Fostering collaborative research for rare genetic disease: The example of Niemann-Pick type C disease

Rare disease represents one of the most significant issues facing the medical community and health care providers worldwide, yet the majority of these disorders never emerge from their obscurity, drawing little attention from the medical community or the pharmaceutical industry. The challenge therefore is how best to mobilize rare disease stakeholders to enhance basic, translational and clinical research to advance understanding of pathogenesis and accelerate therapy development. Here we describe a rare, fatal brain disorder known as Niemann-Pick type C (NPC) and an innovative research collaborative known as Support of Accelerated Research for NPC (SOAR-NPC) which illustrates one pathway through which knowledge of a rare disease and its possible treatments are being successfully advanced. Use of the “SOAR” mechanism, we believe, offers a blueprint for similar advancement for many other rare disorders

Atypical multisensory integration in Niemann-Pick type C disease – towards potential biomarkers

Background: Niemann-Pick type C (NPC) is an autosomal recessive disease in which cholesterol and glycosphingolipids accumulate in lysosomes due to aberrant cell-transport mechanisms. It is characterized by progressive and ultimately terminal neurological disease, but both pre-clinical studies and direct human trials are underway to test the safety and efficacy of cholesterol clearing compounds, with good success already observed in animal models. Key to assessing the effectiveness of interventions in patients, however, is the development of objective neurobiological outcome measures. Multisensory integration mechanisms present as an excellent candidate since they necessarily rely on the fidelity of long-range neural connections between the respective sensory cortices (e.g. the auditory and visual systems). Methods: A simple way to test integrity of the multisensory system is to ask whether individuals respond faster to the occurrence of a bisensory event than they do to the occurrence of either of the unisensory constituents alone. Here, we presented simple auditory, visual, and audio-visual stimuli in random sequence. Participants responded as fast as possible with a button push. One 11-year-old and two 14-year-old boys with NPC participated in the experiment and their results were compared to those of 35 age-matched neurotypical boys. Results: Reaction times (RTs) to the stimuli when presented simultaneously were significantly faster than when they were presented alone in the neurotypical children, a facilitation that could not be accounted for by probability summation, as evidenced by violation of the so-called ‘race’ model. In stark contrast, the NPC boys showed no such speeding, despite the fact that their unisensory RTs fell within the distribution of RTs observed in the neurotypicals. Conclusions: These results uncover a previously undescribed deficit in multisensory integrative abilities in NPC, with implications for ongoing treatment of the clinical symptoms of these children. They also suggest that multisensory processes may represent a good candidate biomarker against which to test the efficacy of therapeutic interventions

Chronic Cyclodextrin Treatment of Murine Niemann-Pick C Disease Ameliorates Neuronal Cholesterol and Glycosphingolipid Storage and Disease Progression

BACKGROUND:Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs). While current treatment therapies are limited, a few drugs tested in Npc1(-/-) mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ) and allopregnanolone, we noted increased lifespan for Npc1(-/-) mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD), the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit. METHODOLOGY/PRINCIPAL FINDINGS:Administration of CD to Npc1(-/-) mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS) type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/-) mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage. CONCLUSIONS/SIGNIFICANCE:Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/-) and Npc2(-/-) mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis

Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann-Pick C disease

Niemann–Pick type C1 (NPC1) disease is a fatal neurodegenerative disease characterized by neuronal lipid storage and progressive Purkinje cell loss in the cerebellum. We investigated whether therapeutic approaches to bypass the cholesterol trafficking defect in NPC1 disease might delay disease progression in the npc1−/− mouse model. We show that the neurosteroid allopregnanolone (ALLO) and T0901317, a synthetic oxysterol ligand, act in concert to delay onset of neurological symptoms and prolong the lifespan of npc1−/− mice. ALLO and T0901317 therapy preserved Purkinje cells, suppressed cerebellar expression of microglial-associated genes and inflammatory mediators, and reduced infiltration of activated microglia in the cerebellar tissue. To establish whether the mechanism of neuroprotection in npc1−/− mice involves GABAA receptor activation, we compared treatment of natural ALLO and ent-ALLO, a stereoisomer that has identical physical properties of natural ALLO but is not a GABAA receptor agonist. ent-ALLO provided identical functional and survival benefits as natural ALLO in npc1−/− mice, strongly supporting a GABAA receptor-independent mechanism for ALLO action. On the other hand, the efficacy of ALLO, ent-ALLO, and T0901317 therapy correlated with the ability of these compounds to activate pregnane X receptor-dependent pathways in vivo. These findings suggest that treatment with pregnane X receptor ligands may be useful clinically in delaying the progressive neurodegeneration in human NPC disease

Niemann-Pick C1 Is Essential for Ebolavirus Replication and Pathogenesis In Vivo

ABSTRACT Recent work demonstrated that the Niemann-Pick C1 (NPC1) protein is an essential entry receptor for filoviruses. While previous studies focused on filovirus entry requirements of NPC1 in vitro, its roles in filovirus replication and pathogenesis in vivo remain unclear. Here, we evaluated the importance of NPC1, and its partner in cholesterol transport, NPC2, by using a mouse model of Ebolavirus (EBOV) disease. We found that, whereas wild-type mice had high viral loads and succumbed to EBOV infection, Npc1−/− mice were entirely free of viral replication and completely protected from EBOV disease. Interestingly, Npc1+/− mice transiently developed high levels of viremia, but were nevertheless substantially protected from EBOV challenge. We also found Npc2−/− mice to be fully susceptible to EBOV infection, while Npc1−/− mice treated to deplete stored lysosomal cholesterol remained completely resistant to EBOV infection. These results provide mechanistic evidence that NPC1 is directly required for EBOV infection in vivo, with little or no role for NPC1/NPC2-dependent cholesterol transport. Finally, we assessed the in vivo antiviral efficacies of three compounds known to inhibit NPC1 function or NPC1-glycoprotein binding in vitro. Two compounds reduced viral titers in vivo and provided a modest, albeit not statistically significant, degree of protection. Taken together, our results show that NPC1 is critical for replication and pathogenesis in animals and is a bona fide target for development of antifilovirus therapeutics. Additionally, our findings with Npc1+/− mice raise the possibility that individuals heterozygous for NPC1 may have a survival advantage in the face of EBOV infection

Performance comparison of biotic indices measuring the ecological status base on soft-bottom macroinvertebrates: a study along the shallow Gomishan lagoon (Southeast Caspian Sea)

Abstract This paper aims to test the suitability of some biotic indices for their application in Southeast Caspian Sea. For this purpose, the ecological quality of the Gomishan lagoon was assessed using three biotic indices (AMBI, BENTIX, BOPA) during summer and autumn 2010. The results from the application of the biotic indices do not highlight a clear distinction between the stations. The results show that two of the indices (AMBI and BENTIX) are very close in terms of diagnosis (good and high) and seem to generally perform better than BOPA. In addition, Principal Component Analysis (PCA) based on abiotic parameters showed clear spatial and temporal differences in environmental variables. However, at this shallow sites with low human pressure and high water residence times, such benthic community composition can be associated with physical stress due to salinity increase and to changes in environmental characteristics, triggered by conventional seasonal variations. Natural variability of transitional waters is a crucial factor for a correct evaluation of the ecological condition of macroinvertebrate communities across the lagoonal system