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.

Assessing occupational exposure to perchloroethylene in dry cleaning.

Occupational exposure to perchloroethylene (PERC) in dry cleaning is analyzed by calculating airborne concentrations for a large set of possible exposure scenarios. Different generations of dry-cleaning machines ranging from vented machines used until the 1980s to nonvented closed-loop machines used since the 1990s are investigated; the geographical scope of the study is Germany. Concentrations are calculated for diffuse emissions, release of contaminated air during loading and unloading, and residual solvent releases from cleaned garments with a dynamic two-box model for near field and far field. The concentration estimates for near field and far field agree well with measured concentrations. The airborne concentrations are compared with maximum workplace concentrations (MAK values). The full set of scenarios shows for which historical situations the workplace concentrations were near the MAK value and that the transition to newer dry-cleaning machines reduced the occupational exposure by more than one order of magnitude. In addition, numbers of exposed workers are estimated for different years. Whereas more than 25,700 workers in the near field were exposed to PERC in 1975, the number has been below 5900 since 2001, which is due mainly to a reduced amount of garments being dry cleaned and, to a lesser extent, to replacement of PERC by nonchlorinated solvents. The results from the scenario-based analysis are consistent with exposure ranges obtained from a Monte Carlo calculation using frequency distributions of key input parameters, such as emission factors, batch times, and room volumes.

Reduction of occupational exposure to perchloroethylene and trichloroethylene in metal degreasing over the last 30 years: influences of technology innovation and legislation.

Occupational exposure to trichloroethylene (TRIC) and perchloroethylene (PERC) in metal degreasing is analyzed by calculating airborne concentrations for a large set of possible exposure scenarios (Scenario-Based Risk Assessment, SceBRA). Different types of degreasing machines ranging from open-top machines used until the 1980s to closed-loop nonvented machines used since the 1990s are investigated; the scope of the study is Germany. Concentrations are calculated for different kinds of releases (emissions from open baths, leakage, release of contaminated air during loading and unloading) with a dynamic two-box model for the near-field and the far-field. The concentration estimates are in good agreement with measured data. The airborne concentrations are compared to maximum workplace concentrations (MAK values). The full set of scenarios shows for which situations MAK values were exceeded and how the transition to newer degreasing machines reduced the occupational exposure by more than one order of magnitude. In addition, numbers of exposed workers are estimated for different years. While more than 25,000 workers in the near-field were exposed to TRIC and PERC in 1985, the number is below 3000 since 1996, which is mainly due to technology changes, rationalization, automatization, and replacement of TRIC and PERC by nonchlorinated solvents.