PdCure.org

  Providing resources and ideas for therapies and medical developments for Parkinson's disease:

 

Parkinson's Disease Research and Development:

There is a lot of research on mice or test hosts which has not reached the level required for FDA human drug trials, but we have found to be noteworthy as it shows promise for future drug development. This research is the domain of university labs and sponsored research in lab rats and controlled laboratory environments. While research on rats has offerred much hope and mice and humans share 95% of the same genes, not all treatments in mice translate to humans, in fact 90% of drugs that show benefit in laboratory animals fail in human trials with only 9.6% making it to market (ref). This has led to the development of transgenic mice who have had human DNA spliced into the mouse DNA so that experiments are more representative of human responses.

Immunotherapy:

This field of study has had some success in the reversal of nerve damage in the optic nerve and spinal cord. It is hoped that the technology derived from this research could be applied to neurodegenerative immunotherapies like Parkinson's disease. The use of the immune system's T-cells to target alpha-synuclein proteins has been targeted as well as the use of macrophages for remyelination and nerve repair. It has been found that Neutrophils (white blood cell Granulocytes) can protect neural cells and tissues from damage and encouraged nerve cell regeneration by secreting growth compounds. So far these studies have occurred in mice only.

Recent studies show that neurons can present MHC-I (major histocompatibility complex - class 1) molecules and therefore may be susceptible to an attack by immune cells. Initial results suggest that antigens are presented by neuronal MHC-I in Parkinson's disease, and that this could lead to T-cell mediated neuronal death.
See Trial NCT02939534: Antigen Presentation and Lymphocyte Response in Parkinson's Disease

Much of the immunotherapy work has been limited by the immune system's inability to operate inside a neuron and thus is limited to extracellular alpha-synuclein fibrils. A field of nanobodies is targeting its ability to penetrate the tough exterior of brain cells and untangle misshapen alpha-synuclein proteins within a neuron (intracellular). The nanobody PFFNB2 targets alpha-synuclein clumps but not single monomer protein molecules which serve a useful purpose within the cell. While PFFNB2 can dissociate alpha-synuclein fibrils, it had to be fused with an adeno-associated virus (AAV-PFFNB2) to be able to inhibit its aggregation. This therapy holds promise for Parkinson's disease, Lewy Body Dementia and related α-synucleinopathies.

See:

Gene Therapy:

Conversion of astrocytes to functional neurons by depleting the RNA-binding protein PTB:

Gene Therapy & Nanobodies:

This research is being developed by a team at Johns Hopkins University in collaboration with the University of Michigan. Gene therapy is used to modify an AAV virus to code for the creation of a nanobody which targets misfolded and aggregated alpha-synuclein proteins within a neuron. It is the only therapy which attempts to cure Parkinson's by addressing intracellular alpha-synuclein. For more information on this therapy, see:

Targeting Mitochondria to Slow the Loss of Brain Cells in Parkinson's:

This approach seeks to slow the progression of Parkinson's disease by targeting problems with energy-producing mitochondria. It is hoped that a molecule can be found to protect mitochondria within dopamine-producing cells.

This research is being performed by:

Targeting Nurr1 Protein:

The molecular pair: Prostaglandin E1 (PGE1), a hormone and Prostaglandin A1 (PGA1), have been found to bind to Nurr1, a class of proteins involved in the development and maintenance of dopamine in the brain. Their binding causes Nurr1 to be activated, resulting in a marked increase in dopamine production while preventing dopamine-producing brain cells from dying. Treatment of Parkinson's mice models showed significant improvements in their motor functions.
Also see inflammation and Nurr1

This research performed by: Nanyang Technological University (NTU), Singapore and Harvard University. Research is continuing as a funded study by the MJF Foundation.

Growth Factors:

There has been some interesting developments in the use of Glial Cell Line Derived Neurotrophic Factor (GDNF), a naturally occurring protein found in our brains, to regenerate dopamine producing neuron cells in patients with Parkinson's to reverse their condition. The experimental procedure required robot assisted brain surgery to install a Convection-Enhanced Delivery (CED) drug delivery pump and four tubes, to supply GDNF to the damaged area of the brain over a period of months. The study was performed at Southmead Hospital, North Bristol UK in affiliation with the Bristol Medical School, University of Bristol, on human patients and funded by Parkinson's UK. The result was 95% meaningful clinical improvement in one or more of the core outcome measures affected by Parkinson's, for the group receiving GDNF for 80 weeks.

Reference: Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson’s Disease (2019) DOI: 10.3233/JPD-191576

Peptides:

Research at the University of Bath in the UK has led to the screening of 209,952 peptides and the discovery of a peptide (4654W) which showed efficacy in the inhibition of alpha-synuclein aggregation. Further research led to the modification of the peptide into newer version known as 4654W(N6A) which was more capable at reducing alpha-synuclein misfolding, aggregation and toxicity.

References:

Exosomes:

Exosomes are extracellular vesicles released by cells as a method of cell-to-cell communications. In Parkinson's research exosomes have been found to be a pathway to deliver RNA segments beyond the blood-brain-barrier to reduce the supply of alpha-synuclein to thwart aggregation. Exosomes are also being considered a possible mechanism of the spread of Parkinson's toxic alpha-synuclein from neuron to neuron. Exosomes might also be considered as biomarkers of Parkinson's itself. Exosomes were discovered in 1983 and their purpose and mechanism are still a mystery to most.

Professor Matthew Wood explains how his team is harnessing exosomes and the rabies virus to cure alpha-synuclein aggregation.

Chemistry - Creative Commons