Key Advances Unveiled at the 25th ASGCT Annual Meeting: Heart Failure Gene Therapy, Non-Viral Editing, and More

Today, the 25th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) has opened. Gene and cell therapies are emerging treatment modalities with the potential to deliver long-lasting effects and even cures through a single treatment. The ASGCT Annual Meeting brings together the latest cutting-edge research in the field of gene and cell therapy. In this article today, the WuXi AppTec content team will share the latest results presented at the ASGCT Annual Meeting with readers.

AskBio Announces First Clinical Trial Results of Gene Therapy for Heart Failure

Asklepios BioPharmaceutical announced the first human clinical trial results of its heart failure gene therapy developed based on the innovative AAV2i8 adenovirus-associated vector. The AAV2i8 vector is an AAV vector that targets the heart for transfection without transfecting the liver. This gene therapy expresses a continuously activated protein phosphatase 1 inhibitor.

Preliminary clinical trial results show that no adverse events related to the investigational therapy were observed in the 3 heart failure patients treated with gene therapy during the 12-month observation period. In terms of efficacy, compared to baseline, all 3 patients achieved clinically meaningful improvements in endpoints such as left ventricular ejection fraction and NYHA heart failure class scores. For specific results, please refer to the table below:

Image Source: Reference [3]

One-step completion of multiple gene editing processes shows potential for non-viral gene editing platforms

PACT Pharma Presents New Data for its Non-Viral Precision Gene Editing Technology PACT^NV. This platform utilizes CRISPR-Cas9 gene editing technology to perform multiple gene edits simultaneously in a single step within the T-cell genome. It can not only knock out the expression of endogenous T-cell receptors (TCRs) in T cells, but also introduce transgenes at the endogenous TRAC locus of the genome to express engineered TCRs targeting patient neoantigens.

▲Introduction to the PACT^NV Technology Platform (Image Source: PACT Pharma's Official Website)

Data presented at the ASGCT annual meeting showed that this system not only knocked out the expression of endogenous TCR, expressed TCR targeting patient neoantigens, but also knocked out the gene expressing TGF-β receptor 2. This means that the resulting T-cell therapy can not only specifically recognize the patient's tumor but also resist TGF-β-mediated immunosuppressive signals. Currently, the company is conducting a Phase 1 clinical trial to evaluate the efficacy of autologous TCR-T cell therapy manufactured using PACT^NV in patients with advanced and metastatic solid tumors.

Rocket Pharmaceuticals' Three Gene Therapies Achieve Positive Progress

Rocket Pharmaceuticals Announces Positive Results from Pivotal Phase 2 Clinical Trial of Gene Therapy RP-L102 for Fanconi Anemia. Mutations in the FANCA gene, which encodes a protein crucial for DNA repair, are found in 60-70% of Fanconi anemia patients. Mutations in the FANCA gene cause chromosomal breakage and increase sensitivity to oxidative and environmental stress. Patients are prone to bone marrow dysfunction and cancer susceptibility.

RP-L102 is a gene therapy that uses a lentiviral vector to deliver the normal FANCA gene and modifies hematopoietic stem cells in vitro. Trial results showed that among the 9 treated patients, 5 exhibited resistance of bone marrow cells to the DNA-damaging agent MMC, indicating enhanced DNA damage repair capability in the patients' bone marrow cells.

In addition, Rocket Pharmaceuticals' gene therapies for Danon Disease and pyruvate kinase deficiency also demonstrated good safety in Phase 1 clinical trials.

Knocking Down Target Protein Expression by 98%, Homing Endonuclease Genome Editing Technology Shows Promise

Precision BioSciences Presents Multiple Preclinical Studies of its ARCUS Genome Editing Technology Platform at the ASGCT Annual Meeting. The ARCUS genome editing technology platform is based on a natural homing endonuclease called I-CreI, designed to knock in, knock out, or repair DNA in living cells and organisms. This endonuclease, classified as a meganuclease, performs highly specific cuts in cellular DNA. It achieves cleavage by recognizing a target sequence comprising 22 base pairs, and due to the longer target sequence, off-target editing is minimized. Additionally, it automatically deactivates after editing, further reducing the risk of off-target effects. Moreover, its small size—only 364 amino acids—makes it easier to deliver to tissues or cells using either viral or non-viral delivery methods.

Image Source: Precision BioSciences Official Website

In non-human primate models, the company's optimized ARCUS nuclease was able to knock down the expression level of the target protein HAO1 by 98%, demonstrating its highly efficient in vivo gene editing capability. The HAO1 protein is a key target for treating Primary Hyperoxaluria Type 1 (PH1).

In addition, the company's gene-editing therapy for clearing the hepatitis B virus effectively targets and degrades covalently closed circular DNA (cccDNA) of the hepatitis B virus in primary human hepatocytes, reducing the expression of hepatitis B surface antigen (HBsAg) by 77%. Dr. Derek Jantz, the company's chief scientific officer, stated that these results demonstrate the high efficiency and flexibility of the ARUCS gene-editing system.

Gene Therapy Expressing Therapeutic Antibodies Achieves Proof of Concept in Treating Brain Metastases

Voyager Therapeutics Announces Preclinical Proof-of-Concept Data for VCAP-102, a Gene Therapy Expressing Anti-HER2 AntibodiesVoyager Therapeutics has announced preclinical proof-of-concept data for its gene therapy, VCAP-102, which expresses anti-HER2 antibodies. This therapy utilizes its TRACER AAV9 vector to deliver a transgene encoding anti-HER2 antibodies. The vector is capable of crossing the blood-brain barrier to express anti-HER2 antibodies in the central nervous system, making it potentially useful for treating brain metastases in patients with HER2-positive breast cancer.

In three different HER2-positive breast cancer mouse models, a single VCAP-102 treatment significantly reduced CNS tumor burden in animals and extended their survival. The median survival of animals receiving gene therapy was 129 days, compared to 94 days in the control group.

References:

[1] AskBio and you shall receive as the Bayer-backed gene therapy maker touts early phase 1 data. Retrieved May 16, 2022, from https://www.fiercebiotech.com/research/early-data-askbios-cardiac-gene-therapy-turns-heads-including-among-its-developers

[2] AskBio to Present 11 Abstracts at Upcoming American Society of Gene and Cell Therapy’s 25th Annual Meeting. Retrieved May 16, 2022, from https://www.askbio.com/askbio-to-present-11-abstracts-at-upcoming-american-society-of-gene-and-cell-therapys-25th-annual-meeting/

[3] A First-in-Human Phase 1 Clinical Gene Therapy Trial for the Treatment of Heart Failure Using a Novel Re-Engineered Adeno-Associated Vector. Retrieved May 16, 2022, from https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=6156

[4] PACT Pharma Highlights Capabilities and Versatility of Novel Non-Viral Gene Editing Technology in Presentation at American Society of Gene & Cell Therapy (ASGCT) 25th Annual Meeting. Retrieved May 16, 2022, from https://www.prnewswire.com/news-releases/pact-pharma-highlights-capabilities-and-versatility-of-novel-non-viral-gene-editing-technology-in-presentation-at-american-society-of-gene--cell-therapy-asgct-25th-annual-meeting-301547277.html

[5] A Versatile, Non-Viral Gene Editing Method for Directing Specificity and Enhancing Function of T Cells. Retrieved May 16, 2022, from https://storage.googleapis.com/pact-assets/ASGCT-2022-Lu/ASGCT-2022-Lu.pdf

[6] Precision BioSciences Announces Preclinical Data Showcasing Premier In Vivo Gene Editing Capabilities at American Society of Gene & Cell Therapy Annual Meeting. Retrieved May 16, 2022, from https://investor.precisionbiosciences.com/news-releases/news-release-details/precision-biosciences-announces-preclinical-data-showcasing

[7] Voyager Therapeutics to Present Preclinical Data from its Vectorized anti-HER2 Antibody Program and a Novel AAV5-Derived TRACER™ Capsid at the 25th American Society of Gene and Cell Therapy Annual Meeting. Retrieved May 16, 2022, from https://ir.voyagertherapeutics.com/news-releases/news-release-details/voyager-therapeutics-present-preclinical-data-its-vectorized

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