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December 20, 2022 / PharmaBIGStar
News/-- As a multifunctional gene editing technology, CRISPR has brought unlimited imagination to gene therapy, and in recent years, the practice of modifying target cells through the use of CRISPR tools in vitro has been widely used, and many related products have entered clinical development
.
But the charm of gene editing is much more than that, and it is the most fascinating thing
that delivers gene editing tools to the body through suitable vectors for direct gene repair to achieve the purpose of radical disease.
However, the application of traditional CRISPR systems in vivo has been limited
due to poor editing efficiency and accuracy, excessive volume and lack of suitable delivery carriers.
Fortunately, in recent years, a variety of new gene editing tools have been developed successively, such as base editors, PRIME editing systems, casX and other more accurate and compact editing tools, coupled with the development of AAV, LNP, VLP and other delivery systems, in vivo gene editing therapy has finally entered the clinic
.
In 2021, Intellia's NTLA-2001 was the first to enter the clinic for the treatment of ATTR patients through an LNP-loaded CRISPR gene editing system targeting TTR genes, creating a precedent
for in vivo gene editing therapy.
At present, 4 in vivo gene editing therapies have entered the registered clinical trial worldwide, and more drug candidates are still in development
.
▲ The world's most advanced in vivo gene editing therapy
▲ In vivo gene editing therapy with the world's top progress▲In recent years, a number of enterprises committed to the development of advanced gene editing therapies have emerged in China, including Bangyao Biotechnology, Boyajiin, Ruifeng Biotechnology, Yinzheng Gene, Ben Lead Gene, Huida Gene, Sprout Gene, Ruizheng Gene, Orthodox Bio, Yaotang Biotechnology, Kejin Biotechnology, Yijielike and other more than 10 companies, each of which has its own unique gene editing system, according to public information, most of them have laid out in vivo gene editing therapy development
.
▲ Domestic in vivo gene editing therapy development enterprises (in no particular order)
▲ Domestic in vivo gene editing therapy development enterprises▲ (in no particular order)Boyajiin
BoyajiinBoyaa Gene has built four platforms based on gene editing technology: a hematopoietic stem cell platform and a universal CAR-T platform for in vitro therapy, an RNA base editing platform for in vivo therapy, and a new drug development platform
for high-energy genome editing screening.
Among them, the RNA single-base editing technology LEAPER™ uses specially designed arRNA (ADAR-recruiting RNA) to recruit endogenous ADAR proteins (adenosine deaminase) to convert specific adenosine into inosine to achieve efficient and accurate editing
of RNA 。 In February this year, Professor Wei Wensheng, founder of Boya Gene Science and Peking University, was in the laboratory
The journal Nature Biotechnology published an article that upgraded LEAPER, designing the arRNA that recruits ADAR into a circular shape to make LEAPER™™
The efficiency and accuracy of in vivo editing in 2.
0 have been further improved
.
In this study, the researchers conducted a proof-of-concept
in human primary cells and organoids using AAV as a vector.
Based on this technology, Boya Genesis is developing therapies for the most severe subtype of mucopolysaccharidosis type I, Hurler syndrome, the nervous system, and diseases such as the liver and muscles, which are still under
research.
At the same time, the company has also cooperated with Professor Sui Ruifang's team at Peking Union Medical College Hospital and the University of Wisconsin-Madison and other scientific research institutions to carry out clinical development
of in vivo gene editing therapy.
Bencade
BencadeThis guide gene has the world's leading innovative gene introduction platform BDlenti and gene editing platform BDmRNA, which use viroid VLP for in vivo delivery, and can ensure the transient expression of gene editing enzymes in vivo (degradation within 72 hours), reduce the probability of gene editing off-target, and improve the safety of
gene editing drugs.
▲ BDmRNA platform (Source: Company official website)
▲ BDmRNA platform (Source: Company official website)Based on the patented technology of BDmRNA gene editing and delivery, this gene has developed a series of pipelines, of which BD111 has the fastest progress, has entered the registration clinical study application stage, and obtained the US FDA orphan drug approval in June 2022 for the treatment of herpesvirus keratitis
.
BD111 delivers CRISPR/Cas9 through the original VLP delivery of this guide to target the genome of HSV-1 of herpes simplex virus, thereby clearing the HSV-1 virus genome and achieving therapeutic purposes
.
At present, the therapy has completed 3 IIT human clinical trials, which is also the second drug candidate in the world to use CRISPR gene editing in the human body
.
Huida Gene
Huida GeneHuida Gene was founded in 2018 by Dr.
Yang Hui and Dr.
Yao Xuan, and the two founding teams discovered two families of RNA editing tools Cas13X and Cas13Y in 2019, which are currently the smallest Cas13 proteins, with knock-down activity close to 100% in vitro tests and an editing efficiency of about 95%
in vivo.
Cas13X/Y can do RNA knock
down, can also be modified to bind to deaminase to achieve RNA single-base editing, and the editing efficiency is close to 80%.
In January 2022, the underlying patent for the technology was officially granted by the U.
S.
Patent Office
.
Based on the CRISPR-Cas13X/Y editing tool, Huida has two pipelines that have entered the IND declaration stage, namely for congenital black montosis type 2 (LCA2) and age-related wet macular degeneration (wet
AMD), using a new AAV serotype for in vivo delivery
.
In addition to RNA editing tools, HuiEdit, a sub-brand of Huida Group, has also developed the DNA editor Cas12Max, which requires only one AAV vector for package delivery
.
In November this year, the Huida Genomics R&D team published an online report entitled "An engineered xCas12i with high" in the journal Protein & Cell
activity, high specificity and broad PAM
range", the previously independently developed DNA editing tool xCas12i protein engineering modification, screening and verification, developed a high-fidelity xCas12i variant with efficient targeted editing activity but extremely low off-target editing activity, also known as hfCas12Max, which can be expected
in the future.
Ruifeng Biotechnology
Ruifeng BiotechnologyRuifeng Biotech is a leading gene editing drug innovation enterprise in China, driven by gene editing technology as the core, and is committed to the birth
of innovative drugs.
At present, there are pipeline layouts
in the fields of genetic diseases, complex diseases and tumors.
Ruifeng Bio's gene editing technology covers both DNA and RNA editing, and has a series of intellectual property CRISPR gene editing tool systems, including: knock
out, knock in, knock down, base editing, and apparent modification
.
According to the company's official website, there are currently a number of in vivo gene editing therapies under development, the specific information has not been disclosed
.
Sprout genes
Sprout genesSprout Gene has the global rights of base editor TAM with independent intellectual property rights (TAM BE base editor technology platform
), is also one of the very few gene therapy companies in the world to use base editing technology for systemic drug delivery, and completed tens of millions of dollars in Series A financing
on November 18, 2022.
▲ TAM Schematic diagram of BE structure (Source: Official website)
▲ TAM Schematic diagram of BE structure (Source: Official website)On September 27, 2022, Sprout Genomics announced that it has entered into a strategic cooperation agreement with WuXi Biologics to provide process development, analytical method development and validation, batch production, and related application document writing services for Sprout's first AAV new drug
.
The first gene editing product independently developed by Sprout Gene, indicated for Duchenne muscular dystrophy (DMD) series of gene mutation diseases
.
Orthodox organisms
Orthodox organismsOrthobio is a biomedical technology company focused on novel gene editing technology, based on variable form base editor tBE (transformer base
Editor), the independent IP base editing system has built a new drug discovery platform that integrates multiple therapeutic fields, which can develop and screen effective therapeutic targets for a variety of genetic diseases or rare diseases for a long time
.
In November 2022, the company completed a new round of financing
of nearly 300 million yuan.
In July 2022, the variable base editing system tBE was officially granted by the United States Patent and Trademark Office (USPTO), becoming the first Chinese-developed base editing tool
independently developed by China to obtain overseas patent authorization.
According to the company's official website, compared with Cas enzyme and general base editing, the new base editing therapy created by tBE has the safest anti-off-target guarantee, higher targeted editing efficiency, better therapeutic effect and lower cytotoxicity
.
▲ Variable form base editing system (source: company official website) The company has created a variety of precision gene editing therapies, which have achieved efficient editing efficiency on disease treatment targets in animals and safety
of undetected off-target.
At present, nearly 10 pipelines in vivo and in vitro have been laid out for genetic diseases, tumors, metabolic diseases, infectious diseases, etc.
, among which in vitro tBE base editing therapy for the treatment of β thalassemia is expected to be declared for IND
in 2023.
Sharp Gene
Sharp GeneFounded in July 2021 by Dr.
Wang Yongzhong, Regent is committed to developing innovative drugs and treatment
options for gene editing in vivo.
Based on the classic CRISPR/Cas9 and LNP technologies, the company has basically opened up RNA
Technology, gene editing and delivery, the first product developed by the three core technology platforms has applied for relevant patents
.
At the same time, Regent is laying out a new generation of gene editing and delivery technology, and plans to complete IND by the end of 2023
Declaration
.
Earlier this year, the company formed a joint venture with N1 Life, a Stanford university-based biotechnology company focused on innovative drug delivery and drug delivery technologies, to jointly develop a larger LNP than the existing LNP
Delivery technologies
that are less toxic, more efficient and can target more organs.
Yaotang Biology
Yaotang BiologyYaotang Biotech is a high-tech biotechnology company
focusing on the development of next-generation mRNA drugs and gene editing drugs by combining mRNA in vivo delivery technology and gene editing technology.
Yaotang Biotech develops in vivo gene editing drugs
for genetic diseases and cardiovascular diseases mainly through the continuous development and optimization of CRISPR-Cas, base editing and other next-generation gene editing tools, as well as innovative improvements to the next-generation mRNA production platform and lipid nanocarrier LNP assembly process.
The company focuses on the development of a new generation of gene editing tools represented by base editing, fully realizes various functions such as gene deletion, replacement, and insertion through a variety of gene editing strategy choices, and realizes rapid iteration of gene editing tools through high-throughput new editing tool mining and high-throughput molecular evolution platform, improving gene editing efficiency and safety; And continue to develop a variety of liposome materials that can obtain independent property rights, and enrich the delivery vehicles
targeting the liver and other tissues and organs.
In vivo delivery based on mRNA-LNP is well suited for transient expression of gene editing tools, enabling efficient gene editing while effectively reducing the risk of
off-targeting.
▲ Yaotang biological gene editing technology (source: company official website)
▲ Yaotang biological gene editing technology (source: company official website)Positive genes
Positive genesFounded in Beijing in 2021, Yinzheng Gene has the world's leading off-target evaluation technology platform with independent intellectual property rights, and is committed to applying this platform technology to the development of safer and more accurate gene-editing drugs, and completed tens of millions of dollars in angel round and pre-A round financing
in May this year.
Positive Gene focuses on development based on CRISPR
The next generation of gene editing tools improves the efficiency and accuracy of gene editing, reduces off-target effects, and forms certain patent barriers
.
At the same time, the company is also developing a new generation of more accurate and diversified gene editing tools to strengthen the company's leading position
in the field of gene editing tools.
At present, the company has successfully developed a series of core underlying technologies
such as a new generation off-target evaluation system and a new generation gene editor.
Relying on the advantages of the underlying technology, Yinzheng Gene takes in vivo gene-editing drugs as the core research and development field, builds a high-throughput drug screening platform and drug evaluation system, and has advanced LNP
Delivery technology companies form partnerships to develop LNP-based in vivo drug delivery systems
.
Ideco
IdecoAccording to public information, the first and only company committed to the development of epigenetic editing therapy in China completed an angel round and pre-A round of financing of $20 million in the first half of this year
.
The company's patented technology platform continues to explore through its developed artificial intelligence algorithms to obtain better CRISPR-Cas components, combined with epigenetic modification enzymes (
epi-enzymes), which regulate the expression of target genes or manipulate the expression
of multiple genes at the same time without changing the DNA sequence.
Combined with its own patented lipid nanoparticle LNP delivery system, the company has now laid out multiple pipelines
.
▲ Egeric's proprietary epigenetic editor (Source: Company official website)
▲ Egeric's proprietary epigenetic editor (Source: Company official website)summary
summaryAlthough no gene-editing therapy has yet been approved for marketing, a variety of gene-editing tools derived from CRISPR are bound to bring great healing potential
for genetic diseases in the future.
According to publicly available information, by Vertex and CRISPR
Exa-cel, the CRISPR gene-editing therapy developed by Therapeutics to treat transfusion-dependent β thalassemia and sickle cell anemia, is expected to be filed before the end of this year, an important step
in CRISPR gene-editing therapy.
The therapy for gene editing directly in the body is that scientists are climbing another mountain, although research and development is not easy, there are many bumps, but it is still worth looking forward to!
Resources:
Resources:
1.
Company official website
Company official website
