Gene therapy for peripheral nervous system diseases

Peripheral nerve diseases, also known as peripheral neuropathies, affect 15-20 million of Americans and diabetic neuropathy is the most common condition. Currently, the treatment of peripheral neuropathies is more focused on managing pain rather than providing permissive conditions for regeneration. Despite advances in microsurgical techniques, including nerve grafting and reanastomosis, axonal regeneration after peripheral nerve injury remains suboptimal. Also, no satisfactory treatments are available at this time for peripheral neurodegeneration occurring in motor neuron diseases (MND), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Peripheral nerves have the inherent capacity of regeneration. Gene therapy strategies focused on neuroprotection may help optimizing axonal regrowth. A better understanding of the cellular and molecular events involved in axonal degeneration and regeneration have helped researchers to identify targets for intervention. This review summarizes the current state on the clinical experience as well as gene therapy strategies for peripheral neuropathies, including MND, peripheral nerve injury, neuropathic pain, and diabetic neuropathy.     

Calcium and the aging nervous system

Many aspects of calcium homeostasis change with aging. Numerous calcium compartments complicate studies of altered calcium regulation. However, age-related decreases in calcium permeation across membranes and mobilization from organelles may be a common fundamental change. Deficits in ion movements appear to lead to altered coupling of calcium-dependent biochemical and neurophysiological processes and may lead to pathological and behavioral changes. The calcium-associated changes during aging probably do not occur with equal intensity in all cell types or in different parts of the same cell. Thus, cells or compartments with a high proportion of calcium activated processes would be more sensitive to diminished calcium availability. These age-related changes may predispose the brain to the development of age-related neurological disorders. The effects of decreased ion movement may be further aggravated by an age-related decline in other calcium-dependent processes. Depression of some of these calcium-dependent functions appears physiologically significant, since increasing calcium availability ameliorates age-related deficits in neurotransmission and behavior. A better understanding of the interactions between calcium homeostasis and calcium-dependent processes during aging will likely help in the design of more effective therapeutic strategies.     

Gene therapy for autoimmune demyelinating disease of the central nervous system.

Gene therapy is currently being explored as a new therapeutic treatment of autoimmune disease. The genetic modification of autoreactive memory T cells (T cell-mediated gene therapy) and autoimmune target tissue (target tissue gene therapy) to produce immunoregulatory cytokines offers a promising way to regulate autoimmunity. Furthermore, regenerative gene therapy offers the possibility of delivering growth factors to damaged autoimmune target tissue as a way of mediating repair. In the current review we discuss the different experimental models that are being used to test the efficacy of gene therapy in that treatment of autoimmune disease. We also discuss the importance of regulating transgene expression to ensure the therapeutic transgene products are delivered specifically to the autoimmune milieu in an antigen-inducible, non-constitutive manner.     

Lipofuscin pigment accumulationin the nervous system of aging mice

This morphologic investigation was undertaken with an inbred strain of C57BL/10 male mice to examine the accumulation of lipofuscin in nerve cells of dorsal ganglia and the cerebellum at 4, 8, 20, and 30 months of age. Histological examinations revealed that at four months of age, cells contained only a few small sudanophilic bodies distributed fairly uniformly throughout the cytoplasm. By 30 months, pigment aggregations became very prominent cytoplasmic features of many nerve cells in the dorsal ganglia and cerebellum. A more detailed examination of neurons from the dorsal ganglia with the electron microscope revealed particles of variable size with a high electron density at four and 8 months. By 20 and 30 months, the pigment bodies appeared to be larger and were more concentrated near the nucleus. In Purkinje cells of the cerebellum the pigment granules were observed only rarely at four and eight months. By 20 and 30 months, the granules in the Purkinje cells appeared to be larger, considerably more numerous, and concentrated between the nucleus and the apical dendrite. The intracellular pigment concentration was also estimated by calculations of the per cent of area occupied by pigment granules as well as by the per cent of the cells that contained pigment bodies at 4, 8, 20 and 30 months. A progressive increase in the intracellular pigment concentration was readily noted.     

Potential involvement of the extracranial venous system in central nervous system disorders and aging

Background

The role of the extracranial venous system in the pathology of central nervous system (CNS) disorders and aging is largely unknown. It is acknowledged that the development of the venous system is subject to many variations and that these variations do not necessarily represent pathological findings. The idea has been changing with regards to the extracranial venous system.

Discussion

A range of extracranial venous abnormalities have recently been reported, which could be classified as structural/morphological, hemodynamic/functional and those determined only by the composite criteria and use of multimodal imaging. The presence of these abnormalities usually disrupts normal blood flow and is associated with the development of prominent collateral circulation. The etiology of these abnormalities may be related to embryologic developmental arrest, aging or other comorbidities. Several CNS disorders have been linked to the presence and severity of jugular venous reflux. Another composite criteria-based vascular condition named chronic cerebrospinal venous insufficiency (CCSVI) was recently introduced. CCSVI is characterized by abnormalities of the main extracranial cerebrospinal venous outflow routes that may interfere with normal venous outflow.

Summary

Additional research is needed to better define the role of the extracranial venous system in relation to CNS disorders and aging. The use of endovascular treatment for the correction of these extracranial venous abnormalities should be discouraged, until potential benefit is demonstrated in properly-designed, blinded, randomized and controlled clinical trials.Please see related editorial: http://www.biomedcentral.com/1741-7015/11/259.

     

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

Without medical progress, dementing diseases such as Alzheimer's disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimer's disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer's patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimer's disease, the phosphorylated tau protein and the beta-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to Delta5-androstene-3beta,17beta-diol and to 7alpha-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer's patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of beta-amyloid deposits.     

Problems in assessing altered calcium homeostasis in the aging nervous system

Defining a role for altered calcium homeostasis on functional deficits in the aging brain is not only hindered by the complexity and abundance of the regulatory systems involved, but also by the inability to assess calcium regulation in vivo.     

Indices of neurotransmitter synthesis and release in aging sympathetic nervous system

Activities of tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and choline acetyltransferase (ChAT) were assayed in sympathetic ganglia and adrenal glands of young and aged Fischer-344 rats. The recovery of reserpine-depleted catecholamine stores and catecholamine loss following inhibition of synthesis and intraneuronal degradation also were assessed in sympathetic ganglia of young and aged rats. No age differences were observed in DBH activity of any tissues examined or in the activities of any enzymes in the coeliac-mesenteric ganglion complex. However, TH and ChAT activities were significantly higher in the superior cervical ganglia and adrenal glands of aged rats. In the hypogastric ganglion, only TH activity was higher in the old rats. Recoveries of reserpine-depleted catecholamine stores in the superior cervical and hypogastric ganglia of aged rats were slower than in young rats. Catecholamine loss following inhibition of synthesis and intraneuronal degradation was faster in the superior cervical ganglia but not in the hypogastric ganglia of old rats as compared with young rats. These findings suggest that neurotransmitter synthesis and release are enhanced with age in the superior cervical ganglion. The lack of age-related changes in the hypogastric ganglion might reflect the different cellular composition as well as the physiological role of this ganglion.     

Normal aging in the central nervous system: quantitative MR diffusion-tensor analysis

The purpose of this study is to elucidate changes in mean diffusivity (ADC) and fractional anisotropy (FA) using MR diffusion tensor imaging (DTI) in the central nervous system during normal aging. We studied 50 normal volunteers (30 men, 20 women; mean age 44.8 +/- 14.0; age range, 21-69 years) without disorders affecting the central nervous system. The frontal, parietal white matter, lentiform nucleus, posterior limb of internal capsule, thalamus, genu and splenium of the corpus callosum were selected for investigation. There was no significant difference in ADC or FA between male and female or between the right and left hemisphere. A significant ADC increase with advancing age was observed in frontal white matter (P = 0.010) and lentiform nucleus (P = 0.022). A significant FA decline was found only in the genu of the corpus callosum (P < 0.001) with advancing age. Quantitative diffusion tensor analysis correlate with normal aging and may help in assessing normal age-related changes and serve as a standard for comparison with neurodegenerative disorders.     

神经系统疾病的干细胞治疗☆

背景：干细胞具有自我更新和多向分化的生物学特性,在生理或病理情况下能维持组织器官内环境的稳定,近年被广泛用于再生医学的研究。 目的：对神经系统疾病的干细胞治疗进展进行综述。 方法：通过Pubmed数据库检索有关干细胞治疗神经系统疾病的相关文献。检索词为“stem cells、Nervous system diseases、therapy”。初检得到298篇文献,最终保留54篇符合标准的文献进行分析。 结果与结论：经过近些年的研究,干细胞被认为是神经损伤和变性疾病的一个很有前景的治疗手段。通过干细胞的移植,取代受损的神经细胞,促进受损神经网络的恢复从而重建神经功能。     

HIV and antiretroviral therapy: Impact on the central nervous system

The HIV pandemic represents a major source of neurological morbidity worldwide. Emerging data from diverse populations indicate that HIV leads to significant neurocognitive impairments that reduce individuals’ ability to contribute to the well being of their families and society. HIV affects vulnerable populations with many comorbidities, but the virus contributes to neurocognitive impairment independent of these conditions. The neuropathological substrate of HIV neurocognitive disorders is damage to synapses and dendrites, without major neuronal loss. This suggests the potential for substantial reversibility if synaptodendritic function can be restored. In the developed world, combination antiretroviral therapy (CART) leads to improved neurocognitive function as well as morbidity and mortality in HIV. CART is being used in increasing numbers of individuals in resource limited settings. New cases of severe dementia are now rare in populations where effective CART has been deployed. While some degree of neurocognitive improvement with CART is almost universal, many individuals do not achieve full restoration of their premorbid neurocognitive status, and milder degrees of impairment remain quite prevalent. Optimizing neurocognitive recovery is likely to require the development of better CNS penetrating antiretroviral regimens and the use of neuroprotective agents.     

Apoptotic proteins in the course of aging of central nervous system in the rat

Studies were performed on the level of cells with damaged DNA (TUNEL), the level of protein engaged in DNA repair (PARP) and the level of proteins indicating the extent of apoptosis (Bax:Bcl-2) (Western blot). The studies were performed on cerebral cortex (GM), white matter (WM), medulla oblongata (MO), cerebellum (C) of rats, 3.0-3.5-, 12-, 24-months of age. The highest levels of DNA injury in GM of 1-year-old rats and in MO of 2-year-old rats were accompanied by peak levels of PARP. In the remaining structures (WM, C) levels of DNA injury showed no correspondence with levels of PARP. Levels of Bax proteins exceeded levels of Blc-2 protein in all cerebral structures of young rats. In old animals, Bax protein continued to exceed Blc-2 levels both in GM and in MO, in which most pronounced fragmentation of DNA was observed. The data indicated that in spite of high level of TUNEL positive cells in aged brain PARP and Bcl-2 are probably engaged in protection of the cells against death.     

中枢神经系统疾病的基因治疗

基因治疗正在成为常规方法难以治愈的中枢神经系统疾病的新的治疗手段。本文概要介绍了中枢神经系统疾病基因治疗的方法和途径;中枢神经系统疾病基因治疗的病毒载体以及目前中枢神经系统疾病基因治疗研究的状况。