scholarly journals Data-driven evolution of neurosurgical gene therapy delivery in Parkinson’s disease

2020 ◽  
Vol 91 (11) ◽  
pp. 1210-1218 ◽  
Author(s):  
R Mark Richardson ◽  
Krystof S Bankiewicz ◽  
Chadwick W Christine ◽  
Amber D Van Laar ◽  
Robert E Gross ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Viral Vector ◽  
Data Driven ◽  
Surgical Approaches ◽  
Acid Decarboxylase ◽  
Projection Neurons ◽  
Virus Serotype ◽  
Vector Delivery

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson’s disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

Gene Therapy in the Management of Parkinson’s Disease: Potential of GDNF as a Promising Therapeutic Strategy

2020 ◽  
Vol 20 (3) ◽  
pp. 207-222
Author(s):  
Tapan Behl ◽  
Ishnoor Kaur ◽  
Arun Kumar ◽  
Vineet Mehta ◽  
Gokhan Zengin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Viral Vector ◽  
Neurodegenerative Disorder ◽  
Dopamine Synthesis ◽  
Motor Symptoms ◽  
Ligand Complex

: The limitations of conventional treatment therapies in Parkinson’s disorder, a common neurodegenerative disorder, lead to the development of an alternative gene therapy approach. Multiple treatment options targeting dopaminergic neuronal regeneration, production of enzymes linked with dopamine synthesis, subthalamic nucleus neurons, regulation of astrocytes and microglial cells and potentiating neurotrophic factors, were established. Viral vector-based dopamine delivery, prodrug approaches, fetal ventral mesencephalon tissue transplantation and dopamine synthesizing enzyme encoding gene delivery are significant therapies evidently supported by numerous trials. The review primarily elaborates on the significant role of glial cell-line derived neurotrophic factor in alleviating motor symptoms and the loss of dopaminergic neurons in Parkinson’s disease. Neuroprotective and neuroregenerative effects of GDNF were established via preclinical and clinical study outcomes. The binding of GDNF family ligands with associated receptors leads to the formation of a receptor-ligand complex activating Ret receptor of tyrosine kinase family, which is only expressed in dopaminergic neurons, playing an important role in Parkinson’s disease, via its association with the essential protein encoded genes. Furthermore, the review establishes delivery aspects, like ventricular delivery of recombinant GDNF, intraparenchymal and intraputaminal delivery using infusion catheters. The review highlights problems and challenges of GDNF delivery, and essential measures to overcome them, like gene therapy combinations, optimization of delivery vectors, newer targeting devices, motor symptoms curbing focused ultrasound techniques, modifications in patient selection criteria and development of novel delivery strategies based on liposomes and encapsulated cells, to promote safe and effective delivery of neurotrophic factor and establishment of routine treatment therapy for patients.

Viral vector-mediated gene therapy for Parkinson's disease

2001 ◽  
Vol 1 (6) ◽  
pp. 496-506 ◽  
Author(s):  
Marina E. Emborg ◽  
Nicole Deglon ◽  
Liza Leventhal ◽  
Patrick Aebischer ◽  
Jeffrey H. Kordower
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Viral Vector

scholarly journals Subthalamic hGAD65 Gene Therapy and Striatum TH Gene Transfer in a Parkinson’s Disease Rat Model

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Deyu Zheng ◽  
Xiaohua Jiang ◽  
Junpeng Zhao ◽  
Deyi Duan ◽  
Huanying Zhao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Glutamic Acid ◽  
Rat Model ◽  
Combination Method ◽  
Combination Group ◽  
Acid Decarboxylase

The aim of the present study is to detect a combination method to utilize gene therapy for the treatment of Parkinson’s disease (PD). Here, a PD rat model is used for thein vivogene therapy of a recombinant adeno-associated virus (AAV2) containing a human glutamic acid decarboxylase 65 (rAAV2-hGAD65) gene delivered to the subthalamic nucleus (STN). This is combined with theex vivogene delivery of tyrosine hydroxylase (TH) by fibroblasts injected into the striatum. After the treatment, the rotation behavior was improved with the greatest efficacy in the combination group. The results of immunohistochemistry showed that hGAD65 gene delivery by AAV2 successfully led to phenotypic changes of neurons in STN. And the levels of glutamic acid and GABA in the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr) were obviously lower than the control groups. However, hGAD65 gene transfer did not effectively protect surviving dopaminergic neurons in the SNc and VTA. This study suggests that subthalamic hGAD65 gene therapy and combined with TH gene therapy can alleviate symptoms of the PD model rats, independent of the protection the DA neurons from death.

Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity

2018 ◽  
Vol 10 (469) ◽  
pp. eaau0713 ◽  
Author(s):  
Martin Niethammer ◽  
Chris C. Tang ◽  
An Vo ◽  
Nha Nguyen ◽  
Phoebe Spetsieris ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Brain Connectivity ◽  
Metabolic Imaging ◽  
Acid Decarboxylase ◽  
Therapeutic Effects ◽  
Imaging Data ◽  
Sham Surgery ◽  
Related Pattern

Gene therapy is emerging as a promising approach for treating neurological disorders, including Parkinson’s disease (PD). A phase 2 clinical trial showed that delivering glutamic acid decarboxylase (GAD) into the subthalamic nucleus (STN) of patients with PD had therapeutic effects. To determine the mechanism underlying this response, we analyzed metabolic imaging data from patients who received gene therapy and those randomized to sham surgery, all of whom had been scanned preoperatively and at 6 and 12 months after surgery. Those who receivedGADgene therapy developed a unique treatment-dependent polysynaptic brain circuit that we termed as theGAD–related pattern (GADRP), which reflected the formation of new polysynaptic functional pathways linking the STN to motor cortical regions. Patients in both the treatment group and the sham group expressed the previously reported placebo network (the sham surgery–related pattern or SSRP) when blinded to the treatment received. However, only the appearance of the GADRP correlated with clinical improvement in the gene therapy–treated subjects. Treatment-induced brain circuits can thus be useful in clinical trials for isolating true treatment responses and providing insight into their underlying biological mechanisms.

scholarly journals Aromatic L‐Amino Acid Decarboxylase Gene Therapy Enhances Levodopa Response in Parkinson's Disease

2020 ◽  
Vol 35 (5) ◽  
pp. 851-858 ◽  
Author(s):  
John G. Nutt ◽  
Carolin Curtze ◽  
Amie Hiller ◽  
Shannon Anderson ◽  
Paul S. Larson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Amino Acid ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase

scholarly journals An Update on Gene Therapy Approaches for Parkinson’s Disease: Restoration of Dopaminergic Function

2021 ◽  
pp. 1-10
Author(s):  
Amber D. Van Laar ◽  
Victor S. Van Laar ◽  
Waldy San Sebastian ◽  
Aristide Merola ◽  
J. Bradley Elder ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Genetic Material ◽  
Unmet Need ◽  
Surgical Approaches ◽  
Nigrostriatal Pathway ◽  
Neuronal Function ◽  
Network Function ◽  
Clinical Gene Therapy

At present there is a significant unmet need for clinically available treatments for Parkinson’s disease (PD) patients to stably restore balance to dopamine network function, leaving patients with inadequate management of symptoms as the disease progresses. Gene therapy is an attractive approach to impart a durable effect on neuronal function through introduction of genetic material to reestablish dopamine levels and/or functionally recover dopaminergic signaling by improving neuronal health. Ongoing clinical gene therapy trials in PD are focused on enzymatic enhancement of dopamine production and/or the restoration of the nigrostriatal pathway to improve dopaminergic network function. In this review, we discuss data from current gene therapy trials for PD and recent advances in study design and surgical approaches.

scholarly journals A Phase I Study of Aromatic L-Amino Acid Decarboxylase Gene Therapy for Parkinson's Disease

2010 ◽  
Vol 18 (9) ◽  
pp. 1731-1735 ◽  
Author(s):  
Shin-ichi Muramatsu ◽  
Ken-ichi Fujimoto ◽  
Seiya Kato ◽  
Hiroaki Mizukami ◽  
Sayaka Asari ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Amino Acid ◽  
Phase I ◽  
Phase I Study ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase

scholarly journals Surgical Management of Parkinson's Disease: Update and Review

2007 ◽  
Vol 13 (4) ◽  
pp. 359-368 ◽  
Author(s):  
Y. Chao ◽  
L. Gang ◽  
Z.L. Na ◽  
W.Y. Ming ◽  
W.S. Zhong ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Brain Stimulation ◽  
Surgical Approaches ◽  
Internal Globus Pallidus ◽  
Ventral Intermediate Nucleus ◽  
Alternative Approaches ◽  
Deep Brain

Although medical therapy is still the mainstay of treatment for Parkinson's disease, the development of surgical precision and decreased morbidity have made stereotatic lesioning and deep brain stimulation more popular. Neurosurgical ablations include pallidotomy, thalamotomy, and, more recently, subthalamotomy. Because of concern over the high risk of side-effects resulting from bilateral ablative procedure, alternative approaches have been explored. With improved deep brain stimulation (DBS) technology, DBS has been successfully applied in the internal globus pallidus, ventral intermediate nucleus and subthalamic nucleus for Parkinson's disease. In addition, recent surgical approaches including biological neurorestorative technologies — surgical therapies with transplantation, gene therapy, and growth factor are all being discussed in this review. Although a great deal of work remains to be done for researchers, advances in surgical therapies for the treatment of Parkinson's disease are moving forward at an unprecedented pace, and, not surprisingly, would give PD patients more choices and hope.

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