If you want to enter the bureau, first look at a summary of the difficulties in the development of fiery nucleic acid drugs

In August 2021, Aibo Bio received more than 4.
5 billion C round of financing, setting a new record for a single financing before the IPO of Chinese biopharmaceutical companies; in November, it received another 300 million US dollars in C + round financing
.

Before 2021 is over, Aibo Bio has received an investment of nearly 7 billion yuan

Capital has really added fuel to the enthusiasm for nucleic acid drug research and development, opening a new tens of billions of dollars for the development of small nucleic acid drugs
.

Figure 1: List of financing of domestic R&D mRNA drug companies since 2019

(Data source: collation of public information)

There are many difficulties in the development of small nucleic acid, what should I do?

There are many difficulties in the development of small nucleic acid, what should I do?

1.
Nucleic acid molecules are unstable and easy to degrade

1.
Nucleic acid molecules are unstable and easy to degrade

mRNA is inherently unstable, susceptible to degradation by nucleases in vivo, and has limited protection from degradation by sequence optimization, base modification, and capping/tailing
.

Therefore, mRNA drugs need a suitable delivery carrier to deliver them into the body in order to have a better immune effect.

2.
Potential side effects of nucleic acid drugs

2.
Potential side effects of nucleic acid drugs

For example, mRNA synthesized in vitro has high immunogenicity and may induce a large number of inflammatory responses
.

3.
Drug delivery systems are key to mRNA drugs

3.
Drug delivery systems are key to mRNA drugs

mRNA drug delivery faces three difficulties: extracellular barrier, endosomal escape and intracellular immunity
.

Because mRNA is large (104-106 Da) and negatively charged, it cannot pass through the anionic lipid bilayer of the cell membrane

4.
The development of mRNA technology is still in its early stages

4.
The development of mRNA technology is still in its early stages

The idea of ​​RNA as a new type of drug form began in the 1990s.
In the first ten years, mRNA was considered too unstable and the cost of high-purity in vitro synthesis was high, and most large companies tried it out
.

Now its large molecular weight and the low tolerance of protein translation machinery for chemical modifications necessary for de-immunogenicity and increased stability also make the development of mRNA drugs lag behind small nucleic acid drugs ASO and siRNA

5.
The mRNA production process is complicated, and there are many "Know-how" links

5.
The mRNA production process is complicated, and there are many "Know-how" links

Figure 2: mRNA production process (source: mRNA vaccines for infectious diseases: principles, delivery and clinical translation)

6.
The pharmacokinetic research of nucleic acid drugs needs to be improved urgently

6.
The pharmacokinetic research of nucleic acid drugs needs to be improved urgently

Although approved or under-development nucleic acid drugs or nucleic acid therapies have achieved phased results, relatively few nucleic acid drugs have relatively complete pharmacokinetic (ADME) data
.

The half-life of naked mRNA therapy is short, and the half-life of in vitro transcribed mRNA (IVT mRNA) and its protein product is a key factor affecting pharmacokinetics (PK) and pharmacodynamics (PD) due to the rapid degradation of a large number of extracellular RNases

7.
Biological analysis is more complex

7.
Biological analysis is more complex

Nucleic acid drugs are generally synthesized by chemical synthesis, and the molecular weight is between small molecule chemical drugs and macromolecular biological agents
.

However, because nucleic acid drugs are charged compounds, which are extremely unstable in the biological environment, and their physicochemical properties are more similar to biological preparations, the clinical trials and biological analysis of nucleic acid drugs are more complicated than biological preparations