Dataset Information

Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease.

ABSTRACT: OBJECTIVE:To investigate the safety and tolerability of convection-enhanced delivery of an adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor into the bilateral putamina of PD patients. METHODS:Thirteen adult patients with advanced PD underwent adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 ?L/hemisphere) at escalating doses: 9 × 1010 vg (n = 6); 3 × 1011 vg (n = 6); and 9 × 1011 vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [18 F]FDOPA-PET scanning preoperatively and 6 and 18 months postoperatively. RESULTS:Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor was tolerated without clinical or radiographic toxicity. Average putaminal coverage was 26%. UPDRS scores remained stable. Ten of thirteen and 12 of 13 patients had increased [18 F]FDOPA Kis at 6 and 18 months postinfusion (increase range: 5-274% and 8-130%; median, 36% and 54%), respectively. Ki differences between baseline and 6- and 18-month follow-up were statistically significant (P?

SUBMITTER: Heiss JD

PROVIDER: S-EPMC6642028 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease.

Heiss John D JD Lungu Codrin C Hammoud Dima A DA Herscovitch Peter P Ehrlich Debra J DJ Argersinger Davis P DP Sinharay Sanhita S Scott Gretchen G Wu Tianxia T Federoff Howard J HJ Zaghloul Kareem A KA Hallett Mark M Lonser Russell R RR Bankiewicz Krystof S KS

Movement disorders : official journal of the Movement Disorder Society 20190530 7

<h4>Objective</h4>To investigate the safety and tolerability of convection-enhanced delivery of an adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor into the bilateral putamina of PD patients.<h4>Methods</h4>Thirteen adult patients with advanced PD underwent adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 μL/hemisphere) at escalating doses: 9 × 10<sup ...[more]

PMID: 31145831

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Project description: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.

Project description:BackgroundPatients with locally-advanced non-small-cell lung cancer (LA-NSCLC) are often ineligible for surgery, so that definitive chemoradiotherapy (CRT) represents the treatment of choice. Nevertheless, long-term tumor control is often not achieved. Intensification of radiotherapy (RT) to improve locoregional tumor control is limited by the detrimental effect of higher radiation exposure of thoracic organs-at-risk (OAR). This narrow therapeutic ratio may be expanded by exploiting the advantages of magnetic resonance (MR) linear accelerators, mainly the online adaptation of the treatment plan to the current anatomy based on daily acquired MR images. However, MR-guidance is both labor-intensive and increases treatment times, which raises the question of its clinical feasibility to treat LA-NSCLC. Therefore, the PUMA trial was designed as a prospective, multicenter phase I trial to demonstrate the clinical feasibility of MR-guided online adaptive RT in LA-NSCLC.MethodsThirty patients with LA-NSCLC in stage III A-C will be accrued at three German university hospitals to receive MR-guided online adaptive RT at two different MR-linac systems (MRIdian Linac®, View Ray Inc. and Elekta Unity®, Elekta AB) with concurrent chemotherapy. Conventionally fractioned RT with isotoxic dose escalation up to 70 Gy is applied. Online plan adaptation is performed once weekly or in case of major anatomical changes. Patients are followed-up by thoracic CT- and MR-imaging for 24 months after treatment. The primary endpoint is twofold: (1) successfully completed online adapted fractions, (2) on-table time. Main secondary endpoints include adaptation frequency, toxicity, local tumor control, progression-free and overall survival.DiscussionPUMA aims to demonstrate the clinical feasibility of MR-guided online adaptive RT of LA-NSCLC. If successful, PUMA will be followed by a clinical phase II trial that further investigates the clinical benefits of this approach. Moreover, PUMA is part of a large multidisciplinary project to develop MR-guidance techniques.Trial registrationClinicalTrials.gov: NCT05237453 .

Project description:PURPOSE:To develop and validate a technique for radiation therapy gating using slow (?1 frame per second) magnetic resonance imaging (MRI) and a motion model. Proposed uses of the technique include radiation therapy gating using T2-weighted images and conducting additional imaging studies during gated treatments. METHODS AND MATERIALS:The technique uses a physiologically guided breathing motion model to interpolate deformed target position between 2-dimensional (2D) MRI images acquired every 1 to 3 seconds. The model is parameterized by a 1-dimensional respiratory bellows surrogate and is continuously updated with the most recently acquired 2D images. A phantom and 8 volunteers were imaged with a 0.35T MRI-guided radiation therapy system. A balanced steady-state free precession sequence with a 2D frame rate of 3 frames per second was used to evaluate the technique. The accuracy and beam-on positive predictive value (PPV) of the model-based gating decisions were evaluated using the gating decisions derived from imaging as a ground truth. A T2-weighted gating offline proof-of-concept study using a half-Fourier, single-shot, turbo-spin echo sequence is reported. RESULTS:Model-interpolated gating accuracy, beam-on PPV, and median absolute distances between model and image-tracked target centroids were, on average, 98.3%, 98.4%, and 0.33 mm, respectively, in the balanced steady-state free precession phantom studies and 93.7%, 92.1%, and 0.86 mm, respectively, in the volunteer studies. T2 model-interpolated gating in 6 volunteers yielded an average accuracy and PPV of 94.3% and 92.5%, respectively, and the mean absolute median distance between modeled and imaged target centroids was 0.86 mm. CONCLUSIONS:This work demonstrates the concept of model-interpolated gating for MRI-guided radiation therapy. The technique was found to be potentially sufficiently accurate for clinical use. Further development is needed to accommodate out-of-plane motion and the use of an internal MR-based respiratory surrogate.

Project description:To investigate the undesired irradiations outside of the treatment field by electron streams in air (air-electron-stream) during magnetic-resonance image-guided radiation therapy (MR-IGRT). A custom-made support phantom adjusting angles between the beam central axis (CAX) and the phantom surface (termed phantom-angles), were used. Using the ViewRay system, a rectangular parallelepiped phantom placed on the support phantom, was irradiated with field sizes of 6.3 cm × 6.3 cm (FS6.3) and 12.6 cm × 12.6 cm (FS12.6) at gantry angles of 0°, 30°, and 330°, and phantom-angles of 10°, 20°, and 30°. For each beam delivery, the isocenter was located at the center of mass of the phantom and 3 Gy was delivered to the isocenter (prescription dose = 3 Gy). The doses given by the air-electron-streams were measured using the EBT3 films on the panels placed orthogonal to the direction of the magnetic field at distances of 10 and 17 cm from CAX. Two dose distributions per irradiation were measured on the panel facing the phantom surface of the incident beam (front panel) and on the panel facing the phantom surface of the beam exit (end panel). We investigated the doses by the air-electron-streams by calculating the average doses inside the circles drawn around a point of the maximum dose with radii of x cm (DRx) from the dose distributions on the panels (x = 1-5 cm). The largest value of DRx was DR1 (1.64 Gy, 55% of the prescription dose) at 10 cm distance from CAX, with FS12.6, at 30° phantom-angle and 330° gantry angle. The average difference of the DR1 at the end panels (FS12.6) between the calculations and measurements was 1.36 Gy. The average global gamma passing rate with 3%/3 mm on the dose distributions at the end panels (FS12.6) was 40.3%. The calculated dose distributions on both panels were not coincident with the measured dose distributions. The Spearman's rank correlation coefficients between the projected areas and the DRx values were always higher than 0.75 (all with p < 0.001). The doses by the air-electron-streams increased with the projected areas of the cross-sections of the treatment beams on the panels.

Dataset Information

Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease.

Publications

Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease.

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