From lab bench to hope: a review of gene therapies in clinical trials for Parkinson's disease and challenges.

Parkinson's disease (PD) is a chronic neurological disorder that is identified by a characteristic combination of symptoms such as bradykinesia, resting tremor, rigidity, and postural instability. It is the second most common neurodegenerative disease after Alzheimer's disease and is characterized by the progressive loss of dopamine-producing neurons in the brain. Currently, available treatments for PD are symptomatic and do not prevent the disease pathology. There is growing interest in developing disease-modifying therapy that can reduce disease progression and improve patients' quality of life. One of the promising therapeutic approaches under evaluation is gene therapy utilizing a viral vector, adeno-associated virus (AAV), to deliver transgene of interest into the central nervous system (CNS). Preclinical studies in small animals and nonhuman primates model of PD have shown promising results utilizing the gene therapy that express glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), aromatic L-amino acid decarboxylase (AADC), and glutamic acid decarboxylase (GAD). This study provides a comprehensive review of the current state of the above-mentioned gene therapies in various phases of clinical trials for PD treatment. We have highlighted the rationale for the gene-therapy approach and the findings from the preclinical and nonhuman primates studies, evaluating the therapeutic effect, dose safety, and tolerability. The challenges associated with gene therapy for heterogeneous neurodegenerative diseases, such as PD, have also been described. In conclusion, the review identifies the ongoing promising gene therapy approaches in clinical trials and provides hope for patients with PD.

Developmental Approaches to Chronic Pain: A Narrative Review.

Chronic pain, which can potentially develop from acute pain, subacute pain, or breakthrough pain, is generally defined as pain persisting for greater than three months with minimal relief. Chronic pain can be associated with a myriad of medical conditions. It is also one of the most common causes of disability, physical suffering, depression, and reduced quality of life. Treatment can vary depending on the underlying pathophysiology and can involve physical therapy, non-pharmaceutical approaches, pharmaceutical drugs, and invasive procedures. Currently available pharmaceutical agents have been effective for short-term management of chronic pain conditions, but few options address chronic pain with long-term efficacy. First-line pharmaceutical agents can potentially include over-the-counter (OTC) or prescription-strength non-steroidal anti-inflammatory drugs (NSAIDs), which have been linked to numerous side effects. If chronic pain persists, steroids are frequently used to provide longer relief. For more progressive or resistant chronic pain and/or in conjunction with invasive procedures, opioids have been utilized for acute treatment and for long-term maintenance. While these agents have proven to be effective for both acute and long-term use due to their modulation at various peripheral and central opioid receptors, they can be associated with numerous side effects and tied to the risk of addiction. As such, an unmet need exists to identify treatment modalities that provide opioid-like pain relief without opioid-induced adverse effects and the potential for addiction. This narrative review will provide an overview of the currently available treatment modalities for chronic pain and their adverse event profiles, as well as a review of therapies that are currently in development and/or preclinical trials for the management and treatment of chronic pain.