Researchers from the Beijing Institute of Brain Disorders have discovered a new method of using exosomes to deliver aptamers that prevent the accumulation of α-synuclein aggregates, which are the cause of Parkinson’s disease .
Like Alzheimer’s, Parkinson’s disease is characterized by protein aggregation caused by a loss of proteostasis, one of the hallmarks of aging. In order for the brain to function properly, non-aggregated α-synuclein proteins are needed in order to facilitate the release of dopamine, a neurotransmitter, in nerve cell synapses. α-synuclein only becomes a problem when proteostasis fails and the proteins misfold, aggregate, and accumulate.
During disease progression, α-synuclein aggregates form into long microscopic fibers, or fibrils, which prevent nerve cells from functioning correctly. These fibrils are harmful to nerve cells and ultimately cause the dopamine-producing cells to die, leaving the brain starved of dopamine, causing the shakes and muscle tremors typically observed in Parkinson’s disease.
Exosomes and Aptamers
Exosomes are signaling ‘packets’, a way in which cells send naturally messages to each other. Because they are encapsulated and wholly taken up into the receptor cell, creating exosomes in the lab can be useful in drug delivery, as they give drugs a direct method of passing through the cellular membrane. Cells selectively uptake exosomes depending on their type, and this is why artificial exosomes are being developed to create a cancer treatment that directly targets cancer cells while limiting toxicity to other cells .
Aptamers, which are molecules that bind to specific proteins , can also be placed inside these exosomes in order to treat proteostasis conditions, and this is the approach that these researchers have taken.
A New Approach
The team discovered a specific sequence of DNA that binds to α-synuclein aggregates, developed a corresponding exosome, and injected the encapsulated DNA into a mouse model of Parkinson’s disease. As this aptamer was guided by exosomes into the brain cells of the mice, it directly bound to α-synuclein aggregates within the cells, rather than outside them; the researchers hoped that this would prevent further intracellular aggregation and thus the plaques, cellular death, and symptoms of Parkinson’s.
The results from this animal trial were positive, proving the researchers’ hopes correct; the treated mice scored higher on behavioral tests and had far less malformed α-synuclein than the control mice, which were injected with an exosome containing a random DNA sequence.
The α-synuclein aggregates are the main component of Lewy bodies in Parkinson’s disease (PD) brain, and it showed immunotherapy could be employed to alleviate α-synuclein aggregate pathology in PD. Recently we have generated DNA aptamers that specifically recognize α-synuclein. In this study, we further investigated the in vivo effect of these aptamers on the neuropathological deficits associated with PD. For efficient delivery of the aptamers into the mouse brain, we employed modified exosomes with the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface. We demonstrated that the aptamers were efficiently packaged into the RVG-exosomes and delivered into neurons in vitro and in vivo. Functionally, the aptamer-loaded RVG-exosomes significantly reduced the α-synuclein preformed fibrils (PFF)-induced pathological aggregates, and rescued synaptic protein loss and neuronal death. Moreover, intraperitoneal administration of these exosomes into the mice with intra-striatally injected α-synuclein PFF reduced the pathological α-synuclein aggregates and improved motor impairments. In conclusion, we demonstrated that the aptamers targeting α-synuclein aggregates could be effectively delivered into the mouse brain by the RVG-exosomes and reduce the neuropathological and behavioral deficits in the mouse PD model. This study highlights the therapeutic potential of the RVG-exosome delivery of aptamer to alleviate the brain α-synuclein pathology.
Exosome and aptamer therapies have significant advantages over antibody therapies, which can stimulate the immune system in unwanted ways, may cause other side effects, and can fail to reach intracellular targets. While DNA aptamers were the focus of this particular study, it may also be possible to use exosomes to deliver other therapies, including rejuvenative therapies, that are difficult to deliver through other methods, and it may also be possible to use exosomes and different aptamers to destroy the aggregates that herald Alzheimer’s disease. More research is needed in these areas.
Of course, this is not the first approach to creating an intracellular therapy for a proteostasis disease; the brain’s natural method of defending against α-synuclein aggregates was studied just last month, and it may be possible for a rejuvenation biotechnology solution to revitalize this cellular machinery, preventing Parkinson’s at its root.
It is not yet clear which future therapies or combinations of therapies will be the first to fully ameliorate or cure Parkinson’s, Alzheimer’s, and other deadly proteostasis diseases. However, it is very clear that such therapies need to be developed, as the cost, in both human lives and financial expenditure, is immense.
 Ren X, Zhao Y, Xue F, Zheng Y, Huang H, Wang W, Chang Y, Yang H, Zhang J, Exosomal DNA aptamer targeting α-synuclein aggregates reduced neuropathological deficits in a mouse Parkinson’s Disease model, Molecular Therapy: Nucleic Acid (2019), doi: https://doi.org/10.1016/j.omtn.2019.07.008.
 Zou, J., Shi, M., Liu, X., Jin, C., Xing, X., Qiu, L., & Tan, W. (2019). Aptamer-Functionalized Exosomes: Elucidating the Cellular Uptake Mechanism and the Potential for Cancer-Targeted Chemotherapy. Analytical chemistry, 91(3), 2425-2430.
 Lakhin, A. V., Tarantul, V. Z., & Gening, L. (2013). Aptamers: problems, solutions and prospects. Acta Naturae (англоязычная версия), 5(4 (19)).