Medicine:Niemann–Pick disease, type C

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Niemann–Pick disease, type C
Protein NPC1 PDB 3GKH.png
Niemann–Pick disease, type C is associated with NPC1 mutations

Niemann–Pick type C (NPC) (colloquially, "Childhood Alzheimer's"[1]) is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people.[2] Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.

Signs and symptoms

Niemann–Pick type C has a wide clinical spectrum. Affected individuals may have enlargement of the spleen (splenomegaly) and liver (hepatomegaly), or enlarged spleen or liver combined (hepatosplenomegaly), but this finding may be absent in later onset cases. Prolonged jaundice or elevated bilirubin can present at birth. In some cases, however, enlargement of the spleen or liver does not occur for months or years – or not at all. Enlargement of the spleen or liver frequently becomes less apparent with time, in contrast to the progression of other lysosomal storage diseases such as Niemann–Pick disease, Types A and B or Gaucher disease. Organ enlargement does not usually cause major complications.[citation needed]

Progressive neurological disease is the hallmark of Niemann–Pick type C disease, and is responsible for disability and premature death in all cases beyond early childhood.[3] Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia).[citation needed]

Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with inturning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, progressive dementia, progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor.[citation needed]

In the terminal stages of Niemann–Pick type C disease, the patient is bedridden, with complete ophthalmoplegia, loss of volitional movement and severe dementia.

Genetics

Approximately 95% of Niemann–Pick type C cases are caused by genetic mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene, referred to as type C2.[4] The clinical manifestations of types Niemann–Pick types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. The NPC1 gene is located on chromosome 18 (18q11-q12) and was described by researchers at the National Institutes of Health in July 1997.[5]

  • The NPC1 gene encodes a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells.[6] A deficiency of this protein leads to the abnormal buildup of lipids and cholesterol within cell membranes.
  • The NPC2 gene encodes a protein that binds and transports cholesterol.[7][8] It has been shown to closely interact with NPC1.[9][10]

"Type D" variant

Type D Niemann–Pick has only been found in the French Canadian population of Yarmouth County, Nova Scotia, and is now known to be allelic with Niemann–Pick type C.

Genealogical research indicates that Joseph Muise (c. 1679–1729) and Marie Amirault (1684 – c. 1735) are common ancestors to all people with Type D. This couple is the most likely origin for the type D variant.[11]

Pathophysiology

Niemann–Pick type C is biochemically, genetically and clinically distinct from Niemann–Pick Types A or and B. In Types A and B, there is complete or partial deficiency of the lysosomal enzyme called acid sphingomyelinase. In Niemann–Pick type C, the protein product of the major mutated gene NPC1 is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes.[12]

Cholesterol and glycolipids have varied roles in the cell. Cholesterol is a major component of cell plasma membranes, which define the cell as a whole and its organelles. It is also the basic building block of steroid hormones, including neurosteroids. In Niemann–Pick type C, large amounts of free or unesterified cholesterol accumulate in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis. The accumulation of glycosphingolipids in the nervous system has been linked to structural changes, namely ectopic dendritogenesis and meganeurite formation, and has been targeted therapeutically.[citation needed]

Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein.

  • Neufeld et al. hypothesized that the accumulation of mannose 6-phosphate receptors (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans Golgi network.[13]
  • Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the trans Golgi Network cannot bud and form.
  • Iouannou, et al. have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1.[14]
  • Recent 2008 evidence indicates that NPC-1 may play an important role in calcium regulation.[15]

Diagnosis

Niemann–Pick type C is diagnosed by assaying cultured fibroblasts for cholesterol esterification and staining for unesterified cholesterol with filipin. The fibroblasts are grown from a small skin biopsy taken from a patient with suspected NPC. The diagnosis can be confirmed by identifying mutations in the NPC1 or NPC2 genes in 80–90% of cases. This specialized testing is available at Thomas Jefferson University Lysosomal Disease Testing Lab[16] and the Mayo Clinic.[17]

Treatment

There is no known cure for Niemann–Pick type C, nor is there any FDA-standard approved disease modifying treatment.[18] Supportive care is essential and substantially improves the quality of life of people affected by NPC. The therapeutic team may include specialists in neurology, pulmonology, gastroenterology, psychiatrist, orthopedics, nutrition, physical therapy and occupational therapy. Standard medications used to treat symptoms can be used in NPC patients. As patients develop difficulty with swallowing, food may need to be softened or thickened, and eventually, parents will need to consider placement of a gastrostomy tube (g-tube, feeding tube).[19]

Arimoclomol

In 2014, the European Medicines Agency (EMA) granted orphan drug designation to arimoclomol for the treatment of Niemann–Pick type C.[20] This was followed in 2015 by the U.S. Food and Drug Administration (FDA).[21] Dosing in a placebo-controlled phase II/III clinical trial to investigate treatment for Niemann–Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016.[22] Arimoclomol, which is orally administered, induces the heat shock response in cells and is well tolerated in humans.[23][24][25][26][excessive citations] In 2018, the Sponsor announced the trial did not meet either its primary or secondary endpoints.[27] On July 17, 2021, the US Food and Drug Administration rejected the New Drug Application for Arimoclomol, and issued a complete response letter to the company Sponsor.[28]

Hydroxypropyl-beta-cyclodextrin (HPbCD)

In April 2009, hydroxypropyl-beta-cyclodextrin (HPbCD) was approved under compassionate use by the U.S. Food and Drug Administration (FDA) to treat Addison and Cassidy Hempel,[29] identical twin girls who had Niemann–Pick type C disease. Medi-ports, similar to ports used to administer chemotherapy drugs, were surgically placed into the twins' chest walls and allow doctors to directly infuse HPbCD into their bloodstreams. Treatment with cyclodextrin has been shown to delay clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan in both the Niemann–Pick type C mice[30] and feline[31] models. This is the second time in the United States that cyclodextrin alone has been administered in an attempt treat a fatal pediatric disease. In 1987, HPbCD was used in a medical case involving a boy with severe hypervitaminosis A.[32]

On May 17, 2010, the FDA granted Hydroxypropyl-beta-cyclodextrin orphan drug status and designated HPbCD cyclodextrin as a potential treatment for Niemann–Pick type C disease. On July 14, 2010, Dr. Caroline Hastings of UCSF Benioff Children's Hospital Oakland filed additional applications with the FDA requesting approval to deliver HPbCD directly into the central nervous systems of the twins in an attempt to help HPbCD cross the blood–brain barrier. The request was approved by the FDA on September 23, 2010, and bi-monthly intrathecal injections of HPbCD into the spine were administered starting in October 2010.[citation needed]

On December 25, 2010, the FDA granted approval for HPbCD to be delivered via IV to an additional patient, Peyton Hadley, aged 13, under an IND with Dr. Diane Williams, through Asante Rogue Regional Medical Center in Medford, Oregon. Soon after in March 2011, approval was sought for similar treatment of his sibling, Kayla, age 11, and infusions of HPbCD began shortly after. Both began intrathecal treatments beginning January 2012. In 2014 Peyton had an intrathecal smart port placed by OHSU's neurosurgeon Dr. Lissa Baird, to alleviate sedation during the intrathecal procedures. It was successful and continues to be used for treatment (currently 2023). They continue in 2023 to receive both IV and IT treatments; 8 hour IV from home twice monthly, and IT twice monthly at Asante Rogue Regional Medical Center, rotating with IV and IT every week. These patients have proven safety and benefit shown by NIH Severity Scale Assessments, one slightly less impacted than projected and the other with a profound impact and benefit than projected.[33]

In April 2011, the National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), announced they were developing a clinical trial utilizing cyclodextrin for Niemann–Pick type C patients.[citation needed]

On September 20, 2011, the European Medicines Agency (EMA) granted HPbCD orphan drug status and designated the compound as a potential treatment for Niemann–Pick type C disease.[citation needed]

On December 31, 2011, the FDA granted approval for IV HPbCD infusions for a fifth child in the United States, Chase DiGiovanni, under a compassionate use protocol. The child was 29 months old at the time of his first intravenous infusion, which was started in January 2012.[34]

Due to unprecedented collaboration between individual physicians and parents of children affected by NPC, approximately 15 patients worldwide have received HPbCD cyclodextrin therapy under compassionate use treatment protocols. Treatment involves a combination of intravenous therapy (IV), intrathecal therapy (IT) and intracerebroventricular (ICV) cyclodextrin therapy.

On January 23, 2013, a formal clinical trial to evaluate HPβCD cyclodextrin therapy as a treatment for Niemann–Pick disease, type C was announced by scientists from the NIH's National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

In January 2021, the Sponsor (Mallinckrodt Pharmaceuticals) concluded that the benefit / risk balance for HPβCD cyclodextrin (adrabetadex) for the treatment of neurologic symptoms of NPC was negative, and that the risks associated with the treatment outweigh the potential benefit. Effective immediately, Mallinckrodt recommended that treatment with adrabetadex be discontinued as soon as possible, with the appropriate physician oversight.[35]

N-Acetyl-Leucine

N-Acetyl-Leucine is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc.[36]

N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of various genetic diseases, including Niemann-Pick Disease Type C. The US FDA has granted IntraBio a Rare Pediatric Disease Designation for N-Acetyl-Leucine for the treatment of NPC.[37]

Observational studies in NPC patients have demonstrated the symptomatic, as well as disease-modifying, neuroprotective effect of treatment. These studies further demonstrated that the treatment is well tolerated, with a good safety profile.[38]

In September 2020, IntraBio announced the successful results of a multinational clinical trial with N-acetyl-L-leucine (IB1001) for NPC, which demonstrated IB1001 demonstrated a statistically significant change in both primary and secondary endpoints, and clinically meaningful improvement in symptoms, functioning, and quality of life.[39] 

IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff)[40] and Ataxia-Telangiectasia.[41] Future opportunities to develop N-Acetyl-Leucine include Lewy body dementia,[42] amyotrophic lateral sclerosis, restless leg syndrome, multiple sclerosis, and migraine.[43]

Other treatments under investigation

One drug that has been tried is Miglustat.[44][45] Miglustat is a glucosylceramide synthase inhibitor, which inhibits the synthesis of glycosphingolipids in cells. It has been shown to delay the onset of disease in the NPC mouse, and published data from a multi-center clinical trial of Miglustat in the United States and England and from case reports suggests that it may ameliorate the course of human NPC.[citation needed]

Several other treatment strategies are under investigation in cell culture and animal models of NPC. These include, cholesterol mobilization, neurosteroid (a special type of hormone that affects brain and other nerve cells) replacement using allopregnanolone,[4][46] rab overexpression to bypass the trafficking block (Pagano lab) and Curcumin as an anti-inflammatory and calcium modulatory agent.[15] The pregnane X receptor has been identified as a potential target.[47]

Neural stem cells have also been investigated in an animal model, and clear evidence of life extension in the mouse model has been shown.[48]

Low cholesterol diets are often used,[49] but there is no evidence of efficacy.[50]

Gene therapy is being used clinically to treat genetic diseases including haemophilia[51] and spinal muscular atrophy.[52] It has been used preclinically, in a mouse model of Niemann-Pick type C, using an adeno-associated virus derived viral vector has been shown to extend lifespan following injection into the lateral ventricles of the neonatal brain.[53] In a separate proof-of-concept study a similar vector, but with a modified capsid capable of delivering genes to the central nervous system following intravenous injection, was given to Niemann-Pick type C mice at around four weeks of age; this resulted in extended lifespan and improved weight gain.[54]

Prognosis

The lifespan of patients with NPC is usually related to the age of onset. Children with antenatal or infantile onset usually succumb in the first few months or years of life, whereas adolescent and adult onset forms of Niemann–Pick type C have a more insidious onset and slower progression, and affected individuals may survive to the seventh decade. Adult cases of NPC are being recognized with increasing frequency. It is suspected that many patients affected by NPC are undiagnosed, owing to lack of awareness of the disease and the absence of readily available screening or diagnostic tests. For the same reasons the diagnosis is often delayed by many years.[citation needed]

Research directions

Loss of myelin in the central nervous system is considered to be a main pathogenic factor. Research uses animal models carrying the underlying mutation for Niemann–Pick disease, e.g. a mutation in the NPC1 gene Niemann–Pick type C disease. In this model the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased.[55] MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths.[56] A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.[55]

Recent neuroimaging studies have shown patients with Niemann–Pick, type C to have a corpus callosum with microstructural abnormalities. Clear reductions in corpus callosum mean thickness and surface area have been shown when compared to age-matched controls.[57][58] Also, studies using diffusion tensor imaging have shown marked reductions in callosal fractional anisotropy, which suggests architectural abnormalities based on the directional flow of water.[58][59] These conclusions suggest that the corpus callosum plays an important role in the disease and should be explored for use as a biomarker of disease progression.[citation needed]

Parents of children with NPC are being studied in an attempt to gain insight into the Ebola virus, which uses the protein encoded by NPC1 to enter cells. Researchers have found that mice with one normal copy of the NPC1 gene are more likely to survive Ebola infection than mice with normal two copies of the gene. Mice lacking any normal copy of NPC1 all survived. Studying cells from parents who are NPC disease carriers may allow for better understanding of how changes to the NPC1 gene affect Ebola risk.[60]

Findings from Zhang et al.[61] suggest that NPC is a late endocytic trafficking disease resulted, at least in part, from disruption of communication within late endocytic (LE) compartments and possibly between LE and other subcellular organelles. Crosstalk between the late endocytic compartment and other organelles such as mitochondria, endoplasmic reticulum, plasma membrane, as well as early endocytic compartments has become one of the most interesting frontiers in neurondegenerative disease research including Alzheimer's disease, Parkinson's disease, as well as lysosomal storage disorders.[62][63]

References

  1. ↑ "What Is 'Childhood Alzheimer's'? An Expert Explains" (in en). https://blogs.webmd.com/webmd-interviews/20170928/what-is-childhood-alzheimers-an-expert-explains. 
  2. ↑ "Niemann-Pick type C disease and intracellular cholesterol trafficking". The Journal of Biological Chemistry 280 (22): 20917–20920. June 2005. doi:10.1074/jbc.R400040200. PMID 15831488. 
  3. ↑ "TNF-alpha plays a role in hepatocyte apoptosis in Niemann-Pick type C liver disease". Journal of Lipid Research 50 (2): 327–333. February 2009. doi:10.1194/jlr.M800415-JLR200. PMID 18815434. 
  4. ↑ 4.0 4.1 "Endogenous and synthetic neurosteroids in treatment of Niemann-Pick Type C disease". Brain Research Reviews 57 (2): 410–420. March 2008. doi:10.1016/j.brainresrev.2007.05.012. PMID 17629950. 
  5. ↑ "NIH Scientists Identify Gene for Fatal Childhood Disorder, Niemann–Pick Type C". Newsroom. National Human Genome Research Institute. July 1997. http://www.genome.gov/10000889. 
  6. ↑ "Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking". The Journal of Clinical Investigation 118 (6): 2281–2290. June 2008. doi:10.1172/JCI32561. PMID 18483620. 
  7. ↑ "Niemann-Pick disease type C2 presenting as fatal pulmonary alveolar lipoproteinosis: morphological findings in lung and nervous tissue". Medical Science Monitor 14 (8): CS71–CS75. August 2008. PMID 18668002. http://www.medscimonit.com/fulltxt.php?ICID=865795. 
  8. ↑ "NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols". The Journal of Biological Chemistry 281 (48): 36710–36723. December 2006. doi:10.1074/jbc.M608743200. PMID 17018531. 
  9. ↑ "NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes". Proceedings of the National Academy of Sciences of the United States of America 105 (40): 15287–15292. October 2008. doi:10.1073/pnas.0807328105. PMID 18772377. 
  10. ↑ "NPC1/NPC2 function as a tag team duo to mobilize cholesterol". Proceedings of the National Academy of Sciences of the United States of America 105 (40): 15223–15224. October 2008. doi:10.1073/pnas.0808256105. PMID 18832164. Bibcode: 2008PNAS..10515223S. 
  11. ↑ "Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D)". American Journal of Human Genetics 30 (5): 530–538. September 1978. PMID 736041. 
  12. ↑ "Mass spectrometry imaging reveals ganglioside and ceramide localization patterns during cerebellar degeneration in the Npc1-/- mouse model". Analytical and Bioanalytical Chemistry 411 (22): 5659–5668. September 2019. doi:10.1007/s00216-019-01989-7. PMID 31254056. 
  13. ↑ "The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo". The Journal of Biological Chemistry 274 (14): 9627–9635. April 1999. doi:10.1074/jbc.274.14.9627. PMID 10092649. 
  14. ↑ "Transmembrane molecular pump activity of Niemann-Pick C1 protein". Science 290 (5500): 2295–2298. December 2000. doi:10.1126/science.290.5500.2295. PMID 11125140. Bibcode: 2000Sci...290.2295D. 
  15. ↑ 15.0 15.1 "Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium". Nature Medicine 14 (11): 1247–1255. November 2008. doi:10.1038/nm.1876. PMID 18953351. 
  16. ↑ "Thomas Jefferson University – Lysosomal Diseases Testing Laboratory". http://www.jefferson.edu/lysolab/tests.cfm+. 
  17. ↑ "Niemann–Pick Diagnosis". http://www.mayoclinic.org/Niemann–Pick/diagnosis.html. 
  18. ↑ "The pathogenesis of Niemann-Pick type C disease: a role for autophagy?". Expert Reviews in Molecular Medicine 10: e26. September 2008. doi:10.1017/S146239940800080X. PMID 18782459. 
  19. ↑ "Niemann–Pick Disease Type C". GeneReviews™ [Internet]. Seattle WA: University of Washington, Seattle. 2013-07-18. NBK1296. https://www.ncbi.nlm.nih.gov/books/NBK1296/. 
  20. ↑ "European Medicines Agency - - EU/3/14/1376". 2018-09-17. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2015/01/human_orphan_001465.jsp&mid=WC0b01ac058001d12b. 
  21. ↑ "Search Orphan Drug Designations and Approvals". https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=458814.  This article incorporates text from this source, which is in the public domain.
  22. ↑ Clinical trial number NCT02612129 for "Arimoclomol Prospective Study in Patients Diagnosed With NiemannPick Disease Type C" at ClinicalTrials.gov
  23. ↑ "Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses". Science Translational Medicine 8 (355): 355ra118. September 2016. doi:10.1126/scitranslmed.aad9823. PMID 27605553. 
  24. ↑ "Targeting protein homeostasis in sporadic inclusion body myositis". Science Translational Medicine 8 (331): 331ra41. March 2016. doi:10.1126/scitranslmed.aad4583. PMID 27009270. 
  25. ↑ "Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats". Free Radical Biology & Medicine 32 (12): 1283–1292. June 2002. doi:10.1016/s0891-5849(02)00833-x. PMID 12057766. 
  26. ↑ "Arimoclomol: a potential therapy under development for ALS". Expert Opinion on Investigational Drugs 18 (12): 1907–1918. December 2009. doi:10.1517/13543780903357486. PMID 19938902. 
  27. ↑ "ORPHAZYME REPORTS ENCOURAGING ARIMOCLOMOL CLINICAL TRIAL TOP-LINE DATA IN NIEMANN-PICK DISEASE TYPE C (NPC)". https://nnpdf.org/files/2018/09/ORPHAZYME-Reports-Arimoclomol-Trial-Data-NPC-9.28.2018.pdf. 
  28. ↑ "ORPHAZYME REPORTS ENCOURAGING ARIMOCLOMOL CLINICAL TRIAL TOP-LINE DATA IN NIEMANN-PICK DISEASE TYPE C (NPC)". https://nnpdf.org/files/2018/09/ORPHAZYME-Reports-Arimoclomol-Trial-Data-NPC-9.28.2018.pdf. 
  29. ↑ "The Addi and Cassi Fund - Niemann Pick Type-C - Childhood Alzheimer's". http://www.addiandcassi.com. 
  30. ↑ "Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression". PLOS ONE 4 (9): e6951. September 2009. doi:10.1371/journal.pone.0006951. PMID 19750228. Bibcode: 2009PLoSO...4.6951D. 
  31. ↑ "2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease". Pediatric Research 68 (1): 52–56. July 2010. doi:10.1203/PDR.0b013e3181df4623. PMID 20357695. 
  32. ↑ "Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake". The Journal of Pediatrics 111 (4): 507–512. October 1987. doi:10.1016/S0022-3476(87)80109-9. PMID 3655980. 
  33. ↑ "Hadley Hope - Niemann–Pick Type C Disease - HOME". http://www.hadleyhope.com. 
  34. ↑ "Chase the Cure". http://www.chasethecure.net. 
  35. ↑ "Letter to Joslyn and Justin". https://nnpdf.org/files/2021/01/MNK-01202021.pdf. 
  36. ↑ "A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia". Trials 22 (1): 84. January 2021. doi:10.1186/s13063-020-05009-3. PMID 33482890. 
  37. ↑ "IntraBio Receives FDA Fast Track Designation for Niemann-Pick Disease" (in en). 2020-03-25. https://www.npuk.org/intrabio-receives-fda-fast-track-designation-for-niemann-pick-disease/. 
  38. ↑ "Acetyl-leucine slows disease progression in lysosomal storage disorders". Brain Communications 3 (1): fcaa148. 2020. doi:10.1093/braincomms/fcaa148. PMID 33738443. 
  39. ↑ "IntraBio Reports Further Detail on Positive Data from IB1001 Multinational Clinical Trial for the Treatment of Niemann-Pick disease Type C". 19 October 2020. http://intrabio.com/2020/10/19/intrabio-reports-further-detail-on-positive-data-from-ib1001-multinational-clinical-trial-for-the-treatment-of-niemann-pick-disease-type-c/. 
  40. ↑ (in en) N-Acetyl-L-Leucine for GM2 Gangliosdisosis (Tay-Sachs and Sandhoff Disease). 28 May 2021. https://clinicaltrials.gov/ct2/show/NCT03759665. Retrieved 2021-08-06. 
  41. ↑ "N-Acetyl-L-Leucine for Ataxia-Telangiectasia" (in en). https://clinicaltrials.gov/ct2/show/NCT03759678. 
  42. ↑ "IntraBio" (in en-GB). http://intrabio.com/2018/12/02/intrabio-announces-clinical-results-for-treatment-of-dementia/. 
  43. ↑ "Prophylactic treatment of migraine with and without aura with acetyl-DL-leucine: a case series". Journal of Neurology 266 (2): 525–529. February 2019. doi:10.1007/s00415-018-9155-6. PMID 30547273. 
  44. ↑ "Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study". The Lancet. Neurology 6 (9): 765–772. September 2007. doi:10.1016/S1474-4422(07)70194-1. PMID 17689147. 
  45. ↑ "Treatment of a child diagnosed with Niemann-Pick disease type C with miglustat: a case report in Brazil". Journal of Inherited Metabolic Disease 31 (Suppl 2): S357–S361. December 2008. doi:10.1007/s10545-008-0923-9. PMID 18937049. 
  46. ↑ "Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice". Journal of Neuroscience Research 82 (6): 811–821. December 2005. doi:10.1002/jnr.20685. PMID 16273542. 
  47. ↑ "Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease". Proceedings of the National Academy of Sciences of the United States of America 103 (37): 13807–13812. September 2006. doi:10.1073/pnas.0606218103. PMID 16940355. Bibcode: 2006PNAS..10313807L. 
  48. ↑ "Neural stem cell implantation extends life in Niemann-Pick C1 mice". Journal of Applied Genetics 48 (3): 269–272. 2007. doi:10.1007/BF03195222. PMID 17666780. 
  49. ↑ "eMedicine – Niemann–Pick Disease : Article by Robert A Schwartz". http://www.emedicine.com/derm/topic699.htm. 
  50. ↑ "Niemann–Pick Disease". http://my.clevelandclinic.org/disorders/Niemann–Pick_Disease_NP/hic_Niemann–Pick_Disease.aspx. 
  51. ↑ "Long-term safety and efficacy of factor IX gene therapy in hemophilia B". The New England Journal of Medicine 371 (21): 1994–2004. November 2014. doi:10.1056/NEJMoa1407309. PMID 25409372. 
  52. ↑ "Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy". The New England Journal of Medicine 377 (18): 1713–1722. November 2017. doi:10.1056/NEJMoa1706198. PMID 29091557. 
  53. ↑ "AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease". Human Molecular Genetics 27 (17): 3079–3098. September 2018. doi:10.1093/hmg/ddy212. PMID 29878115. 
  54. ↑ "Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann-Pick disease type C1 mice". Life Science Alliance 4 (10): e202101040. October 2021. doi:10.26508/lsa.202101040. PMID 34407999. 
  55. ↑ 55.0 55.1 "Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse". Metabolic Brain Disease 26 (4): 299–306. December 2011. doi:10.1007/s11011-011-9263-9. PMID 21938520. 
  56. ↑ "Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS". The Journal of Neuroscience 32 (36): 12528–12542. September 2012. doi:10.1523/JNEUROSCI.1069-12.2012. PMID 22956843. 
  57. ↑ "Size and shape of the corpus callosum in adult Niemann-Pick type C reflects state and trait illness variables". AJNR. American Journal of Neuroradiology 32 (7): 1340–1346. August 2011. doi:10.3174/ajnr.A2490. PMID 21596811. 
  58. ↑ 58.0 58.1 "White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study". Neurology 75 (1): 49–56. July 2010. doi:10.1212/WNL.0b013e3181e6210e. PMID 20484681. 
  59. ↑ "Diffusion tensor imaging in Niemann-Pick Type C disease". Pediatric Neurology 33 (5): 325–330. November 2005. doi:10.1016/j.pediatrneurol.2005.05.004. PMID 16243219. 
  60. ↑ "Researchers Study Ebola Link to Gene in Rare Disease". Wall Street Journal. 2 November 2014. https://online.wsj.com/articles/researchers-study-ebola-link-to-gene-in-rare-disease-1414965218. 
  61. ↑ Zhang M, Dwyer NK, Love DC, Cooney A, Comly M, Neufeld E, Pentchev PG, Blanchette-Mackie EJ, Hanover JA. Cessation of rapid late endosomal tubulovesicular trafficking in Niemann–Pick type C1 disease. Proceedings of the National Academy of Sciences. April 2001, 98 (8) 4466-4471; DOI: 10.1073/pnas.081070898
  62. ↑ "Targeting the role of the endosome in the pathophysiology of Alzheimer's disease: a strategy for treatment". Science of Aging Knowledge Environment 2006 (10): re2. June 2006. doi:10.1126/sageke.2006.10.re2. PMID 16807486. 
  63. ↑ "Crosstalk between Lysosomes and Mitochondria in Parkinson's Disease". Frontiers in Cell and Developmental Biology 5: 110. 2017. doi:10.3389/fcell.2017.00110. PMID 29312935. 

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