Science and Technology Platform Program for Advanced Biological Medicine


Brain cell type specific molecular therapy and brain imaging by development of next generation blood-brain-barrier crossing DNA/RNA heteroduplex oligonucleotide

<Project Leader> Yokota Takanori

Professor, Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Yokota Takanoris

Oligonucleotide therapies are expected as next-generation pharmaceutical products following antibody drugs. Although only three drugs have received marketing authorization until 2015, Exondys 51 (eteplirsen), which is an exon skipping treatment for Duchenne muscular dystrophy, received accelerated approval by FDA in September 2016. Then in December 2016, SPINRAZA (nusinersen) for spinal muscular atrophy was also approved. Besides this, the development of oligonucleotide therapeutics for neurological and muscular diseases has been actively carried out in clinical trials.

Recently, We developed a DNA/RNA heteroduplex oligonucleotide (HDO) as a third-generation nucleic acid drug with a structure different from that of the conventional oligonucleotides for gene silencing, double-stranded RNA of short-interfering RNA (siRNA) and single-stranded DNA of antisense oligonucleotides (ASO). HDO is a fundamental technology born in Japan, and its high effectiveness has led to the establishment of bio-venture, Rena Therapeutics, to achieve its clinical application. In addition, we also succeeded in developing blood-brain-barrier (BBB)-crossing HDO capable of controlling gene expression in the brain by peripheral systemic administration of subcutaneous as well as intravenous injections. BBB-crossing HDO is a breakthrough technology with outstanding novelty and inventive step, and has been already licensed to leading pharmaceutical companies in Japan and the US.

In this project, in order to strengthen the patent as the fundamental technology of BBB-crossing HDO, we will apply for new patent applications as a substance patent, covering optimization of molecular/chemical structures. Specifically, we plan to target neurodegenerative diseases such as Alzheimer’s disease, 1) By elucidation of in vivo pharmacodynamics, BBB-crossing and intracellular mechanism and the mechanism of toxicity, and by optimization of molecule structures, chemical modifications and BBB-crossing ligands of HDO with the goal of improving the effectiveness of the BBB-crossing HDO by 5 times. Moreover, we plan to 2) Develop second ligands and molecular structures that enable target cell subtype-specific gene regulation. Then, we try to 3) Establish brain imaging technology using BBB-crossing HDO labeled with a radioisotope targeting specific receptor-expressing cells with PET / SPECT. Together, we would like to achieve Theranostics (Therapeutics & Diagnostics) with this next-generation BBB-crossing HDO by improving the efficacy and safety of BBB-crossing HDO specific for target cell-type combined with the brain imaging technology. This would enable us to treat common neurological diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis, brain ischemia and multiple sclerosis as well as rare hereditary neurodegenerative diseases. These strengthened patents of next-generation BBB-crossing HDO would be licensed to many pharmaceutical companies both in US/EU and Japan as a fundamental technology.

Figure 1 Figure1: Gene suppression mechanism of DNA/RNA heteroduplex ologonucleotide (HDO)(A) and its in vivo efficacy (B)
(A) After the HDO is introduced into a cell by delivery ligand, complementary RNA (cRNA) is cleaved by RNase making parent antisense strand (ASO gapmer) free and active, and the ASO gapmer inhibits the target RNA RNase H-dependently. (B) The inhibition effect of HDO is much higher than ASO in vivo.
Figure 2 Figure 2: Project Organization Diagram
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