Clinical Applications and Therapeutic Options

Of non-coding RNAs ncRNAs are emerging as central molecules in the development of next generation therapies. Such treatment could be direct by blunting effects of the ncRNAs with antagomirs or delivery of non-coding RNA, when expression levels of these are decreased. Indirect methods iare based on delivery of the same molecules within microvesicles, such as exosomes, or through cells such as adult stem cells. The development of treatments to target any of the non-coding RNAs must consider which vehicle would be most efficient for delivery.

We propose that such vehicle could be exosomes and/or stem cells, both of which can cross the blood brain barrier [157,158]. This section expands on potential issues if exosomes and stem cells would serve as vehicles to deliver RNA as a drug. Exosomes are smaller (˜100 nm) than the larger microvesicles that have a diameter of >100 nm up to 1000 nm.

These microvesicles are different from apoptotic bodies that are derived from fragmentation of cells. Exosomes are derived from the late endosomal compartment as multivesicular bodies.

Exosomes escape degradation and are released into the microenvironment. The content of exosomes is complex and can contain endosomal proteins, membrane proteins, lipids and non-coding RNA. The released exosomes can also express proteins from the originating tissue. As an example, exosomes recovered in the blood of traumatic brain injury subjects express neuronal markers. One of the challenges to target the ncRNA is the continued issue of current treatments that lead to drug refractoriness. The treatment of glioblastoma with the frontline drug temozolomide is an example of how drug-induced release of exosomes can affect therapy.

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Temozolomide used to treat glioblastoma induces the release of exosomes by tumor cells.

The exosomes can cause intercellular communication and communicate with distant sites for feedbackn. As treatment with ncRNA develops, research studies will be necessary to determine if tissues can release exosomes with contents to counteract the effects of the `RNA drug’. The effectiveness of treating with ncRNAs or their antagomirs will require large funding from a government agency or from a large pharmaceutical company to understand the intricate network for antagonist of the targeting treatment. Moreover, there are some problems with exosomes being collected from cells for clinical treatment or specific ncRNA being packaged within a custom-made exosome. As one would imagine, intravenously injected therapeutic exosomes would be quickly cleared by the liver. Thus, therapeutic delivery of exosomes will likely depend on the intrathecal route.

An alternative route is to load the ncRNA into stem cells for delivery to the brain. NSCs and mesenchymal stem cells (MSCs) can cross the blood-brain barrier. If ncRNA are loaded into these cells, they can be released in the brain via exosomes. The use of NSCs could provoke some ethical issues with respect to the cells used for their generation. Bioethical concerns arise with the use of fetal cells from aborted tissues. Similarly, the use of induced pluripotent stem cells (iPS) could be a problem due to the issue of tumor formation. The next well-studied stem cells are the MSCs. While these cells can evade immune rejection, they seem to have an issue with memory. Specifically, bone marrow-derived MSCs show preference for this organ [161]. These cells are used in patients and thus far, there is no safety issue. MSCs can be used as off-the-shelf source.

There are multiple sources of MSCs and this would require research studies to determine what source will be most effective to cross the blood brain barrier. To date, MSCs can be used to deliver ncRNA. However, the source of the MSCs is yet to be determined. In conclusion, ncRNAs discussed in this chapter constitute a new set of molecules for the treatment of neurological disorders. There is a need for continued research studies to determine, which ncRNAs would be most effective and the possibility of refractoriness resulting from other ncRNA-containing exosomes of the brain. Nonetheless, targeting ncRNA for neurological disorders is a viable option that could be successful based on the elucidation of underlying mechanisms.