The first autosomal-dominant gene PARK1 was described by Polymeropoulus and colleagues in 1997 with its effects in mutation in the protein α‐synuclein. The outcomes were supported by the successive discoveries of different genes that represented or caused a risk factor for the Parkins Disease. Due to the massive knowledge that has increased, the pharmaceutical industry as well as scientists progressively changed from classical objectives in the field of pharmacotherapy like transmitter receptor agonists, precursors of transmitters, transmitter degrading enzyme inhibitors, or transmitter uptake blockers. However, the focus of research in new therapies began on the metabolism of α‐synuclein and basic biology as well as related proteins.
The transformation required a shift in build-up and mindset of a new field of research in Perkins Disease that incorporated the establishment of other preclinical models as well as the search of for new primary endpoints for development over various prodromal stages as well as during the early motor exhibition of the Perkins Disease in clinical trials. The search and change are still in progress. The initial compounds have moved into the early clinical test for the modification of the Perkin Disease as presented in the figure below.
Besides this, some compounds like nicotine or caffeine are undergoing testing that may provide the promise of adjusting the course of Perkins Disease, more so on the basis of epidemiological studies. The developments in this field are as discussed below.
Immunotherapy for α‐synucleinopathy
According to Karpinar et al. (2009), α‐synuclein is taken as a significant molecule in the neural death in Perkin’s Disease. Moreover, Luk et al. (2012) and Angot et al. (2010) presents additional evidence that α‐synuclein is associated with propagation and spread of the neurodegenerative development of Perkin Disease through the means of a mechanism that looks like a prion. It is presumed that there is a misfolds of α‐synuclein intracellularly and combines into forms that are toxic, penetrates the extracellular space and is consequently consumed by an adjacent structure of neuronal, resulting into the spread of the toxic seeds of α‐synuclein. Also, Stuendl et al. (2016) show evidence that exists in the correlation of the CSF content of α‐synuclein in exosomes with the disease progression and phenotype. Therefore, passive or active strategies in immunotherapeutic focus on reducing the aggregate level of extracellular toxic α‐synuclein and hence to lower its propagation.
Under the active perspective, there is a subcutaneous administration of short immunogenic peptides. The C‐terminus of α‐synuclein is mimicked by the peptides. Through data available from the press release, it is evident that the vaccine is tested in 12 months in two doses under advanced Perkin Disease through the design of the open label. Additionally, anti‐α‐synuclein‐peptide antibodies in serum developed in half of the patients who were vaccinated, while others contained the antibodies under CSF. A report showed that the vaccine was well tolerated and safe, while patients under the trial are currently on follow-up under a long-term basis. On the other hand, a phase II trial is being undertaken. Moreover, a second group of the peptides is undergoing assessment within a placebo-controlled trial that is randomized with early patients of the Perkin Disease.
A number of companies are presently pursuing the strategy actively. A test of 40 volunteers with health conditions has been completed for a single agent that has entered the clinical phase known as a monoclonal antibody against α‐synuclein (PRX002). Although not published formally, the side effects of the strategy have been pronounced to have happened below 10% of the healthy volunteers, and serious reactions associated with the drug were observed. Excitingly, the antibody treatment resulted in a rapid decrease in the levels of α‐synuclein in serum and dependency on the dose. Subsequently, the sponsor has introduced a clinical trial that is randomized in the subjects of Perkins Disease (Kalia et al. 2015).