
Type A ◽  
Disease Type ◽  
Acid Sphingomyelinase ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Pick Disease

Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. Here, we evaluated the safety of cerebellomedullary (CM) cistern injection of adeno-associated viral vector serotype 9 encoding human ASM (AAV9-hASM) in nonhuman primates (NHP). We also evaluated its therapeutic benefit in a mouse model of the disease (ASM-KO mice). We found that CM injection in NHP resulted in widespread transgene expression within brain and spinal cord cells without signs of toxicity. CM injection in the ASM-KO mouse model resulted in hASM expression in cerebrospinal fluid and in different brain areas without triggering an inflammatory response. In contrast, direct cerebellar injection of AAV9-hASM triggered immune response. We also identified a minimally effective therapeutic dose for CM injection of AAV9-hASM in mice. Two months after administration, the treatment prevented motor and memory impairment, sphingomyelin (SM) accumulation, lysosomal enlargement, and neuronal death in ASM-KO mice. ASM activity was also detected in plasma from AAV9-hASM CM-injected ASM-KO mice, along with reduced SM amount and decreased inflammation in the liver. Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders.

scholarly journals Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C

2017 ◽  
Vol 2 ◽  
pp. 76 ◽  
Author(s):  
Elena-Raluca Nicoli ◽  
David Smith ◽  
Lauren Morris ◽  
Frances M. Platt
Keyword(s):  
Bile Acid ◽  
Mouse Model ◽  
Acid Treatment ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Cholanic Acid ◽  
Pick Disease

Niemann-Pick disease type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and in post-mortem liver from NPC patients. As bile acids regulate the P450 system, we tested bile acid treatment using ursodeoxycholic acid (UDCA; 3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, which is used to treat several cholestatic disorders. In this study, we compared UDCA treatment with the bile acid cholic acid (CA), and found unexpected hepatotoxicity in response to CA in Npc1 mice, but not to UDCA, suggesting that only UDCA should be used as an adjunctive therapy in NPC patients.

scholarly journals Sphingomyelin Lipidosis in a Cat

1987 ◽  
Vol 24 (5) ◽  
pp. 386-391 ◽  
Author(s):  
H. J. Baker ◽  
P. A. Wood ◽  
D. A. Wenger ◽  
S. U. Walkley ◽  
K. Inui ◽  
...  
Keyword(s):  
Lysosomal Storage Disease ◽  
Storage Disease ◽  
Disease Type ◽  
Neurological Dysfunction ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolase ◽  
Ultrastructural Examination ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Pick Disease

A 7-month-old Balinese cat with progressive neurological dysfunction had histopathological lesions of brain, liver, kidney, spleen, and lung consistent with a lysosomal storage disease. Ultrastructural examination revealed lysosomal hypertrophy with membranous inclusions. Hepatic sphingomyelin and cholesterol were elevated 10 times normal, and total phospholipids were increased 3.6 fold. Sphingomyelinase activity measured with 14C labeled sphingomyelin at pH 5.0 was virtually absent in brain and liver. Other lysosomal hydrolase activities were normal or elevated. Clinical, morphological, and biochemical findings suggest that this cat had sphingomyelin lipidosis similar to human Niemann-Pick disease type A, and that feline sphingomyelin lipidosis provides another model of human lysosomal storage disease.

Niemann-Pick Disease Type C with Isolated Splenomegaly: A Case Report in a Child

2021 ◽  
Author(s):  
Bruna Ribeiro Torres ◽  
Daniela Otoni Russo ◽  
Vinícius Andrade Gomes Vuolo ◽  
Tarcísio Silva Borborema ◽  
André Vinícius Soares Barbosa ◽  
...  
Keyword(s):  
Autosomal Recessive Inheritance ◽  
Signs And Symptoms ◽  
Disease Type ◽  
Sphingolipid Metabolism ◽  
Neurological Involvement ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

AbstractNiemann-Pick disease type C is an innate error of lysosomal storage metabolism with an autosomal recessive inheritance pattern. The disease causes intracellular cholesterol accumulation and changes in sphingolipid metabolism. If cholesterol accumulates, the signs and symptoms of visceral involvement predominate. Neurological involvement results from sphingolipid accumulation. A 7-year-old student was referred to a tertiary service for the investigation of asymptomatic splenomegaly. Following an extensive examination, he was diagnosed with Niemann-Pick disease type C. Interestingly, this case's only symptom was splenomegaly.

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