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A New Understanding
When looking at the mechanics of a cell, we can resume the process as such:
- DNA is the template/instruction manual.
- RNA is the actual order being given.
- Proteins are made according to the RNA's orders and are the “machines” actually doing the job needed in the body.
Each of these levels can be modified for therapies. This focused approach is broadly called precision therapy, something we recently explained in detail in the article “Precision Therapies could 6x from 500 billion to 3 Trillion by 2030”.
It was only very recently, less than 20 years ago, that scientists really started to understand how these 3 levels of “coding” worked in our bodies. And even less for them to have practical tools and cheap enough methods to design medicine with them. In 2003, sequencing one human genome did cost $1B. Today it is at $600-$1,000. And the target is to reach a $100-$200 price tag in a few years.
A New Therapeutic Paradigm
The first consequence of all this new knowledge is that we now understand the root cause of many diseases. A defective protein, a missing gene, or a specific hormone not doing its job properly. Instead of blindly modifying the body chemistry and hoping for the best, we know what's wrong.
The second consequence is allowing the pharmaceutical industry to turn its head to the classical approach. It can now start with what is wrong in the body and aim at fixing it.
DNA can solve genetic diseases, but RNA is more versatile. It combines many unique advantages over other types of precision therapies:
- It is entirely “programmable,” as the RNA sequence can be written and programmed for a specific purpose, similarly to digital code.
- Able to easily enter targets like the inside of cells, especially compared to proteins that are blocked by cell membranes.
- Modulable: different concentrations or alternative versions can modulate therapeutic results
- Versatile: RNA has many different functions in cells and so can be used in multiple ways for medical purposes. There are many different types of RNA: mRNA, RNAi, snRNA, miRNA, etc… (if you want a very technical explanation of all RNA types, you can read this Nature article from 2022)
RNA Therapies Growth
RNA technologies patents only took off in 2005 and accelerated from there. The clinical trial pipeline slowly matured, with phase II becoming more numerous in 2010 and phase III in 2017.
The number of RNA therapies in development in 2022 was almost 600, compared to barely 200 in 2010.
RNA's “programmable” aspect makes it much more predictable and easy to understand. It allows for a much quicker development cycle, cutting drug development costs. RNA therapies cost on average, $1.25B to develop and only 5 years, compared to $2B+ and 10 years for chemical drugs and antibodies.
RNA technologies & companies
mRNA vaccine is the most well-known mRNA technology due to Covid-19. It also highlighted the strength of this technology, allowing one to “code” a vaccine in just a few weeks as soon as the virus genome was sequenced.
The technology is now being expanded to many other pathogens beyond Covid. It is also a good candidate for many rare diseases and cancer treatments. The obvious leaders are,
We discussed in detail the future of mRNA therapies in “The Next Application for mRNA Technology: Cancer Therapies.”
RNA Interference (RNAi)
Not all RNA is used to produce proteins. Some RNA is created to interact with other RNA molecules and are called RNAi (for RNA interference). It can cancel the activity of a defective gene or reduce the production of an unwanted protein.
There are also other RNAi drugs in development, of which 5 have reached phase III of clinical trials:
- Fitusiran, by Sanofi (SNY) & Genzyme (private)
- Nedosiran by Dicerna Pharmaceuticals (private)
- Teprasiran by Quark Pharmaceuticals (private)
- Tivanisiran by Sylentis S.A. (private)
- Vutrisiran by Alnylam (ALNY)
RNAi technology is only getting started. More advanced methods are being developed, notably to allow for more precise activity of the RNAi molecule or to limit the need for a carrier like the lipid vesicles also used in mRNA vaccines.
You can read more about RNAi therapies in this article: RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies.
RNA splicing / Antisense oligonucleotides (ASOs)
Some RNA is modified before being used as the template for protein production, a process called “splicing.” Such splicing can be used to remove defective parts of a gene in some genetic diseases. For example, the following drugs use this technology:
This technology is especially promising for neurological disorders and might have the potential for treating Parkinson’s disease or Huntington’s disease, although a research program for Huntington’s disease by Roche and Wave Therapeutics has been stopped in 2021.
micro-RNA (miRNA) & antisense-RNA (asRNA)
MicroRNA and antisense-RNA are naturally occurring RNA that do not encode for any genes. Instead, they regulated the activity of standard mRNA in a quite similar way to RNAi.
Both miRNA and asRNA have been discovered to be involved in multiple diseases. Treatment could provide a rebalance
- Regulus(RGLS), the company, was initially set up as a common venture by RNAi-leader Alnylam (ALNY) and Ionis Pharmaceuticals (IONS). This was done so that Regulus could leverage and combine exclusive licenses for patents from both companies. It has one drug in phase I for kidney disease.
- Ionis Pharmaceuticals(IONS) is a leader in antisense-RNA therapies. It currently has 3 commercialized drugs and a rich pipeline of potential new drugs, of which 9 are in phase III of clinical trials:
- 12 neurological therapies.
- 8 cardiovascular therapies.
- 3 rare disease therapies.
- 8 other diseases (Hepatitis B, kidney diseases, etc…)