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- Triadopathies: An Emerging Class of Skeletal Muscle Diseases. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Aug 29.
The triad is a skeletal muscle substructure responsible for the regulation of excitation-contraction coupling. It is formed by the close apposition of the T-tubule and the terminal sarcoplasmic reticulum. A rapidly growing list of skeletal myopathies, here referred to as triadopathies, are caused by gene mutations in components of the triad. These disorders, at their root, are caused by defects in excitation contraction coupling and intracellular calcium homeostasis. Secondary abnormalities in triad structure and/or function are also reported in several muscle diseases, most notably certain muscular dystrophies. This review highlights the current understanding of both primary and secondary triadopathies, and identifies important concepts yet to be fully addressed in the field. The emphasis of the review is both on the pathogenesis of triadopathies and their potential treatment.
- Gene Therapy for the Nervous System: Challenges and New Strategies. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Aug 27.
Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that gene-based neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.
- Inherited Isolated Dystonia: Clinical Genetics and Gene Function. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Aug 26.
Isolated inherited dystonia-formerly referred to as primary dystonia-is characterized by abnormal motor functioning of a grossly normal appearing brain. The disease manifests as abnormal involuntary twisting movements. The absence of overt neuropathological lesions, while intriguing, has made it particularly difficult to unravel the pathogenesis of isolated inherited dystonia. The explosion of genetic techology enabling the identification of the causative gene mutations is transforming our understanding of dystonia pathogenesis, as the molecular, cellular and circuit level consequences of these mutations are identified in experimental systems. Here, I review the clinical genetics and cell biology of three forms of inherited dystonia for which the causative mutation is known: DYT1 (TOR1A), DYT6 (THAP1), DYT25 (GNAL).
- The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Aug 14.
Mutations in genes encoding nuclear envelope proteins cause a wide range of inherited diseases, many of which are neurological. We review the genetic causes and what little is known about pathogenesis of these nuclear envelopathies that primarily affect striated muscle, peripheral nerve and the central nervous system. We conclude by providing examples of experimental therapeutic approaches to these rare but important neuromuscular diseases.
- Genetics of Alzheimer's Disease. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Aug 12.
The analyses of genetic factors contributing to Alzheimer's disease (AD) and other dementias have evolved at the same pace as genetic and genomic technologies are developed and improved. The identification of the first genes involved in AD arose from family-based studies, but risk factors have mainly been identified by studies comparing groups of patients with groups of controls. The best outcomes have been heavily associated with the capacity of interrogating genetic variability at the genome level without any particular a priori hypothesis. In this review we assess the role of genetic family studies in Alzheimer's disease and other dementias within the current status of dementias' and, particularly, AD's genetic architecture.
- Novel mGluR5 Positive Allosteric Modulator Improves Functional Recovery, Attenuates Neurodegeneration, and Alters Microglial Polarization after Experimental Traumatic Brain Injury. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Aug 6.
Traumatic brain injury (TBI) causes microglial activation and related neurotoxicity that contributes to chronic neurodegeneration and loss of neurological function. Selective activation of metabotropic glutamate receptor 5 (mGluR5) by the orthosteric agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), is neuroprotective in experimental models of TBI, and has potent anti-inflammatory effects in vitro. However, the therapeutic potential of CHPG is limited due to its relatively weak potency and brain permeability. Highly potent, selective and brain penetrant mGluR5 positive allosteric modulators (PAMs) have been developed and show promise as therapeutic agents. We evaluated the therapeutic potential of a novel mGluR5 PAM, VU0360172, after controlled cortical impact (CCI) in mice. Vehicle, VU0360172, or VU0360172 plus mGluR5 antagonist (MTEP), were administered systemically to CCI mice at 3 h post-injury; lesion volume, hippocampal neurodegeneration, microglial activation, and functional recovery were assessed through 28 days post-injury. Anti-inflammatory effects of VU0360172 were also examined in vitro using BV2 and primary microglia. VU0360172 treatment significantly reduced the lesion, attenuated hippocampal neurodegeneration, and improved motor function recovery after CCI. Effects were mediated by mGluR5 as co-administration of MTEP blocked the protective effects of VU0360172. VU0360172 significantly reduced CD68 and NOX2 expression in activated microglia in the cortex at 28 days post-injury, and also suppressed pro-inflammatory signaling pathways in BV2 and primary microglia. In addition, VU0360172 treatment shifted the balance between M1/M2 microglial activation states towards an M2 pro-repair phenotype. This study demonstrates that VU0360172 confers neuroprotection after experimental TBI, and suggests that mGluR5 PAMs may be promising therapeutic agents for head injury.
- Next Generation Sequencing and the Future of Genetic Diagnosis. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Jul 23.
The introduction of next generation sequencing (NGS) has led to an exponential increase of elucidated genetic causes in both extremely rare diseases and common but heterogeneous disorders. It can be applied to the whole or to selected parts of the genome (genome or exome sequencing, gene panels). NGS is not only useful in large extended families with linkage information, but may also be applied to detect de novo mutations or mosaicism in sporadic patients without a prior hypothesis about the mutated gene. Currently, NGS is applied in both research and clinical settings, and there is a rapid transition of research findings to diagnostic applications. These developments may greatly help to minimize the "diagnostic odyssey" for patients as whole-genome analysis can be performed in a few days at reasonable costs compared with gene-by-gene analysis based on Sanger sequencing following diverse clinical tests. Despite the enthusiasm about NGS, one has to keep in mind its limitations, such as a coverage and accuracy of < 100 %, resulting in missing variants and false positive findings. In addition, variant interpretation is challenging as there is usually more than one candidate variant found. Therefore, there is an urgent need to define standards for NGS with respect to run quality and variant interpretation, as well as mechanisms of quality control. Further, there are ethical challenges including incidental findings and how to guide unaffected probands seeking direct-to-customer testing. However, taken together, the application of NGS in research and diagnostics provides a tremendous opportunity to better serve our patients.
- A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Jul 20.
Mutation of the lysosomal hydrolase acid-β-glucosidase (GCase), which leads to reduced GCase activity, is one of the most frequent genetic risk factors for Parkinson's disease (PD) and promotes α-synuclein accumulation in the brain, a hallmark of PD and other synucleinopathies. Whether targeting GCase pharmacologically is a valid therapeutic strategy for sporadic PD in the absence of GCase mutation is unknown. We have investigated whether increasing the stability, trafficking, and activity of wild-type GCase could be beneficial in synucleinopathies by administering the pharmacological chaperone AT2101 (afegostat-tartrate, isofagomine) to mice that overexpress human wild-type α-synuclein (Thy1-aSyn mice). AT2101 administered orally for 4 months to Thy1-aSyn mice improved motor and nonmotor function, abolished microglial inflammatory response in the substantia nigra, reduced α-synuclein immunoreactivity in nigral dopaminergic neurons, and reduced the number of small α-synuclein aggregates, while increasing the number of large α-synuclein aggregates. These data support the further investigation of pharmacological chaperones that target GCase as a therapeutic approach for sporadic PD and other synucleinopathies, even in the absence of glucocerebrosidase mutations.
- Spinal Stimulation for Movement Disorders. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Jul 12.
Epidural spinal cord stimulation (SCS) is currently proposed to treat intractable neuropathic pain. Since the 1970s, isolated cases and small cohorts of patients suffering from dystonia, tremor, painful leg and moving toes (PLMT), or Parkinson's disease were also treated with SCS in the context of exploratory clinical studies. Despite the safety profile of SCS observed in these various types of movement disorders, the degree of improvement of abnormal movements following SCS has been heterogeneous among patients and across centers in open-label trials, stressing the need for larger, randomized, double-blind studies. This article provides a comprehensive review of both experimental and clinical studies of SCS application in movement disorders.
- Nonpharmacological Therapies for Neurologic Devices. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Jul 11.