As of November 22, 2022, the US FDA announced the approval of the AAV gene therapy Hemgenix (AMT-061, CSL222) developed by uniQure and CSL Behring, which is the first FDA-approved gene therapy for adult patients with hemophilia B. It is also the sixth AAV gene therapy to be launched so far. At the same time, as of the end of 2022, there are more than 300 AAV gene therapy drugs in the clinical research stage in the world, of which 14 are in the clinical phase 3 and above, mainly focusing on rare diseases, hemophilia, ophthalmic diseases and other fields.
[1] Cancer Cell: AAV therapy helps the immune system treat brain tumors
2023-05-17 reported that recently, researchers from Uppsala University published a research paper entitled: Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma in the journal Cancer Cell.
The study developed a way to help killer T cells reach brain tumors and fight cancer cells. Using an adeno-associated virus (AAV) vector that specifically infects blood vessels in the brain, they express a factor called LIGHT. This altered tumor vascular function, increasing their ability to transport T cells from the blood to tumor tissue, thereby improving the efficacy of immunotherapy-resistant glial blasts.
This study demonstrates that systemic AAV-LIGHT treatment induces tumor-associated hyperendothelial venules (HEVs) and T-cell-rich tertiary lymphoid structures (TLS), prolonging the gel of resistance to anti-PD-1 mAb therapy. Survival in a mouse model of glioblastoma. AAV-LIGHT treatment also reduced T-cell exhaustion and promoted TCF1+CD8+ stem-like T cells that reside in the TLS and intratumoral antigen-presenting niches. Tumor regression after AAV-LIGHT treatment correlates with tumor-specific cytotoxic/memory T cell responses. This suggests that altering vascular phenotype through vascular-targeted expression of LIGHT can promote potent antitumor T cell responses and prolong glioma survival. These findings have broader implications for the treatment of other immunotherapy-resistant cancers.
原文：Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma
[2] Going deep into the brain: Novartis continues to invest in the development of CNS-targeted AAV gene therapy
2023-03-08 reported that on March 8, 2022, Novartis and AAV carrier development company Voyager Therapeutics announced that they had reached a total of US$1.75 billion in cooperation. Novartis will provide Voyager with an advance payment of US$54 million and up to US$17 million in milestone payments and royalties. This cooperation includes the authorization of AAV capsids for 3 central nervous system (CNS) targets, and the option to use AAV capsids for other 2 CNS targets within one year. One year later, on March 6, 2023, Novartis decided to exercise the above option and pay an additional US$25 million upfront payment on top of the original US$54 million upfront payment. Voyager is also eligible to receive up to US$600 million in related potential Development, regulatory and commercial milestone payments, and related product royalties. Dr. Al Sandrock, CEO of Voyager, said that Novartis had successfully developed the AAV gene therapy Zolgensma and was approved by the FDA for marketing. It is very important to us that a company like Novartis scrutinized our AAV capsid and chose to continue investing after a year of evaluation.
Based on the above cooperation, Novartis will obtain Voyager's proprietary RNA-driven TRACER capsid discovery program and the development rights of specific AAV capsids. Novartis hopes to develop new AAV vectors that break through the blood-brain barrier and target the central nervous system through these collaborations , to treat those diseases deep in the brain.
【3】Science sub-journal: AAV delivers miniature DMD gene to treat DMD golden retriever model
2023-01-12 Report, recently, researchers from Texas A&M University, University of Florida and Solid Biosciences published a study titled: Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy in the journal Science Translational Medicine paper.
The study showed that the mini-Dystrophin gene delivered by AAV can improve the symptoms of the golden retriever muscular dystrophy (GRMD) model without serious adverse events. This suggests that systemic administration of Dystrophin protein via AAV may be a safe gene therapy that provides therapeutic benefit to DMD patients.
原文：Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy
【4】Liu Ruqian's team developed dual AAV vectors, realizing efficient lead editing of multiple organs in vivo for the first time
Reported on 2023-05-09, on May 4, 2023, Liu Ruqian's team published a research paper entitled: Efficient prime editing in mouse brain, liver and heart with dual AAVs in the journal Nature Biotechnology. The study developed an optimized dual AAV delivery system, which achieved unprecedented high-efficiency in vivo lead editing, achieving an editing efficiency as high as 42% in the mouse brain and 46% in the liver. The efficiency of this method has been increased by about 10 times, opening the door for the research and treatment of genetic diseases.
Overall, this study developed and optimized a dual AAV vector system for in vivo delivery of lead editing, achieving the highest potency of in vivo lead editing efficiency in multiple organs in mice, providing a foundation for basic research on lead editing and therapy development has laid a solid foundation.
[5] A new method for generating AAV capsid library based on AI, with a prediction success rate of nearly 90%
2023-05-15 Report, recently, the Broad Institute of MIT and Harvard (Broad Institute of MIT and Harvard) official website issued a press release, introducing how its carrier engineering laboratory solves key problems in gene therapy by combining machine learning methods - Delivery vehicle. The research results have been uploaded to the preprint platform bioRXiv. The scientific research team described in detail the new general machine learning method for engineering multi-trait AAV capsids developed by it - Fit4Function, which generates reproducible screening data through uniformly collected sequence space capsid libraries, so as to train sequence-to-function exact model. And according to six predetermined criteria, different types of libraries generated were verified, and the prediction success rate reached 89%.
According to the press release, the Fit4Function strategy finally makes it possible to predict the universality of AAV capsids in multiple species, and is a key step in the development of machine learning maps that can predict the effect of AAV capsids in dozens of species. This technology has the potential to accelerate the development of innovative gene therapies for more diseases with fewer side effects. The corresponding author of the study is Dr. Benjamin Deverman, and the first and co-corresponding author is Dr. Fatma-Elzahraa Eid. Fatma-Elzahraa Eid noted that the approach was like opening a gold mine, and the results were very exciting. "Machine Learning May Be the Optimal Solution to Protein Engineering Challenges"
[6] Synthetic biology giant Ginkgo acquires AAV vector development company StrideBio to strengthen its gene therapy capabilities
2023-04-07 It was reported that a few days ago, the synthetic biology giant Ginkgo announced the acquisition of StrideBio, an AAV vector development company. This acquisition will bring StrideBio’s AAV capsid discovery and engineering platform STRIVE into Ginkgo’s banner. The specific amount of the acquisition is currently unknown. unknown. As a synthetic biology platform company, Ginkgo doesn't want to develop a biotech therapy, but it wants to create a platform for therapeutics, which is why Ginkgo acquired StrideBio.
In Ginkgo's view, no matter whether a drug is ultimately successful or not, once a drug candidate is available, all resources are directed to the drug candidate and its research and development work, and the platform technology for creating the drug is often overlooked. And if the drug fails, it's usually thought to be a platform problem. What Ginkgo wants to do is to dust off the technology of these neglected platforms and apply the right technology to complex models such as cell therapy and gene therapy. Ginkgo is more interested in StrideBio's intellectual property than its gene therapy manufacturing facility or its core preclinical pipeline for arrhythmogenic right ventricular cardiomyopathy (ARVC), which it will license or sell to partners , Ginkgo will not advance them to the clinical stage.
【7】STTT: Wei Yuquan/Yang Yang/Lu Fang team develops double AAV vector lead editing to treat hereditary blindness
Reported on 2023-02-10, recently, Academician Wei Yuquan, Researcher Yang Yang, and Professor Lu Fang of West China Hospital of Sichuan University published a paper titled: Dual-AAV split prime editor corrects the mutation and phenotype in mice with inherited in the journal Signal Transduction and Targeted Therapy research paper on retinal degeneration. Based on the split intein and double AAV vector, the study optimized the lead editor (PE) and treated the mouse model of congenital amaurosis with precision and efficiency (the highest editing efficiency reached 16 %) repaired the causative gene mutation in mouse retinal cells, restored the expression of RPE65 protein, rescued retinal and visual function, and no off-target editing was detected. This research lays the foundation for the treatment of inherited retinal diseases (IRDs) through lead editing.
Overall, this study demonstrated efficient and precise gene expression in a mouse model of congenital amaurosis with a nonsense mutation in the Rep65 gene by optimizing a lead editor based on a split intein and a double AAV vector. treatment, and achieved a considerable degree of vision recovery and maintenance. This demonstrates the clinical potential of lead editing to correct genetic mutations that cause inherited retinal diseases (IRDs) and restore visual function. This also provides insight into the preclinical development of lead editing therapies for other inherited retinal diseases (IRDs) caused by different mutations.
[8] AAV gene therapy for hemophilia may increase the risk of liver cancer in patients
Reported on 2022-12-14, the journal Molecular Therapy recently published a research paper entitled: Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma. Liver cancer is one of the malignant tumors with the highest incidence rate, and there are still many mysteries about the cause of liver cancer, but this study shows for the first time that misfolded proteins in liver cells play a key role in liver cancer. Expression and misfolding of ectopic coagulation factor VIII in hepatocytes is one of the causes of HCC, suggesting to us that gene therapy for hemophilia A may increase the risk of HCC in some patients after years of treatment.
The study found a direct link between factor VIII misfolding and the development of liver cancer. suggests to us that gene therapy for hemophilia A may increase the risk of liver cancer in some patients after years of treatment. Therefore, the research team suggests that close monitoring of hemophilia A patients receiving gene therapy and the development of better folded factor VIII variants that can be used in gene therapy applications are needed to reduce the risk of liver cancer in patients.
[9] Sub-journal of Nature: Feng Bo's team achieved low-dose AAV delivery of CRISPR gene knock-in for the treatment of genetic diseases
2022-12-02, recently, Feng Bo's team from the Chinese University of Hong Kong published a paper entitled: Low-dose AAV-CRISPR-mediated liver-specific knock-in restored hemostasis in neonatal hemophilia B mice with subtle antibody response in the journal Nature Communications Research Papers.
The research team systematically studied the AAV-CRISPR-mediated knock-in of NHEJ genes in vivo, achieved effective and lower and safer doses of AAV, and achieved effective human source in adult and neonatal mouse hemophilia type B models Knocking in the F9 gene restores the expression of coagulation factor IX, thereby restoring the coagulation function of hemophilia B mice. It is worth mentioning that in neonatal mice that received low doses of AAV-CRISPR, anti-Cas9 and anti-AAV plasma antibodies were almost negligible, which provides a basis for the treatment of genetic diseases by AAV-CRISPR-mediated somatic gene knock-in. support.
原文：Low-dose AAV-CRISPR-mediated liver-specific knock-in restored hemostasis in neonatal hemophilia B mice with subtle antibody response
[10] FDA approves an adenovirus gene therapy for the treatment of bladder cancer
According to a report on 2022-12-19, Dr. Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, said that this approval provides healthcare professionals with an innovative treatment option for high-risk non-muscularis that does not respond to BCG treatment. patients with invasive bladder cancer. This approval addresses an area of urgent need. The FDA remains committed to advancing the development and approval of safe and effective cancer treatments.
The safety and efficacy data of the approved Adstiladrin therapy came from a multicenter clinical trial, which included 157 patients with high-risk BCG non-responsive NMIBC, 98 of whom had BCG non-responsive carcinoma in situ with or without with papillary tumors. Patients received Adstiladrin, injected into the bladder via a urinary catheter, every three months for 12 months or until unacceptable toxicity to treatment or recurrent high-grade NMIBC. Adstiladrin therapy uses a non-replicating adenoviral vector to express the interferon α-2b gene, which is injected into the bladder once every three months through a catheter, causing cells in the bladder wall to produce interferon α-2b protein. Parietal cells transform into microfactories that produce interferon, boosting the body's natural defenses against cancer. Overall, 51 percent of patients achieved a complete response (disappearance of all signs of cancer seen on cystoscopy, tissue biopsy and urine) after receiving Adstiladrin, with a median duration of response of 9.7 months and 46 percent of patients receiving Adstiladrin. Responders remain in complete remission for at least one year. The most common adverse reactions associated with Adstiladrin treatment included bladder voiding, fatigue, bladder spasms, urgency, hematuria, chills, pyrexia, and dysuria.
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