The Parkinsons Institute

Sunnyvale, CA, United States

The Parkinsons Institute

Sunnyvale, CA, United States
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Pahwa R.,University of Kansas Medical Center | Tanner C.M.,The Parkinsons Institute | Tanner C.M.,University of California at San Francisco | Hauser R.A.,University of South Florida | And 8 more authors.
Movement Disorders | Year: 2015

ADS-5102 is a long-acting, extended-release capsule formulation of amantadine HCl administered once daily at bedtime. This study investigated the safety, efficacy, and tolerability of ADS-5102 in Parkinson's disease (PD) patients with levodopa-induced dyskinesia. This was a randomized, double-blind, placebo-controlled, parallel-group study of 83 PD patients with troublesome dyskinesia assigned to placebo or one of three doses of ADS-5102 (260 mg, 340 mg, 420 mg) administered daily at bedtime for 8 weeks. The primary efficacy analysis compared change from baseline to week 8 in Unified Dyskinesia Rating Scale (UDysRS) total score for 340 mg ADS-5102 versus placebo. Secondary outcome measures included change in UDysRS for 260 mg, 420 mg, Fatigue Severity Scale (FSS), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), patient diary, Clinician's Global Impression of Change, and Parkinson's Disease Questionnaire (PDQ-39). ADS-5102 340 mg significantly reduced dyskinesia versus placebo (27% reduction in UDysRS, P=0.005). In addition, ADS-5102 significantly increased ON time without troublesome dyskinesia, as assessed by PD patient diaries, at 260 mg (P=0.004), 340 mg (P=0.008) and 420 mg (P=0.018). Adverse events (AEs) were reported for 82%, 80%, 95%, and 90% of patients in the placebo, 260-mg, 340-mg, and 420-mg groups, respectively. Constipation, hallucinations, dizziness, and dry mouth were the most frequent AEs. Study withdrawal rates were 9%, 15%, 14%, and 40% for the placebo, 260-mg, 340-mg, and 420-mg groups, respectively. All study withdrawals in the active treatment groups were attributable to AEs. ADS-5102 was generally well tolerated and resulted in significant and dose-dependent improvements in dyskinesia in PD patients. © 2015 Adamas Pharmaceuticals, Inc.


Rascol O.,University of Sfax | Fitzer-Attas C.J.,Teva Pharmaceutical Industries | Hauser R.,Parkinsons Disease and Movement Disorders Center | Jankovic J.,Baylor College of Medicine | And 9 more authors.
The Lancet Neurology | Year: 2011

Background: The ADAGIO study investigated whether rasagiline has disease-modifying effects in Parkinson's disease. Rasagiline 1 mg per day, but not 2 mg per day, was shown to be efficacious in the primary analysis. Here, we report additional secondary and post-hoc analyses of the ADAGIO study. Methods: ADAGIO was a placebo-controlled, double-blind, multicentre, delayed-start study, in which 1176 patients with untreated early Parkinson's disease were randomly assigned to receive rasagiline 1 mg or 2 mg per day for 72 weeks (early-start groups) or placebo for 36 weeks followed by rasagiline 1 mg or 2 mg per day for 36 weeks (delayed-start groups). We assessed the need for additional antiparkinsonian therapy and changes in non-motor experiences of daily living and fatigue scales (prespecified outcomes) and changes in unified Parkinson's disease rating scale (UPDRS) scores and subscores in placebo and active groups (post-hoc outcomes). The ADAGIO study is registered with ClinicalTrials.gov, number NCT00256204. Findings: The need for additional antiparkinsonian therapy was reduced with rasagiline 1 mg (25 of 288 [9%] patients) and 2 mg (26 of 293 [9%]) versus placebo (108 of 593 [18%]; odds ratio for 1 mg rasagiline vs placebo 0·41, 95% CI 0·25-0·65, p=0·0002; 2 mg rasagiline vs placebo 0·41, 0·26-0·64, p=0·0001). At week 36, both doses significantly improved UPDRS motor subscores compared with placebo (1 mg rasagiline mean difference -1·88 [SE 0·35]; 2 mg rasagiline -2·18 [0·35]; both p<0·0001) and activities of daily living subscores (ADL; 1 mg rasagiline -0·86 [0·18]; 2 mg rasagiline -0·88 [0·18]; both p<0·0001), and 1 mg rasagiline significantly improved UPDRS mentation subscore (-0·22 [0·08]; p=0·004). At week 72, the only significant difference between early-start and delayed-start groups was for ADL subscore with the 1 mg dose (-0·62 [0·29]; p=0·035). When assessed for the effect on non-motor symptoms at week 36, both doses showed benefits on the Parkinson fatigue scale versus placebo (1 mg rasagiline mean difference -0·14 [SE 0·05], p=0·0032; 2 mg rasagiline -0·19 [0·05], p<0·0001), and the 1 mg dose showed benefits on the scale for non-motor experiences of daily living compared with placebo (mean difference -0·33 [0·17]; p=0·049). The rate of progression of total UPDRS score for patients in the placebo group was 4·3 points [SE 0·3] over 36 weeks, with extrapolation to about 6 units per year. In the placebo group, patients with the lowest quartile of baseline UPDRS scores (≤14; n=160) progressed more slowly than did those with highest scores (>25·5; n=145; mean difference -3·46 [SE 0·77]; p<0·0001). Interpretation: These findings show that rasagiline delayed the need for symptomatic antiparkinsonian drugs and emphasise the contribution of the UPDRS ADL in the response of the rasagiline 1 mg per day early-start versus delayed-start group. The rate of UPDRS deterioration was less than was anticipated from previous studies and correlated with baseline severity. Understanding of the pattern of UPDRS deterioration is essential to assess disease modification. Funding: Teva Pharmaceutical Industries and H Lundbeck A/S. © 2011 Elsevier Ltd.


Jenner P.,King's College London | Langston J.W.,The Parkinsons Institute
Movement Disorders | Year: 2011

The ADAGIO study demonstrated a symptomatic benefit for rasagiline in early Parkinson's disease (PD) and suggested a disease-modifying effect. Evidence indicates that mitochondrial dysfunction plays a role in the pathogenesis of PD and that this may be the site of effect for rasagiline. In this systematic review, evidence for the role of mitochondria in the pathogenesis of PD are reviewed in light of other proposed mechanisms of neuronal degeneration and the actions of rasagiline and its component parts, namely propargylamine and the metabolite, aminoindan. Evidence for the role of mitochondria in the pathogenesis and treatment of PD are reviewed in light of other proposed mechanisms of neuronal degeneration and clinical actions of rasagiline. Monoamine oxidase B (MAO-B) located in the outer mitochondrial membrane controls dopamine metabolism in early PD, and this is the likely location for the symptomatic action of rasagiline. Accumulating evidence indicates that mitochondrial impairment contributes to dopaminergic neuronal loss in PD, either directly or through other mechanisms such as oxidative stress or protein misfolding. Further rasagiline affects numerous mitochondrial mechanisms that prevent apoptotic cell death including prevention of opening of the mitochondrial transition pore, decreased release of cytochrome C, alterations in pro-antiapoptotic genes and proteins, and the nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Thus, the functional neuroprotective actions of rasagiline may not be dependent on MAO-B inhibition, but rather may involve actions of the propargylamine moiety and the aminoindan metabolite. An accumulating body of literature indicates a mitochondrial site of action for rasagiline and highlights the neuroprotective action of the drug, providing strong biological plausibility for disease-modifying effects of the drug such as those observed in ADAGIO. © 2011 Movement Disorder Society.


Zhou W.,University of California at Santa Cruz | Long C.,University of California at Santa Cruz | Reaney S.H.,The Parkinsons Institute | Di Monte D.A.,The Parkinsons Institute | And 4 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2010

Oxidative stress and aggregation of the presynaptic protein α-synuclein (α-Syn) are implied in the pathogenesis of Parkinson's disease and several other neurodegenerative diseases. Various posttranslational modifications, such as oxidation, nitration and truncation, have significant effects on the kinetics of α-Syn fibrillation in vitro. α-Syn is a typical natively unfolded protein, which possesses some residual structure. The existence of long-range intra-molecular interactions between the C-terminal tail (residues 120-140) and the central part of α-Syn (residues 30-100) was recently established (Bertoncini et al. (2005) Proc Natl Acad Sci U S A 102, 1430-1435). Since α-Syn has four methionines, two of which (Met 1 and 5) are at the N-terminus and the other two (Met 116 and 127) are in the hydrophobic cluster at the C-terminus of protein, the perturbation of these residues via their oxidation represents a good model for studying the effect of long-range interaction on α-Syn fibril formation. In this paper we show that Met 1, 116, and 127 are more protected from the oxidation than Met 5 likely due to the residual structure in the natively unfolded α-Syn. In addition to the hydrophobic interactions between the C-terminal hydrophobic cluster and hydrophobic central region of α-Syn, there are some long-range electrostatic interactions in this protein. Both of these interactions likely serve as auto-inhibitors of α-Syn fibrillation. Methionine oxidation affects both electrostatic and hydrophobic long-range interactions in α-Syn. Finally, oxidation of methionines by H2O2 greatly inhibited α-Syn fibrillation in vitro, leading to the formation of relatively stable oligomers, which are not toxic to dopaminergic and GABAergic neurons. © 2009 Elsevier B.V. All rights reserved.


Tanner C.M.,The Parkinsons Institute
Movement Disorders | Year: 2010

Parkinson's disease (PD) is likely due to the combined effects of environment and genes in most cases. Environmental factors inversely associated with PD (or, putative protective factors) include cigarette smoking, use of coffee/caffeine, higher uric acid levels, and anti-inflammatory drug use. Less well-established inverse associations with PD include higher cholesterol levels, statin use, higher dietary vitamin B6, and night shift work. Putative risk factors are pesticide exposure, head trauma, certain occupations, and milk consumption. The pathogenesis of PD may begin decades before motor symptoms. PD may have shared determinants with other neurodegenerative disorders involving abnormal protein aggregation. © 2010 Movement Disorder Society.


Hermanson S.B.,Life Technologies | Carlson C.B.,Life Technologies | Riddle S.M.,Life Technologies | Zhao J.,The Parkinsons Institute | And 3 more authors.
PLoS ONE | Year: 2012

Background: Mutations in the leucine-rich repeat kinase-2 (LRRK2) have been linked to Parkinson's disease. Recent studies show that inhibition of LRRK2 kinase activity decreased the level of phosphorylation at its own Ser910 and Ser935, indicating that these sites are prime targets for cellular readouts of LRRK2 inhibition. Methodology/Principal Findings: Using Time-Resolved Förster Resonance Energy Transfer (TR-FRET) technology, we developed a high-throughput cellular assay for monitoring LRRK2 phosphorylation at Ser935. LRRK2-Green Fluorescence Protein (GFP) fusions were expressed in cells via BacMam. Phosphorylation at Ser935 in these cells is detected using a terbium labeled anti-phospho-Ser935 antibody that generates a TR-FRET signal between terbium and GFP. LRRK2 wild-type and G2019S are constitutively phosphorylated at Ser935 in cells as measured by TR-FRET. The phosphorylation level is reduced for the R1441C mutant and little could be detected for the kinase-dead mutant D1994A. The TR-FRET cellular assay was further validated using reported LRRK2 inhibitors including LRRK2-IN-1 and our results confirmed that inhibition of LRRK2 can reduce the phosphorylation level at Ser935. To demonstrate the utility of this assay for screening, we profiled a small library of 1120 compounds. Three known LRRK2 inhibitors were identified and 16 hits were followed up in the TR-FRET and a cytotoxicity assay. Interestingly, out of the top 16 hits, five are known inhibitors of IκB phosphorylation, two CHK1 and two CDC25 inhibitors. Thirteen hits were further tested in a biochemical LRRK2 kinase activity assay and Western blot analysis for their effects on the phosphorylation of Ser910, Ser935, Ser955 and Ser973. Conclusions/Significance: We developed a TR-FRET cellular assay for LRRK2 Ser935 phosphorylation that can be applied to the screening for LRRK2 inhibitors. We report for the first time that several compounds such as IKK16, CHK1 inhibitors and GW441756 can inhibit LRRK2 Ser935 phosphorylation in cells and LRRK2 kinase activity in vitro. © 2012 Hermanson et al.


McCormack A.L.,German Center for Neurodegenerative Diseases | McCormack A.L.,SRI International | Mak S.K.,The Parkinsons Institute | Henderson J.M.,Stanford University | And 4 more authors.
PLoS ONE | Year: 2010

The protein α-synuclein is involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal α-Synuclein burden. Here, feasibility and safety of α-Synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA) directed against α-Synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of α-Synuclein mRNA and protein in the infused (left) vs. untreated (right) hemisphere and revealed a significant 40-50% suppression of α-Synuclein expression. These findings could not be attributable to non-specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in asynuclein. Infusion with α-Synuclein siRNA, while lowering α-Synuclein expression, had no overt adverse consequences. In particular, it did not cause tissue inflammation and did not change (i) the number and phenotype of nigral dopaminergic neurons, and (ii) the concentrations of striatal dopamine and its metabolites. The data represent the first evidence of successful anti-α-synuclein intervention in the primate substantia nigra and support further development of RNA interference-based therapeutics. © 2010 McCormack et al.


Vangipuram M.,The Parkinsons Institute
Journal of visualized experiments : JoVE | Year: 2013

Tissues and cell lines derived from an individual with disease are ideal sources to study disease-related cellular phenotypes. Patient-derived fibroblasts in this protocol have been successfully used in the derivation of induced pluripotent stem cells to model disease(1). Early passages of these fibroblasts can also be used for cell-based functional assays to study specific disease pathways, mechanisms(2) and subsequent drug screening approaches. The advantage of the presented protocol over enzymatic procedures are 1) the reproducibility of the technique from small amounts of tissue derived from older patients, e.g. patients affected with Parkinson's disease, 2) the technically simple approach over more challenging methodologies using enzymatic treatments, and 3) the time consideration: this protocol takes 15-20 min and can be performed immediately after biopsy arrival. Enzymatic treatments can take up to 4 hr and have the problems of overdigestion, reduction of cell viability and subsequent attachment of cells when not handled properly. This protocol describes the dissection and preparation of a 4-mm human skin biopsy for derivation of a fibroblast culture and has a very high success rate which is important when dealing with patient-derived tissue samples. In this culture, keratinocytes migrate out of the biopsy tissue within the first week after preparation. Fibroblasts appear 7-10 days after the first outgrowth of keratinocytes. DMEM high glucose media supplemented with 20% FBS favors the growth of fibroblasts over keratinocytes and fibroblasts will overgrow the keratinocytes. After 2 passages keratinocytes have been diluted out resulting in relatively homogenous fibroblast cultures which expresses the fibroblast marker SERPINH1 (HSP-47). Using this approach, 15-20 million fibroblasts can be derived in 4-8 weeks for cell banking. The skin dissection takes about 15-20 min, cells are then monitored once a day under the microscope, and media is changed every 2-3 days after attachment and outgrowth of cells.


The invention provides dosage forms and methods utilizing nicotine to treat symptoms of a neurologic disorder. In some embodiments, the invention provides compositions for treatment of gait and balance problems associated with Parkinsons Disease.


Patent
The Parkinsons Institute and Sangamo BioSciences | Date: 2013-12-02

Disclosed herein are in vitro and in vivo methods for screening for compounds that treat diseases and conditions that are related to oxidative stress such as Parkinsons disease

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