Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease.

ObjectiveTo understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery.MethodsFifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 1011 vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 1012 vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 1012 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes.ResultsMRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life.InterpretationNovel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714

Parkinson's Disease with Device, Diary, or in Disguise. Dyskinesia reduction, motor state evaluation, and workforce participation among persons with Parkinson's disease.

INTRODUCTION: In the wait for disease-modifying treatment for Parkinson’s disease (PD), efforts towards improved symptom control and reduced negative effects of PD can result in meaningful change patients. The general efficacy of levodopa-carbidopa intestinal gel (LCIG) in advanced PD has been established, but its effects on dyskinesia need more investigation. The PD Home Diary has been used in clinical trials to evaluate treatment effects for almost 20 years, but needs to be validated. As treatments improve, it is vital to understand how PD affects workforce participation to further reduce the personal and societal effects of PD.AIMS: The overarching aim of this thesis is to increase the knowledge on how health services can support persons with PD. The thesis has two main themes: motor fluctuations and workforce participation. Firstly, the aim was to contribute to a better understanding and utilization of existing tools in the treatment and evaluation of motor fluctuations in PD: LCIG and the PD Home Diary. Secondly, the aim was to improve our understanding of the impact of PD on workforce participation.METHODS: Two clinical observational studies were used to investigate the effects of LCIG on dyskinesia and to validate the PD Home Diary, while one cross-sectional and one longitudinal registry study was designed to investigate workforce participation among persons with PD.RESULTS: LCIG was found to reduce dyskinesia among persons with advanced PD and troublesome dyskinesia at baseline. Motor state assessments from the patient-reported PD Home Diary and those by an experienced observer were found to be in fair agreement. Workforce unavailability was found to be associated with anxiety among working-age persons with PD. Persons with a first sick-leave due to PD exhibited increased sickness absence in the preceding five-year period compared to controls, particularly due to musculoskeletal diagnoses.CONCLUSIONS AND IMPLICATIONS: LCIG is a feasible treatment also for persons with advanced PD and troublesome dyskinesia. The PD Home Diary should not be regarded as interchangeable with the observer assessment gold standard. The association between workforce unavailability and anxiety needs further investigation, but anxiety should nonetheless be treated when identified. Musculoskeletal sickness absence is significantly increased in prodromal and early PD, which emphasizes that functioning and workforce participation is likely to be affected already at the time of diagnosis and thus demands immediate attention

PHARMACOKINETIC AND PHARMCODYNAMIC STUDIES OF APOMORPHINE IN THE TREATMENT OF IDIOPATHIC PARKINSON'S DISEASE

There were two aspects to the study of apomorphine in the treatment of Parkinson' s disease: (i) a clinical pharmacokinetic-pharmacodynamic (PK-PD) study was designed and implemented in response to the challenges of apomorphine dose-titration in Parkinson's disease, and in view of the scarcity of available literature on the PK-PD relationships of apomorphine in Parkinson's disease, (ii) the PK(and tolerability)of apomorphine dosing using novel delivery/formulation combinations were explored in view of the inherent limitations associated with the conventional (ie. subcutaneous) route of administration of apomorphine (e.g. cutaneous nodule formation, needle-phobia). An HPLC assay was developed for the quantification of apomorphine in plasma, and stability issues relating to sample storage and assay were investigated. With regards to the first aspect of the research, simultaneous PK-PD modelling was performed, using an effect compartment model to account for counterclockwise hysteresis in a sub-group of patients. According to the traditional two-stage approach to data analysis, mean (standard deviation) clearance following subcutaneous bolus was 2.2 (0.5) L/kg/h, (apparent) volume of distribution was 1.9 (0.8) L/kg, absorption half-life was 4.1 (2.1) minutes and elimination half-life was 69.5 (21.1)minutes (n=7). Equilibration half-life was estimated for two patients at 8.3 and 16.5 minutes. Focus was given to investigating the relevance of a potential correlation (which had previously been identified using in-house pilot data) between post-distributional apomorphine PK and apomorphine-induced anti-parkinsonian response in patients with Parkinson's disease. It was hypothesised that this particular correlation may be of use in a dose-optimisation scheme. However it was demonstrated that, in the patients studied, the concept could not be applied to apomorphine dose-optimisation. The novel delivery systems under scrutiny were: (i) Britaject® (Britannia Pharmaceuticals Ltd.) apomorphine formulation administered subcutaneously using a needle-free (jet) injector (J-TIP®, National Medical Products Inc.), (ii) an intranasal apomorphine powder formulation delivered using a turbospin insufflator (CDFS), and (iii) an apomorphine hydrogel co-polymer produced as a dosage-form for buccal delivery (Controlled Therapeutics (Scotland) Ltd.). As a result of this work, a rationale for subsequent development of the novel systems was provided. Indeed, the needle-free and buccal systems were, in their existing format, shown not to convey a net advantage over the existing system. However the intranasal formulation, with a mean (standard deviation) relative bioavailability of 41 (18)% (n=16) compared to subcutaneous bolus administration (and with a favourable outcome as regards to tolerability), was considered to be potentially suitable for further development

Rapid quantitative pharmacodynamic imaging by a novel method: theory, simulation testing and proof of principle

Pharmacological challenge imaging has mapped, but rarely quantified, the sensitivity of a biological system to a given drug. We describe a novel method called rapid quantitative pharmacodynamic imaging. This method combines pharmacokinetic-pharmacodynamic modeling, repeated small doses of a challenge drug over a short time scale, and functional imaging to rapidly provide quantitative estimates of drug sensitivity including EC50 (the concentration of drug that produces half the maximum possible effect). We first test the method with simulated data, assuming a typical sigmoidal dose-response curve and assuming imperfect imaging that includes artifactual baseline signal drift and random error. With these few assumptions, rapid quantitative pharmacodynamic imaging reliably estimates EC50 from the simulated data, except when noise overwhelms the drug effect or when the effect occurs only at high doses. In preliminary fMRI studies of primate brain using a dopamine agonist, the observed noise level is modest compared with observed drug effects, and a quantitative EC50 can be obtained from some regional time-signal curves. Taken together, these results suggest that research and clinical applications for rapid quantitative pharmacodynamic imaging are realistic.Comment: 26 pages total, 4 tables, 10 figures. The original PDF file at https://peerj.com/articles/117/ includes active hyperlinks. This version is the final published version. (Differs from v2 only in that I corrected the abstract on the arXiv.org page.

Clinical and PET Imaging Studies in Parkinson’s Disease Motor and Non-Motor Complications: Serotonergic and Dopamimergic Mechanisms and Applications in Treatment

The clinical course of Parkinson’s disease (PD) is complicated by the development of motor and non-motor complications. This thesis, using clinical motor and non-motor assessments and positron emission tomography (PET) imaging with 11C-raclopride, 11CDASB and 18F-DOPA, aims to explore in PD the role of: (1) postsynaptic dopamine D2 receptor dysfunction, (2) serotonergic dysfunction in the development of non-motor symptoms such as depression and body weight change, (3) striatal serotonergic neurons in levodopa- and graft -induced dyskinesias (LIDs and GIDs), and (4) the efficacy of treatment with continuous dopaminergic stimulation. The main findings are as follows: (1) D2 receptor dysfunction in the hypothalamus but not in the putamen was evident in PD, possibly accounting for the development of non-motor symptoms. (2) A staging of serotonergic dysfunction throughout the clinical course of PD has been demonstrated in this thesis and showed that serotonergic system is involved early on. (3) Higher serotonin transporter availability has been found in PD patients with elevated depressive symptoms and in PD patients with significant changes in their body weight. (4) Striatal serotonergic terminals are involved in peak-dose LIDs in PD, and administration of a high bolus dose of a 5-HT1A agonist was able to normalize extracellular dopamine levels and alleviate dyskinesias. (5) Excessive serotonergic innervation was found in two PD patients with GIDs who had experienced major recovery after striatal transplantation with fetal cells. GIDs were markedly attenuated by repeated administration of low doses of a 5-HT1A agonist, which dampens transmitter release from serotonergic neurons, indicating that serotonergic hyperinnervation was the likely cause of GIDs. (6) Continuous dopaminergic stimulation with levodopa intestinal gel induced good clinical response and stable and prolonged synaptic levels of striatal dopamine release. My observations provide fundamental insight for the role and interaction of serotonergic and dopaminergic systems in the pathophysiology of PD and have key implications for the management of motor and non-motor complications with drugs or cell therapies

Integration of Mao-B Inhibitor Rasagiline into Computational Model of Levodopa for the Treatment of Parkinson\u27s Disease

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder in the world after Alzheimer’s. The hallmark symptoms of PD are tremor and rigidity, which are caused by the death of dopaminergic neurons, specifically within the substantia nigra of the basal ganglia. These symptoms are often treated by Levodopa (L-DOPA), MAO-B inhibitors, and other pharmaceuticals with the goal of increasing the dopamine concentration in the brain. To better understand how L-DOPA impacts the brain’s dopamine dynamics, various computational models have been developed. One model, by Véronneau-Veilleux et al. (Chaos 30, 093146, 2020), integrates L-DOPA pharmacokinetics, dopamine dynamics, and a neurocomputational model of the basal ganglia to predict the impact of L-DOPA regimens on a patient\u27s motor function. In this study, we extended the model to investigate an adjunct therapy of L-DOPA with the MAO-B inhibitor Rasagiline utilizing an enzyme inhibition model, which showed a 1.67% increase of dopamine concentration in the brain when compared to L-DOPA therapy alone. Our model provides a foundation for optimizing treatment strategies using both L-DOPA and an adjunct

Gene Therapy for Parkinson's Disease

Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field

Gene and Cell-Based Therapies for Parkinson’s Disease: Where Are We?

Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder that carries large health and socioeconomic burdens. Current therapies for PD are ultimately inadequate, both in terms of symptom control and in modification of disease progression. Deep brain stimulation and infusion therapies are the current mainstay for treatment of motor complications of advanced disease, but these have very significant drawbacks and offer no element of disease modification. In fact, there are currently no agents that are established to modify the course of the disease in clinical use for PD. Gene and cell therapies for PD are now being trialled in the clinic. These treatments are diverse and may have a range of niches in the management of PD. They hold great promise for improved treatment of symptoms as well as possibly slowing progression of the disease in the right patient group. Here, we review the current state of the art for these therapies and look to future strategies in this fast-moving field