Extensive Transduction and Enhanced Spread of a Modified AAV2 Capsid in the Non-human Primate CNS.

The present study was designed to characterize transduction of non-human primate brain and spinal cord with a modified adeno-associated virus serotype 2, incapable of binding to the heparan sulfate proteoglycan receptor, referred to as AAV2-HBKO. AAV2-HBKO was infused into the thalamus, intracerebroventricularly or via a combination of both intracerebroventricular and thalamic delivery. Thalamic injection of this modified vector encoding GFP resulted in widespread CNS transduction that included neurons in deep cortical layers, deep cerebellar nuclei, several subcortical regions, and motor neuron transduction in the spinal cord indicative of robust bidirectional axonal transport. Intracerebroventricular delivery similarly resulted in widespread cortical transduction, with one striking distinction that oligodendrocytes within superficial layers of the cortex were the primary cell type transduced. Robust motor neuron transduction was also observed in all levels of the spinal cord. The combination of thalamic and intracerebroventricular delivery resulted in transduction of oligodendrocytes in superficial cortical layers and neurons in deeper cortical layers. Several subcortical regions were also transduced. Our data demonstrate that AAV2-HBKO is a powerful vector for the potential treatment of a wide number of neurological disorders, and highlight that delivery route can significantly impact cellular tropism and pattern of CNS transduction.

Mental retardation, spasticity, basal ganglia calcification, cerebral white matter lesions, multiple endocrine defects, telangiectasia and atrophic skin: a new syndrome?

We report on an 8-year-old boy with mental retardation and spastic tetraparesis associated with atrophic skin on the face and extremities, telangiectasia, and severe dental caries. Basal ganglia calcification and multiple lesions in the subcortical white matter have been present since infancy. The patient has complications of liver dysfunction, multiple endocrine defects, and elevation of blood/cerebrospinal fluid lactate. Extensive laboratory examinations, including skin and muscle biopsies, and UV- and mitomycin C-sensitivity tests on fibroblasts, provided no evidence of a specific disease entity. No deterioration was noted, and supplementation of riboflavin and other vitamins had no apparent effect on the neurodevelopmental status of this patient. This patient may represent a novel disease entity, with unclear pathogenesis.

Low signal intensity and increased anisotropy on magnetic resonance imaging in the white matter lesion after head trauma: unrecognized findings of diffuse axonal injury.

We report on a four-year-old girl with head trauma caused by a motor vehicle accident. She presented with delirium, oculomotor palsy and ptosis in her left eye, left hemiparesis, and pyramidal signs in all extremities. Computed tomography on the day of admission showed diffuse cerebral edema with right-sided predominance. Magnetic resonance images on day 3 of admission showed lesions of diffuse axonal injury and contusion in the corpus callosum and right occipital and bilateral temporal lobes. There was a low-intensity lesion in the white matter of the right hemisphere on T2-weighted images, fluid-attenuated inversion recovery, T2()-weighted images, apparent diffusion coefficient maps and diffusion-weighted images. This low-intensity lesion disappeared by day 7, and a transient brain atrophy in the right hemisphere appeared on day 28. The low signal intensity in the cerebral white matter was apparently different from that associated with contusion and typical diffuse axonal injury, and might represent a late-onset accumulation of non-heme iron and free radicals in the white matter after head trauma.

Delayed neuropsychiatric syndrome in a child following carbon monoxide poisoning.

Here, we report the case of a five-year-old boy with carbonic monoxide (CO) poisoning. The patient initially recovered after the initiation of hyperbaric oxygen (HBO) therapy, but lethargy as well as visual and gait disturbances appeared two days later. Left hemiparesis and mood lability also subsequently appeared. Slow frontal activity was noted on electroencephalography, while fluid-attenuation inversion recovery and diffusion-weighted magnetic resonance imaging (MRI) revealed high signal-intensity lesions in the hippocampus and deeper layers of the occipital and frontal cerebral cortex. The neurological symptoms subsided gradually during the 10-day course of HBO therapy, but the left-hand paresis and quadrantic hemianopsia persisted, in association with impaired attention, slow mental processing, and incontinence. Lesions in the globus pallidum were noted on follow-up MRI at 14 days, and cortical lesions became evident as linear, low signal-intensity areas on T1-weighted imaging 4 months after presentation. Delayed neuropsychiatric syndrome in CO poisoning is rare in childhood, although children should be carefully monitored after CO exposure. The finding of cortical laminar necrosis in this patient is quite atypical in CO poisoning, and suggests a broader and previously nonpredicted pathomechanism in this condition.

Synaptotagmin I hypothalamic knockdown prevents amygdaloid seizure-induced damage of hippocampal neurons but not of entorhinal neurons.

We have previously demonstrated that an acute pharmacological interruption of the afferent inputs from the hypothalamus to the hippocampus resulted in the blockade of the genesis and spread of intra-amygdala kainate-induced seizure activity in the hippocampus. This finding suggests that a sustained interruption of the hypothalamic stimulative influences may completely prevent amygdaloid seizure-induced hippocampal neuron damage. To test this assumption, we delivered antisense oligodeoxynucleotides (ODNs) against synaptotagmin I, a regulatory protein of the transmitter release machinery, into the hypothalamus by using a Hemagglutinating virus of Japan (HVJ)-liposome-mediated gene transfer technique. Four days prior to the induction of status epilepticus by intra-amygdala injection of kainate, the synaptotagmin I antisense was injected into the supramammillary nucleus (SuM) of the hypothalamus to chronically suppress the stimulative influences to the hippocampus via the reduction of transmitter release. The synaptotagmin I hypothalamic knockdown resulted in the almost complete prevention of seizure-induced damage of hippocampal neurons but not of entorhinal neurons following the kainate-induced amygdaloid seizures. This result suggests that the hypothalamic stimulative influences to the hippocampus have a major contribution to the amygdaloid seizure-induced hippocampal sclerosis, probably via disinhibition mechanism.