The 26th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) will be held in Los Angeles from May 16 to 20, 2023. Founded in 1996, ASGCT has over 5,000 members worldwide. It is the largest non-profit organization specializing in CGT research and also the most authoritative and credible organization in the CGT field. ASGCT gathers thousands of academics, FDA officials, industry representatives, and investors from around the world each year.
With the coexistence of opportunities and challenges in CGT R&D in China in recent years, Vitalgen has been focusing on independent innovation and encouraging its R&D, transformation and clinical teams to work together to continuously transform research into scientific and technological achievements to serve patients by addressing the urgent clinical needs. Vitalgen will present its following development covering the latest advances of the AAV gene therapy for CNS and ophthalmic diseases, CRISPR gene editing and lipid nanoparticle technology platforms on schedule at the meeting in Los Angeles on May 17-18, 2023.
AAV vector-based gene replacement therapy
An Adeno-associated Virus-based Combination Gene Replacement Therapy for Parkinson's Disease
Poster Number: 374
Presentation Date: 2023-5-17
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. The currently available treatments mainly involve the provision of dopamine derivatives instead of modifying the disease progression, and side effects such as dyskinesia caused by elevated levodopa doses make the disease progressively more difficult to manage over time. It is presumed that the progressive decrease in AADC expression in the striatum of patients with advanced PD is one of the main causes for the reduced response to levodopa, and therefore supplementation on striatal AADC has the potential to be an effective long-term treatment for PD.
VGN-R09b, as recombinant AAV9, delivers human AADC and a neurotrophic factor gene sequence that is directly distributed in the striatum. In this study, we performed several assessments of AADC and neurotrophic factor expression, animal behavioral changes and dopaminergic neuron degeneration based on a PD mouse model after intra-striatal delivery of VGN-R09b, and the results suggested that intra-striatal injection of VGN-R09b dose-dependently improved motor disturbance, protected dopaminergic neurons, and increased AADC activity in the PD animal model.
An Adeno-associated Virus-based Gene Replacement Therapy for Type II Gaucher Disease
Poster Number: 881
Presentation Date: 2023-5-18
Gaucher disease (GD) is a rare genetic metabolic disorder caused by a mutation in the glucocerebrosidase (GBA1) that results in reduced glucocerebrosidase (GCase) activity in the body's lysosomes. Type II GD (GD2) is primarily characterized by acute neurological lesions. The enzyme replacement and substrate reduction therapies currently available target only the non-neurological symptoms of GD and cannot cross the blood-brain barrier.
VGN-R08b is an AAV-based gene replacement therapy that transduces neuronal and glial cells when injected via lateral intra-cerebroventricular (ICV) injection. In a cell model of GCase dysfunction, it was shown that VGN-R08b effectively restored GCase activity. In the GD2 mouse model, VGN-R08b significantly improved the vigor, motor activity and motor coordination in the GD model mice. In the IND-enabling toxicology study, preliminary results showed that VGN-R08b was well tolerated. In addition, an investigator-initiated clinical study of VGN-R08b was initiated in March 2023 at Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, and has completed the first subject dosing recently.
Discovery and Characterization of a Safe and Efficacious Gene Replacement Therapy for Treating Bietti Crystalline Dystrophy
Poster Number: 708
Presentation Date: 2023-5-17
Bietti crystalline dystrophy (BCD) is an autosomal recessive, progressive retinal degenerative disease. The pathogenic gene for BCD is CYP4V2, which encodes a protease involved in lipid metabolism, and there is still no effective clinical treatment option available.
VGR-R01 is a ssAAV8-based gene replacement therapy that has been optimized by promoter screening and CYP4V2 gene codon optimization. High expression of functional CYP4V2 was observed both in vitro and in vivo. Strong expression of CYP4V2 with reduced lipid accumulation and attenuated EPA-induced RPE apoptosis were observed in an in vitro pharmacodynamic study of iPSC-RPE in patients with BCD, suggesting that VGR-R01 is beneficial in improving RPE cell function. In the BCD mouse model, improved visual function was found after VGR-R01 injection. And long-term expression of CYP4V2 was mainly found in ocular tissue following administration of VGR-R01, indicating tissue-specific delivery of VGR-R01. No safety concerns were identified for VGR-R01 in toxicology studies in rabbits and non-human primates.
Initial Findings of Retinal Gene Therapy in Patients With Bietti Crystalline Dystrophy
Poster Number: 803
Presentation Date: 2023-5-17
The investigator-initiated clinical trial “An Early Clinical Study of VGR-R01 in the Treatment of Bietti Crystalline Dystrophy (BCD)” (NCT05399069), conducted at Beijing Tongren Hospital Affiliated to Capital Medical University, has completed the dosing of all three subjects. The preliminary results at 3-6 month follow-up visit suggested that VGR-R01 was well tolerated and rapidly improved visual function. Safety results showed no serious adverse events (SAEs) or deaths; all adverse events were found not associated with VGR-R01; the most frequently reported AEs were amotio retinae (associated with surgery) and elevated white blood cell count (associated with prophylactic immunosuppressive therapy). Most AEs were mild in severity and recovery was found without intervention.
The multicenter, dose-escalating Phase I clinical trial of VGR-R01 (NCT05694598) was recently initiated at Beijing Tongren Hospital Affiliated to Capital Medical University (PI Prof. Wei Wenbin) and Shanghai First People's Hospital (PI Prof. Sun Xiaodong). Now the first dose group has been dosed and subject recruitment is still under way.
CRISPR gene editing technology platform
Enhanced AaCas12bMax-Mediated Disruption of a cis-Element in HBG promoter to Generate HPFH Mutations in HSPCs for the Treatment of β-Thalassemia
Poster Number: 1239
Presentation Date: 2023-5-18
Beta-thalassemia is an inherited blood disorder caused by a series of genetic mutations that result in insufficient production of beta hemoglobin. Re-activation of HbF expression in erythroid cells by CRISPR/Cas system editing of hematopoietic stem cells provides an effective and durable treatment for transfusion-dependent beta-thalassemia, with lifelong benefits for patients receiving one treatment.
This study evaluated the efficacy and safety of gene editing of HSPC using a V-B type CRISPR nuclease (AaCas12bMax) with proprietary intellectual property in combination with single-stranded guide RNA (sgRNA) for the treatment of beta-thalassemia. Highly efficient gene editing of LRF binding sites upstream of HBG1/2 was achieved in HSPC from healthy donors and beta-thalassemia patients (both above 90%). It was highly specific for target site editing, and no off-target gene editing was detected at all predicted potential off-target sites by assessment based on a combination of multiple methods. And edited HSPC maintained their normal implantation and genealogical differentiation potential after transplantation into immunodeficient mice compared to unedited HSPC, and a significant increase in HbF protein levels was also observed in erythroid cells derived from edited HSPC. In conclusion, the AaCas12bMax gene editing system developed by Vitalgen with independent intellectual property shows great potential in the treatment of beta-thalassemia.
Lipid nanoparticle technology platform
Rational Designed Cationic Ionizable Lipids with Unique Hyperbranched Structures Exhibited Excellent in vivo Nucleic Acid Delivery Efficiency
Poster Number: 987
Presentation Date: 2023-5-18
Lipid nanoparticles (LNPs) have been extremely successful in nucleic acid-based drug delivery, and LNPs are currently the fastest advancing clinical delivery strategy for in vivo gene editing. CRISPR therapies based on LNP delivery strategies have demonstrated good editing efficiency in early clinical trials, however, extremely high doses (tens of milligram levels) are required. The efficiency of LNP delivery can be improved by enhancing the cationic lipid molecule-mediated lysosomal escape. Based on the hexagonal II phase transition theory, a series of cationic lipid molecule libraries of a completely new structure with independent intellectual property rights were synthesized and screened following rational design and iterative screening strategies. Lipid candidate VG-L52715 showed at least a 10-fold increase in delivery efficiency in mice and rats compared to the FDA-approved LNP prescriptions. VG-L52715 also exhibited an ideal safety and metabolic profile. Only 0.03% of unmetabolized VG-L52715 was found to remain in liver tissue 24 h after IV injection. Gene-editing drugs based on this delivery system are under further evaluation at present. The extremely high delivery efficiency and metabolic profile also facilitate the use of this LNP system for long-term, high-dose, and high-frequency repeat dosing.
