A dose-ranging study of AAV-hAADC therapy in Parkinsonian monkeys.
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ABSTRACT:
SUBMITTER: Forsayeth JR
PROVIDER: S-EPMC2725179 | biostudies-other | 2006 Oct
REPOSITORIES: biostudies-other
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Project description:Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD1. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues1,2. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.
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Project description:Background:Hand functionality and finger dexterity are impaired in patients with Parkinson's disease (PD). These disturbances lead to a dependency in activities of daily living (ADL) and poor quality of life (QoL). Objective:We aimed to evaluate whether a specific occupational therapy (OT) program is effective in improving finger and hand dexterity and its impact on ADL in PD patients. Methods:We retrospectively studied PD patients, hospitalized for a 4-week multidisciplinary intensive rehabilitation treatment (MIRT) between January 2015 and June 2018. All patients underwent 1?h/day OT treatment, 5 days a week. The primary outcome measure was the O'Connor finger dexterity test; secondary outcome measures were the Minnesota dexterity test, UPDRS II, and Self-Assessment Parkinson's Disease Disability Scale (SPDDS). These measures were assessed at admission (T0) and discharge (T1). Results:Based on the Hoehn and Yahr scale (H&Y), patients were divided into two groups: 262 subjects in H&Y stage <3 (early-stage PD patients) and 220 in H&Y stage ?3 (medium-advanced stage PD patients). As expected, at baseline, all measures were worse in higher H&Y stages. After treatment, both groups experienced significant improvements in all outcomes. Significant differences between early-stage and medium-advanced stage PD patients were observed only for the changes in UPDRS II, with a better improvement in patients in H&Y stage ?3. Conclusions:We showed that PD patients who underwent a rehabilitation protocol including OT experienced improvements in finger dexterity and hand functionality. Our results underline the relevance of OT in improving autonomy and QoL in PD patients.
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Project description:X-linked inherited ornithine transcarbamylase deficiency (OTCD) is the most common disorder affecting the liver-based urea cycle, a pathway enabling detoxification of nitrogen waste and endogenous arginine biosynthesis. Patients develop acute hyperammonemia leading to neurological sequelae or death despite the best-accepted therapy based on ammonia scavengers and protein-restricted diet. Liver transplantation is curative but associated with procedure-related complications and lifelong immunosuppression. Adeno-associated viral (AAV) vectors have demonstrated safety and clinical benefits in a rapidly growing number of clinical trials for inherited metabolic liver diseases. Engineered AAV capsids have shown promising enhanced liver tropism. Here, we conducted a good-laboratory practice-compliant investigational new drug-enabling study to assess the safety of intravenous liver-tropic AAVLK03 gene transfer of a human codon-optimized OTC gene. Juvenile cynomolgus monkeys received vehicle and a low and high dose of vector (2 × 1012 and 2 × 1013 vector genome (vg)/kg, respectively) and were monitored for 26 weeks for in-life safety with sequential liver biopsies at 1 and 13 weeks post-vector administration. Upon completion of monitoring, animals were euthanized to study vector biodistribution, immune responses, and histopathology. The product was well tolerated with no adverse clinical events, predominant hepatic biodistribution, and sustained supra-physiological OTC overexpression. This study supports the clinical deployment of intravenous AAVLK03 for severe OTCD.
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Project description:This study assessed the potential for functional and anatomical recovery of the diseased aged primate nigrostriatal system, in response to trophic factor gene transfer. Aged rhesus monkeys received a single intracarotid infusion of MPTP, followed one week later by MRI-guided stereotaxic intrastriatal and intranigral injections of lentiviral vectors encoding for glial derived neurotrophic factor (lenti-GDNF) or beta-galactosidase (lenti-LacZ). Functional analysis revealed that the lenti-GDNF, but not lenti-LacZ treated monkeys displayed behavioral improvements that were associated with increased fluorodopa uptake in the striatum ipsilateral to lenti-GDNF treatment. GDNF ELISA of striatal brain samples confirmed increased GDNF expression in lenti-GDNF treated aged animals that correlated with functional improvements and preserved nigrostriatal dopaminergic markers. Our results indicate that the aged primate brain challenged by MPTP administration has the potential to respond to trophic factor delivery and that the degree of neuroprotection depends on GDNF levels.
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Project description:Activation of the peroxisome proliferator-activated receptor gamma (PPAR-?) has been proposed as a possible neuroprotective strategy to slow down the progression of early Parkinson's disease (PD). Here we report preclinical data on the use of the PPAR-? agonist pioglitazone (Actos®; Takeda Pharmaceuticals Ltd.) in a paradigm resembling early PD in nonhuman primates.Rhesus monkeys that were trained to perform a battery of behavioral tests received a single intracarotid arterial injection of 20 ml of saline containing 3 mg of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Twenty-four hours later the monkeys were assessed using a clinical rating scale, matched accordingly to disability, randomly assigned to one of three groups [placebo (n = 5), 2.5 (n = 6) or 5 (n = 5) mg/kg of pioglitazone] and their treatments started. Three months after daily oral dosing, the animals were necropsied.We observed significant improvements in clinical rating score (P = 0.02) in the animals treated with 5 mg/kg compared to placebo. Behavioral recovery was associated with preservation of nigrostriatal dopaminergic markers, observed as higher tyrosine hydroxylase (TH) putaminal optical density (P = 0.011), higher stereological cell counts of TH-ir (P = 0.02) and vesicular monoamine transporter-2 (VMAT-2)-ir nigral neurons (P = 0.006). Stereological cell counts of Nissl stained nigral neurons confirmed neuroprotection (P = 0.017). Pioglitazone-treated monkeys also showed a dose-dependent modulation of CD68-ir inflammatory cells, that was significantly decreased for 5 mg/kg treated animals compared to placebo (P = 0.018). A separate experiment to assess CSF penetration of pioglitazone revealed that 5 mg/kg p.o. induced consistently higher levels than 2.5 mg/kg and 7.5 mg/kg. p.o.Our results indicate that oral administration of pioglitazone is neuroprotective when administered early after inducing a parkinsonian syndrome in rhesus monkeys and supports the concept that PPAR-? is a viable target against neurodegeneration.
| S-EPMC3166925 | biostudies-other
Project description:BACKGROUND:Inhaled corticosteroids (ICS) offer targeted treatment for bronchopulmonary dysplasia (BPD) with minimal systemic effects compared to systemic steroids. However, dosing of ICS in the management of infants at high-risk of developing BPD is not well established. The objective of this study was to determine an effective dose of ICS for the treatment of ventilator-dependent infants to facilitate extubation or reduce fractional inspired oxygen concentration. METHODS:Forty-one infants born at < 32 weeks gestational age (GA) or < 1250 g who were ventilator-dependent at 10-28 days postnatal age were included. A non-randomized dose-ranging trial was performed using aerosolized inhaled beclomethasone with hydrofluoralkane propellant (HFA-BDP). Four dosing groups (200, 400, 600 and 800 μg twice daily for 1 week) with 11, 11, 10 and 9 infants in each group, respectively, were studied. The primary outcome was therapeutic efficacy (successful extubation or reduction in FiO2 of > 75% from baseline) in ≥60% of infants in the group. Oxygen requirements, complications and long-term neurodevelopmental outcomes were also assessed. RESULTS:The median age at enrollment was 22 (10-28) postnatal days. The primary outcome, therapeutic efficacy as defined above, was not achieved in any group. However, there was a significant reduction in post-treatment FiO2 at a dose of 800 μg bid. No obvious trends were seen in long-term neurodevelopmental outcomes. CONCLUSIONS:Therapeutic efficacy was not achieved with all studied doses of ICS. A significant reduction in oxygen requirements was noted in ventilator-dependent preterm infants at 10-28 days of age when given 800 μg of HFA-BDP bid. Larger randomized trials of ICS are required to determine efficacy for the management of infants at high-risk for development of BPD. TRIAL REGISTRATION:This clinical trial was registered retrospectively on clinicaltrials.gov. The registration number is NCT03503994 .
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Project description:PurposeThis dose-escalation study was performed to determine the recommended phase II dose of oral capecitabine to be delivered concurrently with thoracic radiation therapy and weekly docetaxel in patients with locally advanced esophageal carcinoma.MethodsPatients with operable stage II or III esophageal carcinoma were staged by endoscopic ultrasonography and computed tomography. Two cycles of docetaxel (80 mg/m) and carboplatin (target area under the concentration-time curve: 6 mg/ml × min) were delivered over 6 weeks. This was followed by concurrent weekly docetaxel (15 mg/m), thoracic radiotherapy (50.4 Gy in 28 fractions), and increasing doses of capecitabine (500-3500 mg) given before each fraction of radiotherapy. After restaging, responding patients continued to esophagectomy within 4 to 8 weeks of completing chemoradiotherapy.ResultsForty-four patients were enrolled, and 40 were assessable for the dose-ranging component of concurrent chemoradiotherapy. Endoscopic ultrasonography stages at enrollment were T3N1 (29 patients), T3N0 (4 patients), T2N1 (6 patients), and T4N0 (one patient). The maximum tolerated dose of capecitabine was 3500 mg. Thirty-six patients had surgery; 83% had R0 resection, and 17% had pathological complete response. Median overall survival was 23.5 months, with 34 and 27% alive at 3 and 5 years.ConclusionThe recommended phase II dose of capecitabine is 3500 mg when given concurrently with 50.4 Gy of thoracic radiotherapy in 28 fractions and weekly docetaxel. This trimodality therapy for operable locally advanced esophageal carcinoma was very well tolerated and remarkably active. This regimen holds promise for the treatment of esophageal carcinoma and warrants further investigation.
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Project description:Development of vaccines against mosquito-borne Flaviviruses is complicated by the occurrence of antibody-dependent enhancement (ADE), which can increase disease severity. Long-term delivery of neutralizing antibodies (nAbs) has the potential to effectively block infection and represents an alternative to vaccination. The risk of ADE may be avoided by using prophylactic nAbs harboring amino acid mutations L234A and L235A (LALA) in the immunoglobulin G (IgG) constant region. Here, we used recombinant adeno-associated viruses (rAAVs) to deliver the anti-dengue virus 3 (DENV3) nAb P3D05. While the administration of rAAV-P3D05-rhesus immunoglobulin G1 (rhIgG1)-LALA to rhesus macaques engendered DENV3-neutralizing activity in serum, it did not prevent infection. The emergence of viremia following DENV3 challenge was delayed by 3-6 days in the rAAV-treated group, and replicating virus contained the envelope mutation K64R. This neutralization-resistant variant was also confirmed by virus outgrowth experiments in vitro. By delivering P3D05 with unmutated Fc sequences, we further demonstrated that DENV3 also evaded wild-type nAb prophylaxis, and serum viral loads appeared to be higher in the presence of low levels of unmutated P3D05-rhIgG1. Our study shows that a vectored approach for long-term delivery of nAbs with the LALA mutations is promising, but prophylaxis using a single nAb is likely insufficient at preventing DENV infection and replication.
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Project description:The GABA transporters GAT-1 and GAT-3 are abundant in the external and internal segments of the globus pallidus (GPe and GPi, respectively). We have shown that pharmacological blockade of either of these transporters results in decreased neuronal firing, and in elevated levels of extracellular GABA in normal monkeys. We now studied whether the electrophysiologic and biochemical effects of local intra-pallidal injections of GAT-1 and GAT-3 blockers, or the subcellular localization of these transporters, are altered in monkeys rendered parkinsonian by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The subcellular localization of the transporters in GPe and GPi, studied with electron microscopy immunoperoxidase, was similar to that found in normal animals: i.e., GAT-3 immunoreactivity was mostly confined to glial processes, while GAT-1 labeling was expressed in unmyelinated axons and glial processes. A combined injection/recording device was used to record the extracellular activity of single neurons in GPe and GPi, before, during and after administration of small volumes (1microl) of either the GAT-1 inhibitor, SKF-89976A hydrochloride (720ng), or the GAT-3 inhibitor, (S)-SNAP-5114 (500ng). In GPe, the effects of GAT-1 or GAT-3 blockade were similar to those seen in normal monkeys. However, unlike the findings in the normal state, the firing of most neurons was not affected by blockade of either transporter in GPi. These results suggest that, after dopaminergic depletion, the functions of GABA transporters are altered in GPi; without major changes in their subcellular localization.
| S-EPMC2864357 | biostudies-literature
Project description:BackgroundPhosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of l-dopa-induced dyskinesia. The elevation of cyclic adenosine monophosphate/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce l-dopa-induced dyskinesia.ObjectivesThe present study was aimed at determining the potential antidyskinetic effects of phosphodiesterase 10A inhibitors in a primate model of Parkinson's disease (PD). The experiments performed in this model were also intended to provide translational data for the design of future clinical trials.MethodsFive MPTP-treated macaques with advanced parkinsonism and reproducible l-dopa-induced dyskinesia were used. MR1916, a selective phosphodiesterase 10A inhibitor, at doses 0.0015 to 0.05 mg/kg, subcutaneously, or its vehicle (control test) was coadministered with l-dopa methyl ester acutely (predetermined optimal and suboptimal subcutaneous doses) and oral l-dopa chronically as daily treatment for 5 weeks. Standardized scales were used to assess motor disability and l-dopa-induced dyskinesia by blinded examiners. Pharmacokinetics was also examined.ResultsMR1916 consistently reduced l-dopa-induced dyskinesia in acute tests of l-dopa optimal and suboptimal doses. Significant effects were present with every MR1916 dose tested, but the most effective was 0.015 mg/kg. None of the MR1916 doses tested affected the antiparkinsonian action of l-dopa at the optimal dose. The anti-l-dopa-induced dyskinesia effect of MR1916 (0.015 mg/kg, subcutaneously) was sustained with chronic administration, indicating that tolerance did not develop over the 5-week treatment. No adverse effects were observed after MR1916 administration acutely or chronically.ConclusionsResults show that regulation of striatal cyclic nucleotides by phosphodiesterase 10A inhibition could be a useful therapeutic approach for l-dopa-induced dyskinesia, and therefore data support further studies of selective phosphodiesterase 10A inhibitors for PD therapy. © 2018 International Parkinson and Movement Disorder Society.
| S-EPMC5992016 | biostudies-literature