## msiRNA and Unix

(m|si)RNA and Unix part II

by 20h

## Intro

During the pandemic new practical treatments using RNA have come to life
and will help us cure diseases which thought to be uncurable before.

## Recapitulation

See the talk of last year.

We were talking about how messenger RNA is used to give specific cells
the information to produce something for learning how to defeat the
SARS-CoV-2 virus.

The RNA technology is developing further.

The door to cell specific cell programming in a Unix way is opened.

## Recapitulation: Unix interpretation of mRNA vaccines

mrna-encode -d dendritic ${target} \
	| add-lipid-bubble \
	| stabilize \
	| vaccine-print

$target ... some proteine of sars-cov-2 for example.

-d gives currently the target as "dendritic cells", which we need to
produce specialized actions against a virus like sars-cov-2.

Different targets, by giving specific information to specific
cells can help us with other diseases. see one example at the
end with cancer.

## Recapitulation: The -d flag or destination.

mRNA used has three parts.

	${cap} ${information} ${endsequence}

$cap ... A cap sequence with some additions to tell where the information
         should go.
$information ... What should be pushed into the destination cell.
$endsequence ... Required buffer so the mRNA survives longer and gets
                 more easily read out by the destination cell.

So -d defines which kind of $cap we will need to target a specific
cell.

## First Step: A new value for destination: GalNac

In 1965, Gilbert Ashwell and Anatol Morell discovered a receptor:

	Asialoglycoprotein receptor (ASGPR)

which is specific to hepatocytes (liver cells) accidently in an
experiment, which involved sugar (galactose).

It was found out,t hat N-acetylgalactosamine (GalNac), a galactose
type and four of those sugars have the highest specifity, will most fit
to the ASGPR.

## Second Step: siRNA transport

Over time it was shown, that with this concept of binding to this
receptor on liver cells, things can be transported into a liver cell
specifically: Lipids, small molecules, DNA, and more.

All of those were proven in cell cultures, but no for safety in humans.

siRNA technology was discovered in 2001 and has proven this safety.

They even offer the possibility of mutations and will keep up with
for example virusses.

## siRNA - small interfering RNA

This is a new term, we will need. siRNA were discovered in 2001.

Ribo-Nucleidic Acid is used as internal data structure and control code
in all human cells.

DNA becomes RNA and mostly messenger RNA (as used by the SARS-CoV2
vaccine).

Out of this mRNA are proteins created, which form the base of all cells
and our body.

Small interfering RNA is one form, which can be used to up or down
regulate everything in a cell by interferring with the translation of
mRNA to a proteine.

## Third Step: Finding Diseases controlled by liver cells

Since we know are able to send whatever up and down regulation of some
proteine or gene into liver cells, this can help to cure diseases which
are depending on the liver cells.

## Curing Transthyretin-mediated Amyloidosis

In this disease, the liver produced malformed proteins (transthzretin),
which cause clumps in the heart's main pumping chamber. This then caused
cardiomyopathia makes it over time harder for the heart to pump blood.

The target here is the transthyretin gene, which is corrected to produce
the right gene and no clumps occur.

	% target="transthyretin"
	% sirna-encode -d galnac ${target} \
		| add-lipid-bubble \
		| stabilize \
		| injection-print

## Curing Hepatic Porphyria

Hepatic Porphyria is a disease, where the liver is not able to destroy
porphyrin in the body. Once they accumulated, this causes severe
conditions in the body. One major symptom is a black urine.

Here the target is the Delta-Amniolevulinate-Synthase 1, which controls
the buildup of porphyrine during the heme production. Heme(globine) is
the major transporter of oxygen in your blood.

	% target="ALAS1"
	% sirna-encode -d galnac ${target} \
		| add-lipid-bubble \
		| stabilize \
		| injection-print

## Curing Hemophilia A and B

Hemophilia A and B are deficiencies in certain factors of clotting
factors, which are required for bleeding to stop. Those people died
before modern treatment of internal or external bleeding.

Here the target is the antithrombin 3 (AT3), which results in proper
clotting response for any bleeding.

	% target="AT3"
	% sirna-encode -d galnac ${target} \
		| add-lipid-bubble \
		| stabilize \
		| injection-print

## Curing Hypercholesterinaemia

In hypercholesterinaemia out of several reasons there is too much
cholesterine in the blood. This can over time cause blood vessels to
clog, which sometimes is a heart attack. Here the LDL class of
cholesterine is targeted.

The target used in cholesterine production is the Proprotein Convertase
Subtilisin/Kexin Type 9 gene. It will be downregulated the expression of
this gene.

	% target="faulty-PCSK9"
	% sirna-encode -d galnac ${target} \
		| add-lipid-bubble \
		| stabilize \
		| injection-print

## Curing Hepatitis B Virus infections

The Hepatitis B virus infects liver cells and fast or slowy destroys
them, depending on the immune response of the body. This a major cause of
liver cancer. 257 million people all over the world are infected by this
virus. We have vaccinations against this virus.

Other virus infections can possibly be cured that way too.

Here the target is to send in RNA, which produces wrong virus proteins,
so the resulting viruses do not work.

	% target="invalid-HepatitisB-RNA"
	% sirna-encode -d galnac ${target} \
		| add-lipid-bubble \
		| stabilize \
		| injection-print

## Fourth Step: Using the results in practice.

The above solutions are normally given to the patient as injections. This
only needs to be done every month to quarter.

In the porphyria case, this cure is now actively used to help those
patients having a normal life. Before they regulary had seizures and body
pain.

## The Future

Can we find more targets?

Can we find more diseaes to cure?

The Future is bright.

## Summary

A new targetting mechanism specifically for liver cells allows to cure
diseases, which we were unable to target with regular drugs.

## Questions?

Questions?

## Sources

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305320/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405237/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910670/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994659/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496196/

## Thanks

Thank you!

Comments and critique please send them to:

	Christoph Lohmann <20h@r-36.net>