May 26, 2024

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Innovative mRNA delivery technology leads the wave of gene therapy

Nature: Innovative mRNA delivery technology leads  the wave of gene therapy


Nature: innovative mRNA delivery technology leads  the wave of gene therapy.

The VLP-mRNA delivery technology jointly developed by domestic medical teams is the world’s first gene therapy delivery vector technology.


After years of technology accumulation, the gene therapy industry has gradually matured, leading the third industrial revolution in biomedicine.

But in this field, delivery strategy has always been one of the important bottlenecks that plagued the development of the industry.

In 2020, Jennifer Doudna, who won the Nobel Prize for outstanding contributions in the field of CRISPR, also lamented that “delivery may still be the biggest bottleneck for somatic gene editing.”


Recently, Nature Biomedical Engineering and Nature Biotechnology have successively issued articles pointing to a virus-like particle (VLP) delivery technology between viral vectors and non-viral vectors.

In both research reports, both The delivered CRISPR/Cas9 mRNA showed therapeutic potential in mouse models of wet age-related macular degeneration and herpes stromal keratitis, respectively.


 Innovative mRNA delivery technology leads  the wave of gene therapy 


Nature: innovative mRNA delivery technology leads  the wave of gene therapy



The VLP-mRNA delivery technology is the world’s first gene therapy delivery vector technology developed by the team of Professor Cai Yujia from the Institute of Systems Biomedicine of Shanghai Jiaotong University and the team of Director Hong Jiaxu of the Eye, Ear, Nose and Throat Hospital of Fudan University. Previously, the team also developed an mRNA vaccine for the new coronavirus based on this core VLP-mRNA delivery technology, and published the animal data of the first mRNA COVID-19 candidate vaccine at that time.


VLP-mRNA has a strong potential to solve the bottleneck of delivery technology for somatic gene therapy (including gene editing, etc.). Based on this technology, Professor Cai Yujia as the co-founder of the guide gene has created a BDmRNA technology platform and targeted A wide range of research and development pipelines have been established for various indications, including VLP-mRNA-based gene therapy strategies and vaccines, which are aimed at promoting the clinical transformation of this technology.

In June last year, this cutting-edge company established in 2018 has completed a tens of millions of pre-A round of financing.


Nature: innovative mRNA delivery technology leads  the wave of gene therapy

▲Development pipeline of BDmRNA technology platform (official website of Bendao Gene)





mRNA technology: a new strategy emerging under the COVID-19 epidemic

After years of development, the entire gene therapy industry has been different from the original definition, and has gradually formed multiple subdivisions (for example, according to the level of gene modification, it can be divided into DNA-based gene therapy and RNA-based gene therapy) , And multi-level representative products have emerged.


Among them, the development of new prevention and treatment methods based on mRNA has attracted more and more attention in the past few years.

Among its two attractive applications, one is used as an mRNA vaccine for cancer and viral infections, and the other It is a treatment for non-targetable gene diseases; according to the two studies published above, it will also have a lot to do in the field of gene therapy based on gene editing; specific application areas include infectious disease vaccines, tumor immunotherapy (cancer vaccines), therapeutics Protein replacement therapy and treatment of genetic diseases.


In response to this new coronavirus, vaccine candidates have been developed based on mRNA technology with a very first-mover advantage.

It is not an exaggeration to say that it is the most concerned subdivision in the current biopharmaceutical innovation technology.


The COVID-19 may have created an opportunity for mRNA technology to be more widely known, but in fact, the prospects of this field have been favored by capital at an earlier time.

Since 2015, three representative mRNA therapy companies have been- —Moderna Therapeutics, BioNtech and CureVac — attracted a total of US$2.8 billion in private investment, and has repeatedly passed down the financing myth of the biotechnology industry. Currently, these three companies have been listed on the Nasdaq.



▲Financing of private RNA therapy companies (a) Market value of listed RNA therapy companies (b)

Image source: (Nature Reviews Drug Discovery)



Theoretically, mRNA has the potential to synthesize “any kind of protein”, and it can be used to turn the protein manufacturing engine in the cell into a “drug factory”, which has great hope for the treatment of various diseases.


For mRNA vaccines and certain mRNA drugs, administration is relatively simple. For example, mRNA vaccines against viruses.

After a stabbed arm, muscle cells absorb mRNA and produce viral proteins.

The immune system treats the protein as a foreign substance and produces antibodies and T cells (to make the body resist future invasions).

Currently, SARS- In various viral infectious diseases including CoV-2, relevant candidate products are undergoing clinical development.


In addition, mRNA-based vaccine strategies are particularly promising in the field of tumor immunity, and this is also a major exploration direction for mRNA therapy at present.

These mRNA-based therapies, provided by intramuscular, subcutaneous, or local injection of tumors, encode tumor proteins or immune signaling molecules to help enhance the human immune system’s attack on cancer cells.

It is worth mentioning that, compared to the global vaccine market, the global cancer vaccine market seems to be growing faster.

It was US$4.6 billion in 2019 and is expected to reach US$10.1 billion by 2024, representing a compound annual growth rate of 17.28%.


In contrast, mRNA drugs that replace beneficial proteins to treat chronic diseases are more difficult to enter the clinic than vaccines.

These drugs face the challenge of targeting mRNA to specific tissues and providing powerful and long-lasting benefits without excessive side effects. Therefore, the development of such therapies has been relatively few.


In any case, the results of the emerging mRNA therapy field so far are exciting. A large amount of accumulated related preclinical data and some early clinical data that have already begun have jointly promoted its achievement in the COVID-19 epidemic environment.

Victory, with the further development and maturity of technology, various treatment strategies based on mRNA will gradually realize the idea of ​​treating and preventing human diseases.





Delivery remains the main challenge

At present, in the field of gene therapy, the challenge of delivery systems has become a commonplace question.

The ultimate clinical efficacy of these drugs depends on an efficient delivery system, and the same is true for mRNA therapy.


Although the effectiveness of naked mRNA has been proven in intramuscular injection, subcutaneous injection or intradermal injection, it can avoid other obstacles related to systemic administration of mRNA (for example, removal from the blood stream through the liver, kidney, and spleen);

However, the stratum corneum, the outermost layer of the epidermis, forms a tight barrier to the absorption of topical drug delivery. In the absence of a delivery system, the penetration of mRNA on the cell membrane is very low.


Although strategies such as microperforation, microneedling, electroporation, and super-infiltration have been developed to overcome this obstacle, mRNA has a half-life of about 7 hours and is easily degraded; its inherent instability and high degree of enzymatic degradation Sensitivity, coupled with various obstacles such as the large size and high negative charge of mRNA, has further increased the barriers to the development of its delivery strategy, which has seriously hindered the clinical transformation of this strategy.


Therefore, further improvement of the delivery system of mRNA has always been an important bottleneck in this field.

At present, the scientific community has made many attempts in the two general directions of the main viral vectors and non-viral vectors, and they are between viral vectors and non-viral vectors.

The delivery strategy of the virus-like body (VLP) undoubtedly adds more fresh blood to the current delivery status.


Among the viral vectors, lentiviral vectors can efficiently infect almost all cells, and the delivery efficiency of AAV vectors is also very high. It has been applied to clinical in vivo and in vitro gene therapy and is a relatively mature delivery technology.

However, viral vectors have key defects related to genome integration and possible host rejection (immunogenicity and cytotoxicity).

In addition, when AAV is used to deliver gene editing tools such as CRISPR, it may face the safety problem of long-term or even life-long expression of editing tools, and it may also cause potential off-target and immune responses.

Therefore, in the field of mRNA delivery, the demand for non-viral vectors has also been stimulated.


Vectors based on lipids or lipid compounds (lipidoids) represent the most commonly used non-viral vectors.

Various synthetic and naturally derived lipids have been used to form liposomes or lipid nanoparticles (LNPs), both of which have been reported to be effective in delivering mRNA-based vaccines.

Among them, LNP is currently the most widely used in the field of nucleic acid medicine. A wide range of delivery types.

Because it is easier to absorb by antigen-presenting cells, it is most commonly used in vaccines.

At present, the three major mRNA vaccine giants, Moderna, CureVac and BioNTech, all use LNP delivery technology. However, the delivery efficiency of LNP in the application of gene therapy in vivo is not high.


Although these delivery vectors have been widely used in basic research and clinical research of gene therapy and mRNA vaccines, in the specific subdivision of gene editing technologies such as CRISPR, their clinical application has double standards of safety and effectiveness.

Safety issues and the efficiency challenges of non-viral vectors such as LNP make the delivery system still need to be further developed and explored.


The VLP delivery system uses the principle of mRNA stem-loop structure and the specific recognition of phage capsid protein, and through viral engineering technology, the advantages of both virus and mRNA are perfectly combined to create a new delivery technology VLP-mRNA.

On the one hand, it uses The outer shell of the virus makes it particularly efficient in infecting cells.

On the other hand, based on the transient characteristics of mRNA itself, it can make gene editing therapy safer and more controllable.

It has been shown in the research of delivering CRISPR/Cas9 that it is not Compared with the viral system expressing Cas9, Cas9 mRNA delivered by VLP-mRNA, the existence time of Cas9 is only 72 hours, and at the same time, it can significantly reduce or even completely avoid off-target effects.


In addition, in terms of gene load, AAV vectors can only deliver genes with a size of 4.7 kb, while the classic CRISPR/Cas9 editing system is larger.

Usually, it is impossible to deliver the entire CRISPR/Cas9 system through a single viral vector, but requires two viruses.

The carrier is delivered separately. VLP-mRNA can deliver the entire CRISPR element (Cas9 and gRNA), overcoming the limitation of AAV vector carrying capacity.

At the same time, with the further development of gene editing technology, larger base editing tools have gradually entered the field of gene editing research and development, and VLP-mRNA is also expected to become its advantageous delivery tool.





The emergence of a new type of strategy is not a veto of the previous traditional methods, but more to fill in the gaps in the entire potential application field.

It is believed that as more and more technical bottlenecks are broken, mRNA vaccines and other treatment strategies based on mRNA, as well as the potential of the entire gene therapy field will be further released, and ultimately benefit the majority of patients.






Nature: innovative mRNA delivery technology leads the wave of gene therapy

(source:internet, reference only)

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