Extracellular vesicles-loaded protein replacement therapies with mRNA: A novel method of mRNA delivery opens the door to other gene therapies

Recently, the team of Dr.
Andrew Lee and Dr.
Li Li, founders of Sper Biologics, published a report entitled "Intradermally delivered mRNA-encapsulating of extracellular vesicles" in the international academic journal Nature Biomedical Engineering (impact factor: 29.
2).
Extracellular vesicles for collagen-replacement therapy
).
The new delivery system used in the paper has the potential to help mRNA and gene therapies overcome many of the obstacles currently
faced.

After the age of 30, human skin loses about 1% of collagen every year because the expression of related genes decreases with age
.
There is no substitute for the loss of collagen caused by aging, and wrinkles directly caused by aging are formed on the face, hands, neck and other body parts
.
In recent years, collagen-related products have been widely used in related aging fields, and a number of popular products
have been born.
The efficient delivery and long-term stable expression of collagen play a crucial role in its efficacy, and related technological breakthroughs are of great significance for further alleviating aging
.

According to the article, in order to solve the loss of collagen caused by aging in the skin, the relevant team has created a new gene therapy platform based on non-viral vector technology and reproducible administration, using extracellular vesicles (EVs) to deliver the mRNA encoding collagen to skin cells, where mRNA can encode and express the corresponding protein, thereby functioning
.
This cell-derived mRNA therapy upregulates the expression of natural collagen in skin cells, compensates for the loss of collagen caused by aging/photoaging, and greatly improves aging symptoms
such as wrinkles.

In fact, this "dream-like" technology is close to reality, and Dr.
Andrew Lee, Dr.
Li and Dr.
Ni Jia's Siper Biologics is perfecting this gene therapy and is expected to achieve the first clinical application
in collagen loss patients.

According to reports, Sper Biotech is the world's first company
focusing on the development of cell-derived mRNA innovative therapies and related delivery tools.
Based on independent innovation and research and development and cooperation with leading medical institutions and universities around the world, the company has developed non-synthetic, mass-producible and clinically value-oriented cell-derived mRNA therapies, providing a new possible direction
for the next generation of gene therapy methods.
Currently, the company's innovative R&D pipeline COL1A1-EV mRNA for aging-related collagen damage has received ethical approval for the first human clinical trial, and is expected to begin dosing
the first subjects in the summer of 2023.
SPO will also become the first biopharmaceutical company
in the world to test reproducible non-viral gene therapy products in humans.

Spiper's "cell-derived RNA therapy" is based on the principle of replacing aging-related protein loss in the human body, and transports the mRNA encoding these proteins that are downregulated with aging into cells to compensate for the loss
caused by aging/photoaging through the body's own cells.

This also determines that mRNA drugs need to enter the cytoplasm to function, and how to efficiently and specifically deliver mRNA into the cell is the key to the effectiveness of
the therapy.

In this regard, SPO Biologics creatively chose extracellular vesicles (EVs) as a "transporter"
for mRNA delivery.
As a naturally occurring intercellular messenger system, extracellular vesicles exist in all tissues and biological fluids, and can release active ingredients such as proteins and nucleic acids into various tissues
in a targeted manner.

It is worth mentioning that based on the cell-derived mRNA technology platform with independent intellectual property rights, SPI Bio can directly produce mRNA drugs wrapped in extracellular vesicles through cells, and related drugs also show more reliable safety, stronger lysosomal escape ability and better biofilm permeability
.
This technology has a wide range of practical applications, is suitable for most genes (regardless of gene size), and the extracellular vesicles modified by SPO Bio have a high degree of tissue-specific targeting ability and can be targeted to specific organs, providing a natural, safe and efficient innovative gene therapy
.

In contrast, relatively common gene therapies that deliver target genes by adeno-associated virus (AAV)-based viral vectors have significant risks at the level of immunogenicity, virulence or gene integration, which has led to the failure of related drug clinical trials in the past few years
.
In addition, because AAV is too small, about 80% of the human gene sequence cannot be successfully loaded, resulting in a very limited
range of use.
To make matters worse, due to the presence of anti-AAV neutralizing antibodies, patients develop an immune response when they receive the same AAV vehicle-delivered drug treatment again, so repeated dosing
is not possible.

In contrast, "cell-derived mRNA therapy" does not use viral components, has an innate advantage in the field of immunogenicity and toxicity, and does not cause a strong immune response like AAV, so multiple administrations
can be achieved.
Extracellular vesicles can hold larger loads, large enough to carry nucleic acid sequences up to 14K in length, making them more widely applicable
.

Even compared with the widely used LNP delivery technology, "cell-derived mRNA therapy" uses bio-derived delivery tools, which has advantages
over chemically synthesized LNP in terms of safety and extrahepatic targeting accuracy.
Taking the preclinical trial data published by SperBio as an example, compared with other delivery vectors, local reactions such as inflammation and skin redness and swelling when mRNA is delivered by EV are lighter, and the translation efficiency of mRNA is higher
.

Also according to preclinical research data, on the photoaging model of nude mice, after injection of COL1A1-EV mRNA, it was observed that collagen expression in the dermis of mice increased significantly, back wrinkles were significantly improved, and wrinkle area was significantly reduced
.
Regular injections into wrinkled skin produce large amounts of collagen, and the anti-wrinkle effect lasts for up to 70 days after a single dose, and longer with regular injections every 2-3 months
.
What's more, the therapy achieves protein replacement
by supplementing mRNA so that autologous cells express natural products and distribute them into the skin.
This process, which occurs through the body's natural adjustment, avoids the risk of
collagen displacement, deformation, swelling, etc.
after injection.

The application of cutting-edge technology in the consumer market has also brought considerable development prospects
for Spiper's "cell-derived mRNA therapy".

According to Frost & Sullivan's data, the global non-surgical medical cosmetology market reached US$32 billion in 2021, and nearly RMB100 billion in China
.
Among them, the terminal market size of several varieties of products such as botulinum toxin, hyaluronic acid and collagen is close to 50%
of non-surgical medical cosmetology.
Global medical beauty giant Allergan's botulinum toxin products are properly secured, with global net revenue (non-terminal) of US$2.
223 billion in 2021, and US$1.
535 billion
for high-end hyaluronic acid product Joaden.
Compared with regenerated collagen products and highly competitive hyaluronic acid products, as well as botulinum toxin products with high market concentration, it is still in its infancy, but with the technological breakthrough of domestic players in recombinant collagen, the penetration rate of regenerated collagen products has grown rapidly
.
In this context, Spiper Biologics has higher safety and better therapeutic effect of "cell-derived mRNA therapy", which is undoubtedly expected to open up a tens of billions of blue ocean market
.

The transformation and application of cutting-edge technology is inseparable from the team, capital and pipeline
.

SPO has gathered a complete team
with rich experience in nanodrug delivery vehicle development, cell and gene therapy development and collaboration, and innovative drug development and industrialization.
The company has set up a team of 25 people, who are responsible for CMC, quality, clinical sample production and clinical research management
.
Dr.
Andrew Lee, co-founder of SPO Biologics, specializes in cell and gene therapy, has published more than 50 articles and led multiple cell therapies from research to clinic; Another founder, Dr.
Li Li, has more than 30 years of experience in nanoscale engineering and lipid particle formulation, and has published more than 400 articles and more than 30 patents
.
Dr.
Ni Jia, the general manager of the company, has more than 14 years of drug research and development experience in the industry and has led the development of more than 7 new drug INDs, including China's first PROTAC drug, with experience
in leading the whole process of drug development to marketing.

The pipeline application prospect full of imagination space has also enabled Sipo Biotech to successfully gain the favor
of capital.
In 2021, the company completed a series A financing
co-led by IDG Capital, Shangjun Capital and Shanda Investment.
With this funding, the first phase of GMP standard production facilities of 2,000 square meters of Sipo Biotech has been completed and put into operation
in 2022.
According to reports, the GMP standard production facility can meet the needs of phase 1-3 clinical production, and also allows Sipo Biologics to have the world's first cell-derived mRNA gene therapy production line
.
The company's clinical development pipeline has subsequently been approved by IRB to begin its first human clinical trials
in 2023.

Spiper Biologics is full of confidence in the safety and efficacy of COL1A1-EV mRNA, and plans to apply for IND in China, the United States and Australia, bringing new possibilities
to the broad anti-aging market from the perspective of gene therapy.

In fact, the scope of application of "cell-derived mRNA therapy" is not limited to the field of anti-aging
.
Cell-derived mRNA delivery represents a new universal approach to gene therapy whose potential functions also include treating diseases
caused by the loss or damage of the body's proteins.
Many rare genetic disorders are caused by missing or underexpressed genes/
proteins.
For example, dystrophin can be formed by delivering the corresponding mRNA to treat Duchenne muscular dystrophy; Rare diseases such as epidermal flarrhoea bullosa can be treated by delivering type VII collagen mRNA; It can also be used more in
tumor treatment.

Starting from the skin, Spiper Biotech will replace the collagen lost due to aging or photoaging through gene therapy, and then take rare diseases as the first indication and main direction
.
In this process, SPI also hopes to grow into a leader in the next generation of non-viral gene therapy, bringing new possibilities
to more clinical unsolved problems.