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1.  Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease 
Brain  2013;136(8):2419-2431.
The pace of nigrostriatal degeneration, both with regards to striatal denervation and loss of melanin and tyrosine hydroxylase-positive neurons, is poorly understood especially early in the Parkinson’s disease process. This study investigated the extent of nigrostriatal degeneration in patients with Parkinson’s disease at different disease durations from time of diagnosis. Brains of patients with Parkinson’s disease (n = 28) with post-diagnostic intervals of 1–27 years and normal elderly control subjects (n = 9) were examined. Sections of the post-commissural putamen and substantia nigra pars compacta were processed for tyrosine hydroxylase and dopamine transporter immunohistochemistry. The post-commissural putamen was selected due to tissue availability and the fact that dopamine loss in this region is associated with motor disability in Parkinson’s disease. Quantitative assessments of putaminal dopaminergic fibre density and stereological estimates of the number of melanin-containing and tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (both in total and in subregions) were performed by blinded investigators in cases where suitable material was available (n = 17). Dopaminergic markers in the dorsal putamen showed a modest loss at 1 year after diagnosis in the single case available for study. There was variable (moderate to marked) loss, at 3 years. At 4 years post-diagnosis and thereafter, there was virtually complete loss of staining in the dorsal putamen with only an occasional abnormal dopaminergic fibre detected. In the substantia nigra pars compacta, there was a 50–90% loss of tyrosine hydroxylase-positive neurons from the earliest time points studied with only marginal additional loss thereafter. There was only a ∼10% loss of melanized neurons in the one case evaluated 1 year post-diagnosis, and variable (30 to 60%) loss during the first several years post-diagnosis with more gradual and subtle loss in the second decade. At all time points, there were more melanin-containing than tyrosine hydroxylase-positive cells. Loss of dopaminergic markers in the dorsal putamen occurs rapidly and is virtually complete by 4 years post-diagnosis. Loss of melanized nigral neurons lags behind the loss of dopamine markers. These findings have important implications for understanding the nature of Parkinson’s disease neurodegeneration and for studies of putative neuroprotective/restorative therapies.
doi:10.1093/brain/awt192
PMCID: PMC3722357  PMID: 23884810
Parkinsons disease; human brain; morphometry; substantia nigra; neuroscience
2.  Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients 
Neurology  2013;80(18):1698-1701.
Objective:
In an effort to account for deficiencies in axonal transport that limit the effectiveness of neurotrophic factors, this study tested the safety and feasibility, in moderately advanced Parkinson disease (PD), of bilaterally administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen plus substantia nigra (SN, a relatively small structure deep within the midbrain, in proximity to critical neuronal and vascular structures).
Methods:
After planning and minimizing risks of stereotactically targeting the SN, an open-label, dose-escalation safety trial was initiated in 6 subjects with PD who received bilateral stereotactic injections of CERE-120 into the SN and putamen.
Results:
Two-year safety data for all subjects suggest the procedures were well-tolerated, with no serious adverse events. All adverse events and complications were expected for patients with PD undergoing stereotactic brain surgery.
Conclusions:
Bilateral stereotactic administration of CERE-120 to the SN plus putamen in PD is feasible and this evaluation provides initial empirical support that it is safe and well-tolerated.
Classification of evidence:
This study provides Class IV evidence that bilateral neurturin gene delivery (CERE-120) to the SN plus putamen in patients with moderately advanced PD is feasible and safe.
doi:10.1212/WNL.0b013e3182904faa
PMCID: PMC3716474  PMID: 23576625
3.  Parkinson's Disease Gene Therapy: Success by Design Meets Failure by Efficacy 
Molecular Therapy  2014;22(3):487-497.
Over the past decade, nine gene therapy clinical trials for Parkinson's disease (PD) have been initiated and completed. Starting with considerable optimism at the initiation of each trial, none of the programs has yet borne sufficiently robust clinical efficacy or found a clear path toward regulatory approval. Despite the immediately disappointing nature of the efficacy outcomes in these trials, the clinical data garnered from the individual studies nonetheless represent tangible and significant progress for the gene therapy field. Collectively, the clinical trials demonstrate that we have overcome the major safety hurdles previously suppressing central nervous system (CNS) gene therapy, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, these studies also demonstrated controlled, highly persistent generation of biologically active proteins targeted to structures deep in the human brain. Therefore, a renewed, focused emphasis must be placed on advancing clinical efficacy by improving clinical trial design, patient selection and outcome measures, developing more predictive animal models to support clinical testing, carefully performing retrospective analyses, and most importantly moving forward—beyond our past limits.
doi:10.1038/mt.2013.281
PMCID: PMC3944322  PMID: 24356252
4.  The Alcohol Clinical Trials Initiative (ACTIVE): Purpose and Goals for Assessing Important and Salient Issues for Medications Development in Alcohol Use Disorders 
Neuropsychopharmacology  2011;37(2):402-411.
Although progress has been made in the treatment of alcohol use disorders, more effective treatments are needed. In the last 15 years, several medications have been approved for use in alcohol dependence but have only limited effectiveness and clinical acceptance. While academics have developed some ‘standards' for the performance of clinical trials for alcohol dependence, they vary considerably, in the type of populations to be studied, the length of trials, salient outcome measures, and data analyses to be used (especially in the treatment of missing data). This variability impedes the commercial development of medications to treat alcohol dependence. Using a model similar to that used to develop an expert consensus for medications to improve cognitive aspects of schizophrenia (MATRICS) and in the treatment of pain (IMMPACT), a workgroup has been formed under the auspices of ACNP, known as the ACTIVE (Alcohol Clinical Trials Initiative) group, to evaluate data from completed clinical trials to develop a consensus on key issues in the conduct of clinical trials in alcohol dependence. ACTIVE consists of academic experts, industry representatives, and staff from the Food and Drug Administration, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse. This paper describes the rationale behind the effort, its history and organization, and initial key questions that have been identified as the primary focus of the workgroup. Future papers will focus on knowledge gained from the re-analysis of completed trials and provide consensus opinions regarding the performance of clinical trials that might be undertaken in the future.
doi:10.1038/npp.2011.182
PMCID: PMC3242301  PMID: 21900883
addiction and substance abuse; clinical pharmacology/clinical trials; alcohol and alcoholism; drug discovery/development; neuropharmacology; addiction and substance abuse; clinical pharmacology/clinical trials; alcohol and alcoholism; drug discovery/development; alcohol
5.  Adenosine Receptor Prodrugs: Synthesis and Biological Activity of Derivatives of Potent, A1-Selective Agonists 
5′-Ester derivatives of the potent adenosine agonists N6-[4-[[[[4-[[[(2-acetylaminoethyl)amino] carbonyl] methyl] anilino] carbonyl] methyl] phenyl] adenosine (N-AcADAC; 1) and N6-cyclopentyladenosine (CPA; 2) were prepared as prodrugs. Both alkyl esters or carbonates (designed to enter the brain by virtue of increased lipophilicity) and 1,4-dihydro-1-methyl-3- [(pyridinylcarbonyl)oxy] esters designed to concentrate in the brain by virtue of a redox delivery system were synthesized. In the 5′-blocked form, the adenosine agonists displayed highly diminished affinity for rat brain A1-adenosine receptors in binding assays. The dihydropyridine prodrug 29 was active in an assay of locomotor depression in mice, in which adenosine agonists are highly depressant. The behavior depression was not reversible by peripheral administration of a non-central nervous system active adenosine antagonist. In an assay of the peripheral action of adenosine (i.e., the inhibition of lipolysis in rats), the parent compounds were highly potent and the dihydropyridine prodrug was much less potent.
PMCID: PMC3459066  PMID: 8138909
6.  Synthesis and Biological Activity of N6-(p-Sulfophenyl)alkyl and N6-Sulfoalkyl Derivatives of Adenosine: Water-Soluble and Peripherally Selective Adenosine Agonists 
Journal of medicinal chemistry  1992;35(22):4143-4149.
A series of N6-(p-sulfophenyl)alkyl and N6sulfoalkyl derivatives of adenosine was synthesized, revealing that N6-(p-sulfophenyl)adenosine (10b) is a moderately potent (Ki vs [3H]PIA in rat cortical membranes was 74 nM) and A1-selective (120-fold) adenosine agonist, of exceptional aqueous solubility of >1.5 g/mL (≈3 M). Compound 10b was very potent in inhibiting synaptic potentials in gerbil hippocampal slices with an IC50 of 63 nM. At a dose of 0.1 mg/kg ip in rats, 10b inhibited lipolysis (a peripheral A1 effect) by 85% after 1 h. This in vivo effect was reversed using the peripherally selective A1-antagonist 1,3-dipropyl-8-[p-(carboxyethynyl)phenyl]xanthine (BW1433). The same dose of 10b in NIH Swiss mice (ip) was nearly inactive in locomotor depression, an effect that has been shown to be centrally mediated when elicited by lower doses of other potent adenosine agonists, such as N6-cyclohexyladenosine (CHA) (Nikodijevic et al. FEBS Lett. 1990, 261, 67). HPLC studies of biodistribution of a closely related and less potent homologue, N6-[4-(p-sulfophenyl)butyl]adenosine indicated that a 25 mg/kg ip dose in mice resulted in a plasma concentration after 30 min of 0.46 μg/mL and no detectable drug in the brain (detection limit <0.1% of plasma level). Although 10b at doses >0.1 mg/kg in mice depressed locomotor activity, this depression was unlike the effects of CHA and was reversible by BW1433. These data suggest that 10b is a potent adenosine agonist in vivo and shows poor CNS penetration.
PMCID: PMC3420980  PMID: 1433217
7.  Postischemic IGF-1 gene transfer promotes neurovascular regeneration after experimental stroke 
Promoting neural regeneration after cerebral infarction has emerged as a potential approach for the treatment of stroke. Insulin-like growth factor 1 (IGF-1) possesses both neurotrophic and angiogenic properties. The aim of this study is to determine whether postischemic gene transfer of IGF-1 enhances neurovascular regeneration in a mouse model of permanent focal cerebral ischemia. Long-term cerebral IGF-1 overexpression was achieved with adeno-associated viral vector (AAV) via stereotaxic injection at 24 h after stroke. AAV-GFP or saline was injected as control. The success of postischemic gene transduction was confirmed by a strong green fluorescent protein signal and by increased IGF-1 protein expression in the peri-infarct region. Postischemic gene transfer of IGF-1 significantly enhanced vascular density at 8 weeks post stroke in the peri-infarct and injection needle tract area compared to AAV-GFP or saline treatment, as shown by immunohistochemical staining with vascular marker lectin. Furthermore, increased vascular density was associated with improved local vascular perfusion. Immunohistochemical staining with neuronal progenitor marker DCX and cell proliferation marker BrdU indicated that AAV-IGF-1 treatment potently increased neurogenesis compared to AAV-GFP injection. These data demonstrate that postischemic treatment of IGF-1 effectively promoted neural and vascular regeneration in the chronic stage of cerebral infarction.
doi:10.1038/jcbfm.2009.75
PMCID: PMC2763573  PMID: 19513085
angiogenesis; IGF-1; neurovascular; regeneration; stroke
8.  Therapeutic potential of CERE-110 (AAV2-NGF): Targeted, stable, and sustained NGF delivery and trophic activity on rodent basal forebrain cholinergic neurons 
Experimental neurology  2008;211(2):574-584.
Treatment of degenerating basal forebrain cholinergic neurons with nerve growth factor (NGF) in Alzheimer’s disease has long been contemplated, but an effective and safe delivery method has been lacking. Towards achieving this goal, we are currently developing CERE-110, an adeno-associated virus-based gene delivery vector that encodes for human NGF, for stereotactic surgical delivery to the human nucleus basalis of Meynert. Results indicate that NGF transgene delivery to the targeted brain region via CERE-110 is reliable and accurate, that NGF transgene distribution can be controlled by altering CERE-110 dose, and that it is possible to achieve restricted NGF expression limited to but covering the target brain region. Results from animals examined at longer time periods of 3, 6, 9 and 12 months after CERE-110 delivery indicate that NGF transgene expression is stable and sustained at all time points, with no loss or build-up of protein over the long-term. In addition, results from a series of experiments indicate that CERE-110 is neuroprotective and neurorestorative to basal forebrain cholinergic neurons in the rat fimbria-fornix lesion and aged rat models, and has bioactive effects on young rat basal forebrain cholinergic neurons. These findings, as well as those from several additional non-clinical experiments conducted in both rats and monkeys, led to the initiation of a Phase I clinical study to evaluate the safety and efficacy of CERE-110 in Alzheimer’s disease subjects, which is currently ongoing.
doi:10.1016/j.expneurol.2008.03.004
PMCID: PMC2709503  PMID: 18439998
adeno-associated virus; Alzheimer’s disease; basal forebrain cholinergic neurons; CERE-110; dose-response; gene delivery; nerve growth factor; neurotrophin; nucleus basalis of Meynert; trophic activity
9.  Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS 
Brain research  2007;1185:256-265.
The potent neuroprotective activities of neurotrophic factors, including insulin-like growth factor 1 (IGF-1), make them promising candidates for treatment of amyotrophic lateral sclerosis (ALS). In an effort to maximize rate of motor neuron transduction, achieve high levels of spinal IGF-1, and thus enhance therapeutic benefit, we injected an adeno-associated virus 2 (AAV2)-based vector encoding human IGF-1 (CERE-130) into lumbar spinal cord parenchyma of SOD1G93A mice. We observed robust and long-term intraspinal IGF-1 expression and partial rescue of lumbar spinal cord motor neurons, as well as sex-specific delayed disease onset, weight loss, decline in hindlimb grip strength and increased animal survival.
doi:10.1016/j.brainres.2007.09.034
PMCID: PMC2265207  PMID: 17963733
Adeno; associated virus; insulin; like growth factor 1; gene therapy; neurodegeneration; amyotrophic lateral sclerosis; neuroprotection
10.  Insulin Growth Factor-1 Gene Transfer Enhances Neurovascular Remodeling and Improves Long-Term Stroke Outcome in Mice 
Background and Purpose
Insulin-like growth factor I (IGF-1) is a pleiotropic growth factor that has been demonstrated to protect against acute ischemic brain injury. Whether IGF-1 improves long-term functional outcome after ischemic stroke is not known. The aim of this study is to examine whether IGF-1 overexpression through adeno-associated virus (AAV) -mediated gene transfer enhances neurovascular remodeling and improves functional outcome in a mouse model of focal cerebral ischemia.
Methods
Long-term cerebral IGF-1 overexpression was achieved with the AAV transduction system through stereotaxic injection. Control mice were injected with AAV–green fluorescent protein or saline. Three weeks after gene transfer, the mice underwent permanent distal middle cerebral artery occlusion. Histological and behavioral analyses were performed at day 21 after middle cerebral artery occlusion.
Results
IGF-1 gene transfer compared with control treatment significantly improved motor performance assessed by sensorimotor tests. The functional recovery was accompanied by reduced volume of cerebral infarction. Immunohistochemical analysis with endothelial cell marker CD31 revealed that IGF-1 gene transfer potently increased neovessel formation in the periinfarct and injection needle tract area compared with AAV–green fluorescent protein transduction. Increased vascular density was associated with increased local vascular perfusion. Additionally, AAV-IGF-1 treatment enhanced neurogenesis in the subventricular zone compared with AAV–green fluorescent protein treatment.
Conclusions
These data demonstrate that IGF-1 overexpression promoted long-lasting functional recovery after cerebral infarction. The improved functional performance was paralleled by enhanced neovascularization and neurogenesis.
doi:10.1161/STROKEAHA.107.500801
PMCID: PMC2553752  PMID: 18309153
angiogenesis; gene transfer; IGF-1; neurogenesis; stroke

Results 1-10 (10)