Gene therapy for neurotransmitter‐related disorders DOI Creative Commons
Wing Chu, Joanne Ng, Simon N. Waddington

et al.

Journal of Inherited Metabolic Disease, Journal Year: 2024, Volume and Issue: 47(1), P. 176 - 191

Published: Jan. 1, 2024

Abstract Inborn errors of neurotransmitter (NT) metabolism are a group rare, heterogenous diseases with predominant neurological features, such as movement disorders, autonomic dysfunction, and developmental delay. Clinical overlap other disorders has led to delayed diagnosis treatment, some conditions refractory oral pharmacotherapies. Gene therapies have been developed translated clinics for paediatric inborn metabolism, 38 interventional clinical trials ongoing date. Furthermore, efforts in restoring dopamine synthesis neurotransmission through viral gene therapy Parkinson's disease. Along the recent European Medicines Agency (EMA) Healthcare Products Regulatory (MHRA) approval an AAV2 supplementation AADC deficiency, promising efficacy safety profiles can be achieved this diseases. In review, we present preclinical advances address NT‐related diseases, summarise potential challenges that require careful considerations NT studies.

Language: Английский

Biopharmaceutical Manufacturing: Historical Perspectives and Future Directions DOI Creative Commons
Alana C. Szkodny, Kelvin H. Lee

Annual Review of Chemical and Biomolecular Engineering, Journal Year: 2022, Volume and Issue: 13(1), P. 141 - 165

Published: March 18, 2022

This review describes key milestones related to the production of biopharmaceuticals—therapies manufactured using recombinant DNA technology. The market for biopharmaceuticals has grown significantly since first biopharmaceutical approval in 1982, and scientific maturity technologies used their manufacturing processes concomitantly. Early relied on established unit operations, with research focused process scale-up improved culture productivity. In early 2000s, changes regulatory frameworks introduction Quality by Design emphasized importance developing deliver a desired product quality profile. As result, companies adopted platform understanding dynamic interplay between processing conditions. consistent reproducible today's industry have set high standards efficacy, quality, safety, as continues evolve coming decade, intensified capabilities an expanded range therapeutic modalities will likely become routine.

Language: Английский

Citations

46
Targeted Liposomes: A Nonviral Gene Delivery System for Cancer Therapy DOI Creative Commons
Marcela Tavares Luiz, Jessyca Aparecida Paes Dutra, Larissa Bueno Tofani

et al.

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(4), P. 821 - 821

Published: April 8, 2022

Cancer is the second most frequent cause of death worldwide, with 28.4 million new cases expected for 2040. Despite de advances in treatment, it remains a challenge because tumor heterogenicity and increase multidrug resistance mechanisms. Thus, gene therapy has been potential therapeutic approach owing to its ability introduce, silence, or change content human genetic code inhibiting progression, angiogenesis, metastasis. For proper delivery genes cells, requires use vectors protecting transporting into cells. Among these vectors, liposomes have nonviral vector used their low immunogenicity toxicity. Furthermore, this nanosystem can surface modified ligands (e.g., antibodies, peptides, aptamers, folic acid, carbohydrates, others) that be recognized high specificity affinity by receptor overexpressed increasing selective tumors. In context, present review address discuss main targeting functionalize improving application cancer treatment.

Language: Английский

Citations

46
Stability and Dissociation of Adeno-Associated Viral Capsids by Variable Temperature-Charge Detection-Mass Spectrometry DOI Open Access

Marius M. Kostelic,

Jack P. Ryan,

Levi S. Brown

et al.

Analytical Chemistry, Journal Year: 2022, Volume and Issue: 94(34), P. 11723 - 11727

Published: Aug. 18, 2022

Adeno-associated viral (AAV) vectors have emerged as gene therapy and vaccine delivery systems. Differential scanning fluorimetry or differential calorimetry is commonly used to measure the thermal stability of AAVs, but these global methods are unable distinguish stabilities different AAV subpopulations in same sample. To address this challenge, we combined charge detection-mass spectrometry (CD-MS) with a variable temperature (VT) electrospray source that controls solution prior electrospray. Using VT-CD-MS, measured empty filled capsids. We found AAVs ejected their cargo first formed intermediate capsids before completely dissociating. Finally, observed pH stress caused major decrease stability. This new approach better characterizes dissociation providing simultaneous measurement pathways subpopulations.

Language: Английский

Citations

39
Non-viral chimeric antigen receptor (CAR) T cells going viral DOI Creative Commons
Hyatt Balke‐Want, Vimal Keerthi,

Amaia Cadiñanos-Garai

et al.

Immuno-Oncology Technology, Journal Year: 2023, Volume and Issue: 18, P. 100375 - 100375

Published: March 9, 2023

Language: Английский

Citations

35
Challenges in scaling up AAV-based gene therapy manufacturing DOI Creative Commons

Ziyu Jiang,

Paul A. Dalby

Trends in biotechnology, Journal Year: 2023, Volume and Issue: 41(10), P. 1268 - 1281

Published: April 30, 2023

Accelerating the scale up of adeno-associated virus (AAV) manufacture is highly desirable to meet increased demand for gene therapies. However, development bioprocesses AAV therapies remains time-consuming and challenging. The quality by design (QbD) approach ensures bioprocess designs that desired product safety profile. Rapid stress tests, developability screens, scale-down technologies have potential streamline manufacturing within QbD framework. Here we review how their successful use antibody translating AAV, but also this will depend critically on improved analytical methods adaptation tools as more understanding gained critical attributes required therapy.

Language: Английский

Citations

34
Stabilization challenges and aggregation in protein-based therapeutics in the pharmaceutical industry DOI Creative Commons
Mahdie Rahban, Faizan Ahmad, Mieczyslaw A. Piatyszek

et al.

RSC Advances, Journal Year: 2023, Volume and Issue: 13(51), P. 35947 - 35963

Published: Jan. 1, 2023

Protein-based therapeutics have revolutionized the pharmaceutical industry and become vital components in development of future therapeutics. They offer several advantages over traditional small molecule drugs, including high affinity, potency specificity, while demonstrating low toxicity minimal adverse effects. However, manufacturing processes protein-based presents challenges related to protein folding, purification, stability immunogenicity that should be addressed. These proteins, like other biological molecules, are prone chemical physical instabilities. The drugs throughout entire manufacturing, storage delivery process is essential. occurrence structural instability resulting from misfolding, unfolding, modifications, as well aggregation, poses a significant risk efficacy these overshadowing their promising attributes. Gaining insight into alterations caused by aggregation impact on for advancement refinement Hence, this review, we discussed some features during production, formulation stabilization strategies engineering computational methods prevent aggregation.

Language: Английский

Citations

33
An Overview of the Stability and Delivery Challenges of Commercial Nucleic Acid Therapeutics DOI Creative Commons
Rahul G Ingle, Wei‐Jie Fang

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(4), P. 1158 - 1158

Published: April 6, 2023

Nucleic acid (NA)-based biopharmaceuticals have emerged as promising therapeutic modalities. NA therapeutics are a diverse class of RNA and DNA include antisense oligonucleotides, siRNA, miRNA, mRNA, small activating RNA, gene therapies. Meanwhile, posed significant stability delivery challenges expensive. This article discusses the opportunities for achieving stable formulations NAs with novel drug systems (DDSs). Here we review current progress in issues significance DDSs associated NA-based biopharmaceuticals, well mRNA vaccines. We also highlight European Medicines Agency (EMA) US Food Drug Administration (FDA)-approved their formulation profiles. could impact future markets if remaining requirements addressed. Regardless limited information available therapeutics, reviewing collating relevant facts figures generates precious resource experts familiar therapeutics' profile, challenges, regulatory acceptance.

Language: Английский

Citations

32
Research Status and Prospect of Non-Viral Vectors Based on siRNA: A Review DOI Open Access

Liangnan Tong,

Danqing Liu,

Zhiyue Cao

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3375 - 3375

Published: Feb. 8, 2023

Gene therapy has attracted much attention because of its unique mechanism action, non-toxicity, and good tolerance, which can kill cancer cells without damaging healthy tissues. siRNA-based gene downregulate, enhance, or correct expression by introducing some nucleic acid into patient Routine treatment hemophilia requires frequent intravenous injections missing clotting protein. The high cost combined causes most patients to lack the best resources. siRNA potential lasting even curing diseases. Compared with traditional surgery chemotherapy, fewer side effects less damage normal cells. available therapies for degenerative diseases only alleviate symptoms patients, while drugs upregulate expression, modify epigenetic changes, stop disease. In addition, also plays an important role in cardiovascular diseases, gastrointestinal hepatitis B. However, free is easily degraded nuclease a short half-life blood. Research found that be delivered specific through appropriate vector selection design improve therapeutic effect. application viral vectors limited their immunogenicity low capacity, non-viral are widely used immunogenicity, production cost, safety. This paper reviews common recent years introduces advantages disadvantages, as well latest examples.

Language: Английский

Citations

30
Enzymatic Bioconjugation: A Perspective from the Pharmaceutical Industry DOI Creative Commons
Aaron Debon,

Elina Siirola,

Radka Šnajdrová

et al.

JACS Au, Journal Year: 2023, Volume and Issue: 3(5), P. 1267 - 1283

Published: May 4, 2023

Enzymes have firmly established themselves as bespoke catalysts for small molecule transformations in the pharmaceutical industry, from early research and development stages to large-scale production. In principle, their exquisite selectivity rate acceleration can also be leveraged modifying macromolecules form bioconjugates. However, available face stiff competition other bioorthogonal chemistries. this Perspective, we seek illuminate applications of enzymatic bioconjugation an expanding palette new drug modalities. With these applications, wish highlight some examples current successes pitfalls using enzymes along pipeline try illustrate opportunities further development.

Language: Английский

Citations

30
Chromatographic strategies for the analytical characterization of adeno-associated virus vector-based gene therapy products DOI Creative Commons
Szabolcs Fekete, Megane K. Aebischer, Mateusz Imiołek

et al.

TrAC Trends in Analytical Chemistry, Journal Year: 2023, Volume and Issue: 164, P. 117088 - 117088

Published: May 10, 2023

In recent years, the biopharmaceutical industry's interest in gene therapy modalities has increased dramatically. To warrant their quality during manufacturing and upstream/downstream process, fit-for-purpose analytical methods play a crucial role overall control strategy. However, characterization of products remains challenging due to large size, structural complexity, heterogeneity, potential instability, limited sample availability. addressing some these challenges with innovative approaches, liquid chromatography (LC) based have become an integral part currently used toolbox. This review focuses on both established emerging trends LC analysis adeno-associated virus (AVV) vector-based products. Each method is discussed highlight advantages, drawbacks, unique capabilities AAV transfer vehicles corresponding impurities. Taken together, this provides guidance selection LC-based for routine testing extended

Language: Английский

Citations

25