1. Please introduce yourself and your role at BIORCHESTRA.
I’m Branden Ryu, founder, chief executive officer, and the chairman of BIORCHESTRA. I earned my Ph.D. degree from the Graduate school of medicine at the University of Tokyo and I spent some time at Harvard medical school as a researcher. After my research career, I found BIORCHESTRA to focus on developing RNA-based therapeutics in 2016.
I have discovered the novel RNA biomarker and invented the novel Antisense Oligonucleotide (ASO) modality to treat neurodegenerative diseases. BIORCHESTRA has expanded the new RNA modalities to cure neurological disorders including genetic rare diseases. Based on these scientific results, I have filed more than 85 patent applications since 2017.
2. What does your process for developing RNA-based therapeutics for neuroinflammatory diseases look like?
BIORCHESTRA discovered miRNA-485-3p, a "molecular switch" in cells that can control the pathological protein production, neuro-inflammation and other Alzheimer’s disease related symptoms.
Following injection of this specific microRNA into the mammalian brain, we verified that this microRNA triggers the production of amyloid plaque, hyperphosphorylated tau, neuronal damage due to neuroinflammation as well as cognitive impairment. Similar observations were made in primary neuronal culture and glial cell culture where microRNA-485-3p overexpression led to the production of amyloid plaque, hyperphosphorylated and cleaved tau and proinflammatory biomarkers. Therefore, to study the potential of this specific microRNA to be utilized as a therapeutic target in AD, a transgenic AD mouse model was treated with an ASO complementary to this specific microRNA. This proof-of-concept study showed that microRNA inhibition resulted in a reduction in amyloid β/tau accumulation, neuroinflammation as well as an improvement in cognitive function.
That is Over-expression of miRNA-485-3p leads to a deficiency of one the validated binding target proteinPGC1 alpha, which are linked to neurodegeneration and neuroinflammation in the brain. In other words, we confirmed that over-expression of miRNA-485-3p leads to a deficiency of PGC1 alpha, which are linked to neurodegeneration and neuroinflammation in the brain.
To reverse epigenetic changes caused by miRNA-485-3p, we have developed BMD-001, a therapeutic agent and also developed proprietary PEG-based polymeric polyion complex to deliver miRNA-485-3p ASO into neurological cell.
3. How are you overcoming the challenge of tissue-specific delivery to the central nervous system, across the blood-brain barrier?
The delivery of ASO have been studied to enhance their stability for therapeutic application. Moreover, it is more difficult to target delivery of brain region due to the BBB issue.
BIORCHESTRA have developed a proprietary brain-specific drug delivery system, BDDS™ independently. The basic structure of DDS is ion-complex micelle in combination with cationic polymer and therapeutic RNA (antisense oligonucleotide, ASO). In order to enhance the delivery efficacy of ASO into the brain, we installed brain specific ligand on the surface of micelles, which enables delivery of ASO safely into the cytoplasm as well as BBB penetration. This specific ligand targets transporter which is over-expressed brain epithelial cell and parenchyma. The micelles are transferred into the brain parenchyma by receptor-mediated transcytosis mechanism and internalized into the brain cells by receptor-mediated endocytosis mechanism.
Polyion complex micelle, formed by ion interaction between cationic polymer and ASO, is our platform technology for an efficient delivery of therapeutic ASO to the brain. For the development of ASO delivery system via intravenous injection route, it should be considered the two major factor: stability and targetability. As we mentioned above, we designed brain specific ligand installed stable ASO delivery system. From the results, we could observe that the micelles are stable in a blood stream enough to be accumulated into the brain in vivo. The micelles also showed the higher cellular uptake in neurological cells than naked ASOs, and higher brain accumulation behavior in vivo experiment. Finally, we could achieve that the efficient delivery of therapeutic ASO into target cells over the brain.
We developed and applied a brain-specific drug delivery system using our proprietary technology to safely deliver Alzheimer's disease drug candidates to neurological cells through intravenous injection and we confirmed that our BDDS™ can achieve therapeutic levels of BBB penetration in animal models. In addition, BDDS™ efficiently delivers the drug to deep brain regions such as striatum, hippocampus, thalamus, hypothalamus as well as spinal cord.
There is high probability of extending our business because BDDS™ can be applied to RNA, mRNA, siRNA, protein, and small molecule drugs, etc.
4. Can you outline your plans for the next few years for BIORCHESTRA?
We will file our first IND for BMD-001 clinical trials soon. In addition, we will verify our drug delivery system, BDDS™ through open innovation with global big pharmaceutical companies by establishing a stable production system in the pilot plant, which will be operating from this year, and continue to develop next-generation delivery systems such as mRNA delivery system to the CNS.
Our mission is to change the therapeutic paradigm from treating the symptoms to providing fundamental cure of the diseases.
5. What are you most looking forward to at the RNA Therapeutic Modalities Summit?
Through the RNA Therapeutics Modalities Summit, I will introduce our technology that disease-modifying therapies for neurodegenerative diseases using RNA therapeutics and a proprietary polyion-complex-micelle-based delivery system, BDDS™. And I will seek global partners to collaborate in the areas of R&D and the commercialization.
