Human Gene Therapy Clinical Development最新文献

Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector AGTC-501, also designated AAV2tYF-GRK1-RPGRco, to treat retinitis pigmentosa (RP) in patients with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. The vector contains a codon-optimized human RPGR cDNA (RPGRco) driven by a photoreceptor-specific promoter (G protein-coupled receptor kinase 1, GRK1) and is packaged in an AAV2 capsid with three surface tyrosine residues changed to phenylalanine (AAV2tYF). We conducted a safety and potency study of this vector administered by subretinal a injection in the naturally occurring RPGR-deficient Rd9 mouse model. Sixty Rd9 mice (20 per group) received a subretinal injection in the right eye of vehicle (control) or AAV2tYF-GRK1-RPGRco at one of two dose levels (4 × 10⁸ or 4 × 10⁹ vg/eye) and were followed for 12 weeks after injection. Vector injections were well tolerated, with no systemic toxicity. There was a trend towards reduced electroretinography b-wave amplitudes in the high vector dose group that was not statistically significant. There were no clinically important changes in hematology or clinical chemistry parameters and no vector-related ocular changes in life or by histological examination. Dose-dependent RPGR protein expression, mainly in the inner segment of photoreceptors and the adjacent connecting cilium region, was observed in all vector-treated eyes examined. Sequence integrity of the codon-optimized RPGR was confirmed by sequencing of PCR-amplified DNA, or cDNA reverse transcribed from total RNA extracted from vector-treated retinal tissues, and by sequencing of RPGR protein obtained from transfected HEK 293 cells. These results support the use of rAAV2tYF-GRK1-RPGRco in clinical studies in patients with XLRP caused by RPGR mutations.

The era of gene therapy has begun. In recent years, potentially breakthrough datasets and rapidly expanding company pipelines have begun to overshadow the unfulfilled promise characteristic of the gene therapy sector in decades prior. One barometer for progress in the space can be seen in stock markets, where NASDAQ-listed in vivo gene therapy companies we follow have increased from 4 companies with $1.9 billion in market capitalization on January 31, 2014, to 24 companies with $30.5 billion in market capitalization on October 31, 2018. For many in the financial community, a tangible signal for the emergence of the broader gene therapy space is the recent notable mergers and acquisitions activity, a signal that previously heralded the arrival of blockbuster biotechnologies like monoclonal antibodies. Notably, Novartis' $8.7 billion acquisition of in vivo adeno-associated virus 9-based gene therapy player, AveXis, earlier this year has focused many on looking for new investment opportunities in the space, thereby increasing interest in the valuation of gene therapy companies. This perspective discusses the theoretical underpinnings of company valuation and explains why traditional approaches have limitations when valuing in vivo gene therapy companies, which produce single treatments that may achieve durable or curative benefits. We use the AveXis case study to illustrate certain points on the valuation of breakthrough innovation that we think have broader applicability throughout the in vivo gene therapy space. This publication is the first in a three-part series. Future discussions in this series on in vivo gene therapy companies will explore real-world approaches and considerations that have already proven successful in mitigating the limitations of traditional valuation approaches as well as those that may soon emerge.

MicroRNAs (miRNAs) are widely expressed and regulate most biological functions. According to several research groups, miR-451 expression is decreased in glioma cells. A previous study also confirmed that miRNA-451 inhibits the PI3K/AKT signaling pathway by directly targeting CAB39, which inhibits glioma cell growth and proliferation and induces apoptosis. However, the specific regulatory mechanism is unclear. Mammalian target of rapamycin (mTOR) is a central regulator of the differentiation, proliferation, and migration of a variety of cells. Hypoxia-inducible factor (HIF)-1α is involved in tumor cell migration and invasion. Close relationships among VEGF overexpression, tumor progression, and poor clinical outcomes have been reported. However, whether miRNA-451 influences glioma cell proliferation and invasion by regulating mTOR, HIF-1α, and VEGF expression remains unknown. This study aimed to assess the effects of miRNA-451 on glioma cell proliferation and invasion in vivo and in vitro by investigating its mechanism. Related gene-protein interactions were also predicted and verified. By targeting CAB39, miRNA-451 likely represses the mTOR/HIF-1α/VEGF pathway to inhibit glioma cell proliferation and invasion. Reverse transcription polymerase chain reaction confirmed that transfection of glioma cells with a lentivirus containing miRNA-451 elevated the expression level of miR-451. Upregulation of miR-451 expression suppressed the growth and invasion of glioma cells in vitro and in vivo by targeting CAB39 and modulating the mTOR/HIF-1α/VEGF signaling pathway. Based on these results, miR-451 suppresses glioma cell proliferation and invasion in vitro and in vivo via suppression of the mTOR/HIF-1α/VEGF signaling pathway by targeting CAB39. Therefore, miR-451 may be a new target for glioma treatment.

Advanced therapy medicinal products (ATMPs) represent a new generation of biopharmaceuticals that comprise gene therapy medicinal products (GTMPs), somatic cell therapy products (CTMPs), tissue engineered products (TEPs), and combined advanced therapy medicinal products (cATMPs). The joint effort of the academia-industry-regulatory triangle translated scientific progress into ten authorized ATMPs in the European Community. This notion holds promise for the whole field of ATMP therapies that have been increasingly evaluated in a number of clinical studies, also in the Czech Republic (CR). Here, we prepared an overview of regulatory framework, past and present clinical studies, and already authorized ATMPs in the CR. Clinical studies on ATMPs in the CR were mapped using public databases, particularly ClinicalTrials.gov, the European Union Clinical Trials Register, and the State Institute for Drug Control database. We found 50 registered clinical studies using ATMPs in the CR that mostly involve CTMPs (n = 36), followed by GTMPs (n = 4) and TEPs (n = 4). The majority of the studies use autologous ATMPs (76%) and are aimed at the treatment of oncologic conditions (58%) and musculoskeletal disorders (24%). The most frequent autologous cell type was dendritic cells (42%), bone marrow mononuclear cells (16%) and bone marrow mesenchymal stromal cells (13%). Allogeneic ATMPs (12%) are mostly aimed at the treatment of venous ulcers (33%) and utilize keratinocytes and fibroblasts (33%). In summary, ATMPs are increasingly tested in clinical trials in the CR, which will most likely lead to their translation into broader clinical use. However, to stimulate market viability of registered ATMPs, implementation of the sophisticated reimbursement system will be required.

Achromatopsia is an autosomal recessively inherited congenital defect characterized by a lack of cone photoreceptor function, leading to severely impaired vision. In this clinical study, achromatopsia patients were treated with a single subretinal injection of rAAV.hCNGA3 to restore cone function. The focus of this trial was on the safety of the treatment. After surgery, patients were monitored in eight extensive visits during the first year, followed by a 4-year follow-up period with annual visits. For essential complementation of the standard ophthalmological and systemic examinations, disease-specific methods were developed to assess the safety, efficacy, and patient-reported outcomes in this trial.