biorchestra

why rna-based
therapeutics?

Proteins are crucial molecules in our cells and are required by
all living organisms. The interaction between microRNA and
messenger RNA (mRNA) produces a transient set of
information cells use to express a protein from information
coded in the DNA.

Protein drugs made by recombinant protein technology
generate more than $200 billion in annual sales worldwide.
However, many proteins are present in cells, 1) including
enzymes related to epigenetics, 2) proteins expressed by
mitochondrial DNA, and 3) other important intracellular
proteins, which are considered inaccessible targets by
recombinant protein technology. If we develop RNA drugs that
can precisely regulate the expression of these proteins using
cytoplasmic gene expression systems inside the body, we can
make a bigger therapeutic impact than the protein drugs
currently on the market.

Several advantages can be obtained by directly using the
cytoplasmic gene expression system inside the body. Proteins
expressed and regulated inside the body can more strongly
mimic original proteins than proteins produced in

vitro. This induces minimal immunogenicity.

The production of proteins in vitro is time-consuming and
process-intensive and the proteins may be unstable
depending on the type of protein produced. Furthermore,
implementing a strategy for producing or regulating multiple
proteins will face even more technical limitations. To address
these unmet needs, we are developing RNA sequences and
RNA delivery technology that deliver mRNA or microRNA
regulators effectively and safely.

Delivering modified mRNAs into the cytoplasm can mimic
proteins that function as epigenetic enzymes, viral antigens
and antibodies. The delivered microRNA regulators can
control multiple protein functions impaired in diseases, such
as neurodegenerative diseases. Moreover, unlike DNA-
targeting therapeutics like gene therapy, which may insert
DNA into the chromosome permanently, the effects of RNA-
based therapeutics can be temporary, thus reducing the risk
of irreversible cellular DNA changes that may induce
tumorigenesis.

BMD-001

Drugs targeting the brain

BMD-001 : Alzheimer’s disease

Investment in global Alzheimer’s disease treatment market
has been declining since new antibody therapeutics targeting
ther abnormal form of amyloid beta that exists outside of
cells produced from neurons and the abnormal form of tau
protein that exists inside and outside of neurons in order to
treat Alzheimer’s disease, as well as the development of
compounds targeting BACE1 of neurons, ended up with
failures. Much attention is being drawn to those companies
which are conducting research on the development of a
mechanism to uptake the abnormal form of beta by treating
agonist antibody to the microglial triggering receptor
expressed on myeioid cells 2 (TREM2), a pamyloidlasma
membrane protein of glial cells. We believe that multiple-
target treatment can produce extensive effects in case of

disease with complex mechanisms in combination with
natural aging, such as Alzheimer’s disease. One type of
microRNA controls many messenger RNA (mRNA). We have
discovered a specific microRNA that controls mRNA of
Master regulator of mitochondria (Gene A), NAD-dependent
deacetylase (Gene B), and Scavenger’s receptor (Gene C),
which are all related to Alzheimer’s disease, and developed
the antisense oligonucleotide (ASO) of degrading this
microRNA specifically (Figure 4). This reproduces actual
therapeutic effect by making it possible to control the
expression of three types of mRNAs by delivering ASO to
cytoplasm and degrading on microRNA and to increase or
activate the expression of a protein which has been reduced
or become dysfunctional due to aging and disease
conditions.

Figure 4. BMD-001 for Alzheimer’s disease or neurodegenerative diseases.

Delivering ASO

BMD-001 enables delivery of our ASO more safely and efficiently into the target brain site by passing through
the Blood Bain Barrier(BBB) via transporter mediated transcytosis as well as endocytosis into the cytoplasm of our target cells (Figure 5).

Figure 5. Delivering antisense oligonucleotide (ASO) for Alzheimer’s disease.

IV injection strategy (Alzheimer’s disease)
– Patient friendly way with repeated administration

In an animal model, it treated complicated Alzheimer’s
disease effectively through multi-functions in multi-spots by
successfully delivering RNA sequence to neurons and brain
immune cells without side effects. As this drug has been
found to have therapeutic effect in this animal model in a
severe conditions, it is likely to become a therapeutic agent

with extensive effects for patients in both early and terminal
stages of the disease. It is noteworthy that the technology
can treat Alzheimer’s disease effectively, because it can
target the interaction between microRNA and mRNA, which
has been out of reach until now, and can well deliver the drug
to both neurons and brain immune cells (Figure 6).

Figure 6. Multi-functions of BMD-001 in neurons and brain immune cells.

Neurodegenerative diseases can make you unable to recognize your loved one
and lose important memories and make it impossible to move freely

There are two major types of cells in the human brain. One is
neurons which are responsible for cognitive abilities and the
other is glial cell which cleans the surroundings of neurons
and support their structure.
The neurodegenerative proteinpathies (Figure 7), which
should be self-degraded, are caused by dysfunction of both
cells, depending on aging and genetic or environmental

factors, and accumulate inside and outside of the cells,
leading to cytotoxicity and eventually cell death. In the current
technology, new drugs are being developed that have a
mechanism to remove toxic substances accumulated outside
the cell using biopharmaceutical called ‘Antibody’, rather than
restoring the intracellular functions (Figure 8).

Figure 7. Disease-causing the neurodegenerative proteinpathies in brain.

Drugs on the current market are also medicines that inhibit
the enzyme Acetylcholinesterase, which catalyzes the
breakdown of a neurotransmitter (Acetylcholine) delivered
signals between cells. It is obviously clear that antibodies for
targeting toxic substances under development, and drugs on
the market are also excellent drugs (Figure 8).However, We
are moving one step further to develop drug to treat
diseases. Ultimately, since the accumulation of these toxic
substances is caused by intracellular dysfunction, we have
developed a new biopharmaceutical to treat the inside of the
cell. As the conditions of aging and disease progresses, cells
also get sick and unable to respond on various stimuli
because of lack of expression or loss of function in the

proteins that maintain health, and eventually the cells die.
Brain immune cells in normal people scavenge and degrade
different types of toxins and regulate inflammatory
responses. The neuronal cells in normal people block the
production of toxic substances well and maintain the
pathway, which transmit a signal through neurotransmitters.
Therefore, our brain is free of toxic substances and we can
think very well. We are demonstrating a mechanism for
restoring sick cells to conditions like normal brain cells. The
function of the cells is to return to normal brain that was
healthy (Figure 9). This is a powerful effect that can be
applied to many neurodegenerative diseases, such as Lou
Gehrig’s disease.

Figure 8. Type of drugs to treat existing Alzheimer’s disease.

Brain cells are recovered

Figure 9. Therapeutic effects of BMD-001 in Alzheimer’s disease brain.

This has the potential to have a fundamental therapeutic
effect that is completely different in concept from the relief of
symptom of drugs that are either FDA-approved or under
development. Recently, the drug has also been shown to

improve neuromuscular function in Lou Gehrig’s disease. We
believe that it can be an innovative new drug for aging-related
diseases such as neurodegenerative disease and
neuromuscular disease.