Gene therapy for neurological disorders: progress and prospects.

This corrects the article DOI: 10.1038/nrd.2018.110.

Gene therapy for neurological disorders: progress and prospects.

Adeno-associated viral (AAV) vectors are a rapidly emerging gene therapy platform for the treatment of neurological diseases. In preclinical studies, transgenes encoding therapeutic proteins, microRNAs, antibodies or gene-editing machinery have been successfully delivered to the central nervous system with natural or engineered viral capsids via various routes of administration. Importantly, initial clinical studies have demonstrated encouraging safety and efficacy in diseases such as Parkinson disease and spinal muscular atrophy, as well as durability of transgene expression. Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.

Cognitive executive impairment and dopaminergic deficits in de novo Parkinson's disease.

Cognitive impairment in Parkinson's disease (PD) is common and does directly impact patients' everyday functioning. However, the underlying mechanisms of early cognitive decline are not known. This study explored the association between striatal dopaminergic deficits and cognitive impairment within a large cohort of early, drug-naïve PD patients and tested the hypothesis that executive dysfunction in PD is associated with striatal dopaminergic depletion. A cross-sectional multicenter cohort of 339 PD patients and 158 healthy controls from the Parkinson's Progression Markers Initiative study was analyzed. Each individual underwent cerebral single-photon emission CT (SPECT) and a standardized neuropsychological assessment with tests of memory as well as visuospatial and executive function. SPECT imaging was performed with [(123) I]FP-CIT, and specific binding ratios in left and right putamen and caudate nucleus were calculated. The association between specific binding ratios, cognitive domain scores, and age was analyzed using Pearson's correlations, partial correlation, and conditional process analysis. A small, but significant, positive association between total striatal dopamine transporter binding and the attention/executive domain was found (r = 0.141; P = 0.009) in PD, but this was not significant after adjusting for age. However, in a moderated mediation model, we found that cognitive executive differences between controls and patients with PD were mediated by an age-moderated striatal dopaminergic deficit. Our findings support the hypothesis that nigrostriatal dopaminergic deficit is associated with executive impairment, but not to memory or visuospatial impairment, in early PD.

Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations.

Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic-pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.

Biosignatures for Parkinson's disease and atypical parkinsonian disorders patients.

Diagnosis of Parkinson' disease (PD) carries a high misdiagnosis rate due to failure to recognize atypical parkinsonian disorders (APD). Usually by the time of diagnosis greater than 60% of the neurons in the substantia nigra are dead. Therefore, early detection would be beneficial so that therapeutic intervention may be initiated early in the disease process. We used splice variant-specific microarrays to identify mRNAs whose expression is altered in peripheral blood of early-stage PD patients compared to healthy and neurodegenerative disease controls. Quantitative polymerase chain reaction assays were used to validate splice variant transcripts in independent sample sets. Here we report a PD signature used to classify blinded samples with 90% sensitivity and 94% specificity and an APD signature that resulted in a diagnosis with 95% sensitivity and 94% specificity. This study provides the first discriminant functions with coherent diagnostic signatures for PD and APD. Analysis of the PD biomarkers identified a regulatory network with nodes centered on the transcription factors HNF4A and TNF, which have been implicated in insulin regulation.

Association of SNCA with Parkinson: replication in the Harvard NeuroDiscovery Center Biomarker Study.

BACKGROUND: Mutations in the α-synuclein gene (SNCA) cause autosomal dominant forms of Parkinson's disease, but the substantial risk conferred by this locus to the common sporadic disease has only recently emerged from genome-wide association studies. METHODS: We genotyped a prioritized noncoding variant in SNCA intron 4 in 344 patients with Parkinson's disease and 275 controls from the longitudinal Harvard NeuroDiscovery Center Biomarker Study. RESULTS: The common minor allele of rs2736990 was associated with elevated disease susceptibility (odds ratio, 1.40; P = .0032). CONCLUSIONS: This result increases confidence in the notion that in many clinically well-characterized patients, genetic variation in SNCA contributes to "sporadic" disease.

Predictors of cognitive outcomes in early Parkinson disease patients: The National Institutes of Health Exploratory Trials in Parkinson Disease (NET-PD) experience.

Cognitive dysfunction is an important aspect of Parkinson disease (PD) and is increasingly being examined in various large scale PD clinical studies. However, the sensitivity of some of the cognitive measures used for detecting change in cognitive status in early PD patients is not known nor is the relationship between cognitive outcome measures and other motor and non-motor disease characteristics and various demographic parameters in early PD patients. The current analysis of the NET-PD cohort (i.e., untreated patients) was undertaken to: 1) assess which (if any) baseline demographic parameters correlate with baseline cognitive measures and any potential change in cognitive measures over the 12-18 months evaluation period; 2) assess the extent to which cognitive measures employed (i.e., Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Frontal Assessment Battery (FAB) and Letter-Number Sequencing) are sensitive to change over time; 3) examine whether initiation of symptomatic therapy is associated with change in cognitive status. At baseline, NET-PD subjects had no significant impairment on the assessments employed. Only education and age were significant predictors of cognitive score at baseline. None of the summary measures were indicative of change in cognitive status over the 12-18 months of study. These results suggest either the cognitive domains examined are not affected in the population examined or that more sensitive measures of cognition than those currently employed may need to be considered for use in a large trial setting in which an early, highly educated PD population is studied.

Neuroprotection trials in Parkinson's disease: systematic review.

Treatments to slow the progression are a major unmet need in Parkinson's disease. Detailed assessment of randomized trials testing putative neuroprotective drugs was undertaken to inform the design, reporting, and interpretation of future studies. This study is a systematic review of trials testing neuroprotective drugs. Data were extracted independently by two coauthors. Fifteen completed, published trials involving 4,087 participants tested 13 different drugs in 18 double-blind comparisons with placebo. Seven comparisons involving 2,000 subjects assessed MAO-B inhibitors. The primary outcome was change in the Unified Parkinson's Disease Rating Scale score in eight trials and time to need for dopaminergic therapy in seven. Mean participant age was 62 years, 35% were women, the interval from diagnosis to entry averaged 11 months, and the number of participants averaged 272 (largest = 806). Follow-up averaged <16 months in all but two trials. Detailed randomization methods and success of double-blinding were reported in 20% and 13%, respectively. Based on the investigators' conclusions, six trials were interpreted as consistent with a neuroprotective effect, three as negative, and five as either confounded or not meeting criteria for futility. Neuroprotection trials have involved relatively uniform groups of participants early in the clinical disease course, with outcomes weighted heavily toward motor deterioration. Future trials should include participants with wider ranges of disease stages and assess broader neurological outcomes.

Biomarkers in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder that is largely diagnosed and managed clinically. Biomarkers, as indicators of underlying biological processes, offer the potential to identify individuals at risk for PD, screen new therapies, assist in the diagnosis and help optimize management of PD. However, to date, biomarkers, despite their considerable promise, have had limited utility in clinical trials and practice.