Showing papers by "Charles H. Vite published in 2015"

Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease

Abstract: Niemann-Pick type C1 (NPC) disease is a lysosomal storage disease caused by mutations in the NPC1 gene, leading to an increase in unesterified cholesterol and several sphingolipids, and resulting in hepatic disease and progressive neurological disease. We show that subcutaneous administration of the pharmaceutical excipient 2-hydroxypropyl-β-cyclodextrin (HPβCD) to cats with NPC disease ameliorated hepatic disease, but doses sufficient to reduce neurological disease resulted in pulmonary toxicity. However, direct administration of HPβCD into the cisterna magna of presymptomatic cats with NPC disease prevented the onset of cerebellar dysfunction for greater than a year and resulted in a reduction in Purkinje cell loss and near-normal concentrations of cholesterol and sphingolipids. Moreover, administration of intracisternal HPβCD to NPC cats with ongoing cerebellar dysfunction slowed disease progression, increased survival time, and decreased the accumulation of brain gangliosides. An increase in hearing threshold was identified as a potential adverse effect. These studies in a feline animal model have provided critical data on efficacy and safety of drug administration directly into the central nervous system that will be important for advancing HPβCD into clinical trials.

Forecasting Seizures Using Intracranial EEG Measures and SVM in Naturally Occurring Canine Epilepsy

Abstract: Management of drug resistant focal epilepsy would be greatly assisted by a reliable warning system capable of alerting patients prior to seizures to allow the patient to adjust activities or medication Such a system requires successful identification of a preictal, or seizure-prone state Identification of preictal states in continuous long- duration intracranial electroencephalographic (iEEG) recordings of dogs with naturally occurring epilepsy was investigated using a support vector machine (SVM) algorithm The dogs studied were implanted with a 16-channel ambulatory iEEG recording device with average channel reference for a mean (st dev) of 3804 (+875) days producing 2202 (+1041) days of intracranial EEG recorded at 400 Hz for analysis The iEEG records had 516 (+528) seizures identified, of which 358 (+304) seizures were preceded by more than 4 hours of seizure-free data Recorded iEEG data were stratified into 11 contiguous, non-overlapping frequency bands and binned into one-minute synchrony features for analysis Performance of the SVM classifier was assessed using a 5-fold cross validation approach, where preictal training data were taken from 90 minute windows with a 5 minute pre-seizure offset Analysis of the optimal preictal training time was performed by repeating the cross validation over a range of preictal windows and comparing results We show that the optimization of feature selection varies for each subject, ie algorithms are subject specific, but achieve prediction performance significantly better than a time-matched Poisson random predictor (p<005) in 5/5 dogs analyzed

Mechanism of Neuromuscular Dysfunction in Krabbe Disease

Abstract: The atrophy of skeletal muscles in patients with Krabbe disease is a major debilitating manifestation that worsens their quality of life and limits the clinical efficacy of current therapies. The pathogenic mechanism triggering muscle wasting is unknown. This study examined structural, functional, and metabolic changes conducive to muscle degeneration in Krabbe disease using the murine (twitcher mouse) and canine [globoid cell leukodystrophy (GLD) dog] models. Muscle degeneration, denervation, neuromuscular [neuromuscular junction (NMJ)] abnormalities, and axonal death were investigated using the reporter transgenic twitcher–Thy1.1–yellow fluorescent protein mouse. We found that mutant muscles had significant numbers of smaller-sized muscle fibers, without signs of regeneration. Muscle growth was slow and weak in twitcher mice, with decreased maximum force. The NMJ had significant levels of activated caspase-3 but limited denervation. Mutant NMJ showed reduced surface areas and lower volumes of presynaptic terminals, with depressed nerve control, increased miniature endplate potential (MEPP) amplitude, decreased MEPP frequency, and increased rise and decay rate constants. Twitcher and GLD dog muscles had significant capacity to store psychosine, the neurotoxin that accumulates in Krabbe disease. Mechanistically, muscle defects involved the inactivation of the Akt pathway and activation of the proteasome pathway. Our work indicates that muscular dysfunction in Krabbe disease is compounded by a pathogenic mechanism involving at least the failure of NMJ function, activation of proteosome degradation, and a reduction of the Akt pathway. Akt, which is key for muscle function, may constitute a novel target to complement in therapies for Krabbe disease.

A review of gene therapy in canine and feline models of lysosomal storage disorders.

Abstract: Lysosomal storage disorders (LSDs) are inherited diseases that result from the intracellular accumulation of incompletely degraded macromolecules. The majority of LSDs affect both the peripheral and central nervous systems and are not effectively treated by enzyme replacement therapy, substrate reduction therapy, or bone marrow transplantation. Advances in adeno-associated virus and retroviral vector development over the past decade have resurged gene therapy as a promising therapeutic intervention for these monogenic diseases. Animal models of LSDs provide a necessary intermediate to optimize gene therapy protocols and assess the safety and efficacy of treatment prior to initiating human clinical trials. Numerous LSDs are naturally occurring in large animal models and closely reiterate the lesions, biochemical defect, and clinical phenotype observed in human patients, and whose lifetime is sufficiently long to assess the effect on symptoms that develop later in life. Herein, we review that gene ...

Canine status epilepticus treated with fosphenytoin: A proof of principle study

Abstract: Objectives There are a limited number of marketed intravenous antiepileptic drugs (AEDs) available for status epilepticus (SE). All were first developed for chronic therapy of epilepsy, not specifically for SE. Epilepsy and canine SE (CSE) occur naturally in dogs with prevalence, presentation, and percentage of refractory cases similar to human epilepsy. The objective of this study was to determine if CSE treated with fosphenytoin (FOS) results in a similar responder rate as for people.