Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease

Abstract

Cell transplantation and gene therapy each show promise to enhance the treatment of Parkinson's disease (PD). However, because cell transplantation and gene therapy generally require direct delivery to the central nervous system, clinical trial design involves unique scientific, ethical, and financial concerns related to the invasive nature of the procedure. Typically, such biologics have been tested in PD patients who have not received any neurosurgical intervention. Here, we suggest that PD patients undergoing deep brain stimulation (DBS) device implantation are an ideal patient population for the clinical evaluation of cell transplantation and gene therapy. Randomizing subjects to an experimental group that receives the biologic concurrently with the DBS implantation-or to a control group that receives the DBS treatment alone-has several compelling advantages. First, this study design enables the participation of patients likely to benefit from DBS, many of whom simultaneously meet the inclusion criteria of biologic studies. Second, the need for a sham neurosurgical procedure is eliminated, which may reduce ethical concerns, promote patient recruitment, and enhance the blinding of surgical trials. Third, testing the biologic by "piggybacking" onto an established, reimbursable procedure should reduce the cost of clinical trials, which may allow a greater number of biologics to reach this critical stage of research translation. Finally, this clinical trial design may lead to combinatorial treatment strategies that provide PD patients with more durable control over disabling motor symptoms. By combining neuromodulation with biologics, we may also reveal important treatment paradigms relevant to other diseases of the brain.

Old and new challenges in Parkinson's disease therapeutics

“…Also, some studies have shown that molecules secreted by hMSCs promote nervous tissue regeneration through activation/modulation of endogenous neuro-restorative processes. In the future, such molecules could be an efficacious add-on if combined with cell transplantation, pharmacological or surgical strategies (Buttery and Barker, 2014;Choi et al, 2010;Rowland et al, 2015;Yao et al, 2016). Although most of the available results support hMSCs secretome as a promising cell-free therapy and a potential off-the-shelf product for PD, current sources of MSCs do not allow for the isolation of a sufficient number of cells for their widespread clinical use, instead relying on invasive, expensive and labor-intense isolation protocols that yield MSCs with limited proliferative capacity (Teixeira et al, 2016b).…”

Implantation of autologous peripheral nerve grafts into the substantia nigra of subjects with idiopathic Parkinson's disease treated with bilateral STN DBS: a report of safety and feasibility

“…The strategy of combining the delivery of biological therapy with DBS surgery has been recently gaining momentum. 26 DBS therapy alone is insufficient for treating all of the symptoms associated with PD, and so, new therapies need to be developed to enhance the therapeutic benefits of DBS. The combined strategy outlined here presents one means of fulfilling this goal.…”

“…Third, DBS therapy was amenable to testing the effects of an intervention on the baseline components of PD. Although this approach has been proposed previously for investigating a gene therapy approach, 7,26 it was not actually performed. Thus we report the first clinical study to involve the investigation of a surgical therapeutic intervention in combination with DBS therapy.…”

Deep brain stimulation for movement disorders: update on recent discoveries and outlook on future developments

“…While DBS in itself may be one of the most exciting and intriguing recent achievements in the treatment of brain disorders, the surgical procedure inevitably required, might in itself facilitate trials of experimental biologic approaches that require co-administration of a gene, growth factor or cell therapy being directly delivered to the central nervous system [109]. Many of the patients meeting inclusion criteria for DBS trials would also be suitable for such biological trials.…”