Human gene therapy approaches for the treatment of Parkinson's disease: An overview of current and completed clinical trials.

@article{Hitti2019HumanGT,
  title={Human gene therapy approaches for the treatment of Parkinson's disease: An overview of current and completed clinical trials.},
  author={Frederick L. Hitti and Andrew Il Yang and Pedro Gonzalez-Alegre and Gordon Baltuch},
  journal={Parkinsonism \& related disorders},
  year={2019}
}
Gene Therapy in the Management of Parkinson's Disease: Potential of GDNF as a Promising Therapeutic Strategy.
TLDR
The review primarily elaborates the significant role of glial cell-line derived neurotrophic factor in alleviating motor symptoms and loss of dopaminergic neurons in Parkinson's disease and establishes delivery aspects, like ventricular delivery of recombinant GDNF, intraparenchymal and intraputaminal delivery using infusion catheters.
Growth Factor Therapy for Parkinson’s Disease: Alternative Delivery Systems
TLDR
This review will give a short overview of some of the alternative delivery systems, with a focus on ex vivo gene therapy and biomaterial-aided protein and gene delivery, and will provide some perspectives on their potential for clinical development and translation.
Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease
TLDR
This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease and suggest mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders.
Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine
TLDR
The development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.
Emerging Targeted Therapeutics for Genetic Subtypes of Parkinsonism
TLDR
The current obstacles towards the development of precision interventions in Parkinson’s disease are reviewed and the clinical trials that target genetic forms of PD, i.e., GBA-associated and LRRK2-associated PD are discussed.
Comparative efficacy of surgical approaches to disease modification in Parkinson disease
TLDR
Data underlying surgical approaches proposed to impart disease modification in PD are compared, showing that though targeted to engage potential mechanisms of PD these surgical approaches remain experimental, indicating the difficulty in translating therapeutic concepts into clinical practice.
Understanding the Potential of Genome Editing in Parkinson’s Disease
TLDR
The main biological pathways that become disrupted in Parkinson’s disease and their potential as gene therapy targets are highlighted and a comprehensive review of novel delivery vehicles available for gene-editing applications is performed.
Targeting Age-Related Neurodegenerative Diseases by AAV-Mediated Gene Therapy.
  • U. Cagin
  • Biology
    Advances in experimental medicine and biology
  • 2021
TLDR
The advantages of AAV-based gene therapies are discussed with emphasis on efforts of developing novel capsids with superior therapeutic efficacy and the results of clinical trials on AD, PD, and ALS are summarized.
Precision medicine in Parkinson’s disease: emerging treatments for genetic Parkinson’s disease
TLDR
Clinical trials that target genetic forms of Parkinson’s disease, i.e., GBA -associated and LRRK2 -associated PD, are reviewed, finding six ongoing studies which explicitely recruit GBA-PD patients, and two studies which recruit LRRk2 -PD patients.
Restoring Function to Dopaminergic Neurons: Progress in the Development of Cell-Based Therapies for Parkinson’s Disease
TLDR
The potential for cell-based therapies in Parkinson’s disease to restore the function of dopaminergic neurons is focused on, previous attempts to harness such strategies are critically reviewed, potential benefits and predicted limitations are discussed, and how previous roadblocks may be overcome are addressed.
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References

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Results from a phase I safety trial of hAADC gene therapy for Parkinson disease
TLDR
These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit.
Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity
TLDR
Brain metabolic network analysis in patients with PD showed that after gene therapy, patients developed a treatment-specific brain metabolic network involving motor-cortical regions, which indicates that treatment-induced brain circuits can thus be useful in clinical trials for isolating true treatment responses and providing insight into their underlying biological mechanisms.
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This Review focuses on disease-modifying and symptomatic therapies under development for Parkinson disease, and explores the novel PD treatment strategies currently being investigated, including pharmaceuticals, cell therapies, immunotherapies, gene therapies and new technologies.
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This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson’s Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.
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TLDR
A two-pronged treatment strategy, composed of MR image-guided focused ultrasound (FUS) and brain-penetrating nanoparticles (BPN), that provides widespread but targeted GDNF transgene expression in the brain following systemic administration, thereby potentially providing a novel means to treat Parkinson's disease.
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TLDR
The findings provide class IV evidence regarding the safety and efficacy of AADC gene therapy and warrant further evaluation in a randomized, controlled, phase 2 setting.
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TLDR
Insights into the organization of the basal ganglia in the normal and PD conditions has permitted the design of new treatment strategies that reduce the risk of developing motor complications and the development of putative neuroprotective drugs that might slow or stop disease progression.
Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson's disease.
TLDR
Data indicate stable transgene expression over 4 years after vector delivery and continued safety, but emphasize the need for a controlled efficacy trial and the use of a higher vector dose.
CDNF Protein Therapy in Parkinson’s Disease
TLDR
The history of growth factor-based clinical trials in Parkinson’s disease (PD) is reviewed, how CDNF differs from the previously tested growth factors is discussed, and a new protein can now be added to this list, as cerebral dopamine neurotrophic factor (CDNF) has recently entered clinical trials.
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