mRNA-Based Therapy for Neurological Disorders
Because of poor nerve regeneration and difficulties in accurately targeting neural tissues, neurological disorders are difficult to cure. mRNA-based therapeutics hold promise as an alternative for treating neurological disorders. Synthetic mRNA can produce the desired proteins in their native forms for mature non-dividing neural cells without the need for being transported to their nuclei. In the area of neurological diseases, synthetic mRNA has been applied for administering a neurotrophic factor. High local concentrations of the neurotrophic factor can be achieved by directly transducing host cells near the degenerating neurons. Creative Biogene is a leading service provider in mRNA-based drug research and development. Our extensive experience, an excellent team of experts, and advanced technology platforms make us an ideal partner for worldwide customers. Here, we give an overview of advancements in mRNA-based protein replacement therapy in neurological disorders, hoping to promote the development and research of mRNA-based therapy.
mRNA-based therapy for neurological disorders
To enhance nerve regeneration and for nerve protection, a series of bioactive factors, such as brain-derived neurotrophic factor (BDNF), nerve growth factor, and neurotrophin-3, have been investigated. Since the macromolecular proteins cannot access the blood-brain barrier (BBB), peripheral administration of these factors in the form of recombinant proteins is hindered. Moreover, these proteins have poor stability under physiological conditions and their half-life in the central nervous system (CNS) is considerably short. Synthetic mRNA can rapidly and efficiently produce the desired proteins for mature non-dividing neural cells without the need for being transported to their nuclei. Therefore, mRNA-based therapeutics hold promise as an alternative approach for administering a neurotrophic factor. Similar to other diseases, there are two major challenges of mRNA-based therapeutics for neurological disorders, including stability and translation efficiency of mRNA as well as immunogenicity of mRNA. To achieve effective mRNA administration, it is very essential to develop suitable carriers targeting neural tissue.
mRNA administration for treating sensory nerve disorders
To test mRNA administration for treating sensory nerve disorders, researchers used a mouse model of olfactory dysfunction. The olfactory neurogenesis is based on the olfactory epithelium, where olfactory receptor neurons (ORNs) are continuously generated and replaced. During the process, BDNF (one of the neurotrophic factors) plays an important role in promoting ORNs survival and differentiation. Researchers applied BDNF-expressing mRNA into the nasal cavity using polyplex nanomicelles. These nanomicelles are based on the self-assembly of polyethylene glycol (PEG)–polyamino acid block copolymer, featuring a core–shell structure surrounded by a PEG outer layer and an inner core of a functionalized polyamino acid, poly[N'-[N-(2-aminoethyl)-2-aminoethyl] aspartamide] [PAsp (DET)]. The results showed that mRNA enabled efficient, sustained protein expression in nasal tissues. And BDNF-expressing mRNA repaired the olfactory epithelium to a nearly normal architecture, remarkably promoting neurological recovery of olfactory function.
Treatment of neurological disorders by introducing mRNA in vivo using polyplex nanomicelles. (Baba, M., et al, 2015)
mRNA therapeutics for preventing ischemic neuronal death
A lack of oxygen to brain tissue, also known as ischemia, leads to neuronal death, which causes serious lifelong neurological deficits. Currently, there are no effective treatments that successfully prevent neuronal death after ischemia. Based on the same neurotrophic factor (BDNF) and mRNA delivery system (polyplex nanomicelles), researchers tested the effectiveness of the mRNA therapy on the rat model of transient global ischemia (TGI). BDNF-expressing mRNA remarkably increased the survival of hippocampal neurons along with a rapid rise of BDNF in the hippocampus. Notably, the results showed that mRNA administration on Day 2 after TGI showed better effects than the administration immediately after TGI. In addition, long-term therapeutic benefits were observed by dosing twice Day 2 and 5.
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- Baba, M., et al. (2015). "Treatment of neurological disorders by introducing mRNA in vivo using polyplex nanomicelles." Journal of controlled release, 201, 41-48.
- Fukushima, Y.,et al. (2021). "Treatment of ischemic neuronal death by introducing brain-derived neurotrophic factor mRNA using polyplex nanomicelle." Biomaterials, 270, 120681.