User:PainProf/sandbox/Parkinson's Research

Research
There are currently no disease modifying drugs for Parkinson's disease. A number of approaches have reached clinical trials in recent years including cell therapies, gene therapies and neuroprotective agents. Rapid progress in genetics has enabled the development of a number of new animal models for Parkinson's disease and induced pluripotent stem cell therapies recently reached phase I clinical trials.

Animal models
PD is not known to occur naturally in any species other than humans, animal models reflect some features of the disease and are used in research to develop and test treatments. The appearance of parkinsonism in a group of drug addicts in the early 1980s who consumed a contaminated batch of the synthetic opiate MPPP led to the discovery of the chemical MPTP as an agent that causes parkinsonism in non-human primates as well as in humans. Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat and the fungicide maneb. Models based on toxins are most commonly used in primates. Transgenic rodent models that replicate various aspects of PD have been developed. The use of neurotoxin 6-hydroxydopamine, creates a model of Parkinson's disease in rats by targeting and destroying dopaminergic neurons in the nigrostriatal pathway when injected into the substantia nigra. Whilst previously animal models focused entirely on developing symptoms, animal models focused on the causative agents of Parkinson's such as alpha-synuclein dysfunction have been developed. These rely on genetic modification to express proteins such as alpha-synuclein. Various protein modifications enable modelling of parkinsonism. These animal models may more faithfully recapitulate the pathology of parkinson's disease and are widely used to understand the disease mechanisms. They also allow for the development of disease modifying therapies that focus on alpha-synuclein for instance.

Stem Cell Models
Stem cell models of Parkinson's, typically differentiated (or changed) into dopaminergic neurons derived from patients and embryos play an increasingly important role in pre-clinical research. The first robust models for pluripotent stem cell differentiation into dopaminergic neurons were described in 2011.

Gene therapy
Gene therapy typically involves the use of a non-infectious virus (i.e., a viral vector such as the adeno-associated virus) to shuttle genetic material into a part of the brain. The gene used leads to the production of an enzyme that helps to manage PD symptoms or protects the brain from further damage. In 2010 there were four clinical trials using gene therapy in PD. There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown. One of these reported positive results in 2011, but the company filed for bankruptcy in March 2012.

Neuroprotective treatments
Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments. However, none of them have been conclusively demonstrated to reduce degeneration. Agents currently under investigation include, antiglutamatergics, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrials (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF). Reducing alpha-synuclein pathology is a major focus of preclinical research. A vaccine that primes the human immune system to destroy alpha-synuclein, PD01A (developed by Austrian company, Affiris), entered clinical trials and a phase 1 report in 2020 suggested safety and tolerability. In 2018, an antibody, PRX002/RG7935, showed preliminary safety evidence in stage I trials supporting continuation to stage II trials.

Cell-based therapies
Since early in the 1980s, fetal, porcine, carotid or retinal tissues have been used in cell transplants, in which dissociated cells are injected into the substantia nigra in the hope that they will incorporate themselves into the brain in a way that replaces the dopamine-producing cells that have been lost. More recently, these sources of tissues have been largely replaced by induced pluripotent stem cell derived dopaminergic neurons as this is thought to represent a more feasible source of tissue. There was initial evidence of mesencephalic dopamine-producing cell transplants being beneficial, double-blind trials to date have not determined whether there is a long-term benefit. An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dyskinesia. In 2020, a first in human clinical trial reported the transplantation of induced pluripotent stem cells into the brain of a person suffering from Parkinson's disease.

Other
Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias. Its usefulness in PD is an open research topic. Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins or food additives improve symptoms. There is no evidence to substantiate that acupuncture and practice of Qigong, or T'ai chi, have any effect on the course of the disease or symptoms. Fava beans and velvet beans are natural sources of levodopa and are eaten by many people with PD; their intake is not free of risks as life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome.

The role of the gut–brain axis and the gut flora in Parkinsons became a topic of study in the 2010s, starting with work in germ-free transgenic mice, in which fecal transplants from people with PD had worse outcomes. Some studies in humans have shown a correlation between patterns of dysbiosis in the gut flora in the people with PD, and these patterns, along with a measure of severity of constipation, could diagnose PD with a 90% specificity but only a 67% sensitivity. As of 2017 some scientists hypothesized that changes in the gut flora might be an early site of PD pathology, or might be part of the pathology.

Adenosine receptors (specifically A2A) have been explored as an avenue for novel drugs for Parkinson's. Of these, istradefylline was approved for medical use in the United States in 2019 as an add-on treatment to the levodopa/carbidopa regime.