An update on advanced therapies for Parkinson's disease: From gene therapy to neuromodulation.
Authors: Serva SN, Bernstein J, Thompson JA, Kern DS, Ojemann SG
Advanced Parkinson's disease (PD) is characterized by increasingly debilitating impaired movements that include motor fluctuations and dyskinesias. At this stage of the disease, pharmacological management can result in unsatisfactory clinical benefits and increase the occurrence of adverse effects, leading to the consideration of advanced therapies. The scope of this review is to provide an overview of currently available therapies for advanced PD, specifically levodopa-carbidopa intestinal gel, continuous subcutaneous apomorphine infusion, radiofrequency ablation, stereotactic radiosurgery, MRI-guided focused ultrasound, and deep brain stimulation. Therapies in clinical trials are also discussed, including novel formulations of subcutaneous carbidopa/levodopa, gene-implantation therapies, and cell-based therapies. This review focuses on the clinical outcomes and adverse effects of the various therapies and also considers patient-specific characteristics that may influence treatment choice. This review can equip providers with updated information on advanced therapies in PD to better counsel patients on the available options.
Introduction
Purpose
Other
Study Objective
To provide an updated overview of currently available and investigational advanced therapies for Parkinson's disease, focusing on their clinical outcomes, adverse effects, and patient-specific factors that influence treatment choice.
Disease model
Advanced Parkinson's disease (PD)
MRI or image guidance method
MRI-guided focused ultrasound
Cargo name and characteristics
Levodopa–carbidopa intestinal gel — small‑molecule drugs (levodopa and carbidopa) delivered as an intestinal gel; Continuous subcutaneous apomorphine infusion — small‑molecule dopamine agonist (apomorphine); Novel subcutaneous carbidopa/levodopa formulations — small‑molecule combination formulations; Gene‑implantation therapies — gene therapy cargo delivered by viral vectors (e.g., AAV or other viral vectors carrying therapeutic genes); Cell‑based therapies — cellular implants (stem cells or neural progenitor cells)
Route of administration
Intestinal/jejunal enteral infusion (levodopa–carbidopa intestinal gel); subcutaneous infusion (continuous apomorphine, subcutaneous carbidopa/levodopa formulations); intracerebral delivery/implantation (gene-implantation therapies, cell-based therapies, and deep brain stimulation electrode implantation); ablative/radiosurgical techniques are non-drug/non-injectable procedures
Outcomes and Safety
Summary of Outcomes
Advanced therapies for Parkinson's produced meaningful motor benefit: LCIG and CSAI reduced daily OFF time by ~1.9–4.4 h and increased ON time without troublesome dyskinesia, MRgFUS (targets VIM, STN, GPi) yielded 36–62% improvements in tremor/motor scores with some persistent sensory, speech and gait adverse events, and DBS reduced UPDRS-III scores by ~23–54%; the reviewed MRgFUS studies reported different brain targets rather than multiple sonication parameter sets.
Duration of biological effect
1.91–4.4 h
Safety-related matter
The review highlights multiple safety concerns across advanced PD therapies, noting that pharmacological management can increase adverse effects and that device- or procedure-based options carry specific risks. Reported adverse effects include infection and implant issues (LCIG, DBS), skin irritation/nodules/infections for subcutaneous infusions, surgical hemorrhage risk (DBS, RF), exposure to ionizing radiation and delayed response (SRS), MRI-compatibility and skull/acoustic limitations plus procedure-related neurological events (MRgFUS) such as paresthesia, dysarthria, weakness, gait disturbance, and new or worsened dyskinesias.
Brain Region
Ultrasound Parameters
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
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