Adeno-associated virus as a delivery vector for gene therapy of human diseases

Adeno-associated virus(AAV)has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues.Recombinant AAV(rAAV)has been engineered for enhanced specificity and developed as a tool for treating various diseases.However,as rAAV is being more widely used as a therapy,the increased demand has created challenges for the existing manufacturing methods.Seven rAAV-based gene therapy products have received regulatory approval,but there continue to be concerns about safely using high-dose viral therapies in humans,including immune responses and adverse effects such as genotoxicity,hepatotoxicity,thrombotic microangiopathy,and neurotoxicity.In this review,we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing technologies.We discuss how rAAVs are being employed in ongoing clinical trials for ocular,neurological,metabolic,hematological,neuromuscular,and cardiovascular diseases as well as cancers.We outline immune responses triggered by rAAV,address associated side effects,and discuss strategies to mitigate these reactions.We hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

Is smaller better?Vaccine targeting recombinant receptorbinding domain might hold the key for mass production of effective prophylactics to fight the COVID-19 pandemic

A recent report by Yang et al.published in Nature reported a recombinant vaccine utilizing recombinant receptor-binding domain(RBD)of SARS-CoV-2 Spike Protein.1 This vaccine candidate successfully induced potent functional antibody responses in the immunized mice,rabbits,and non-human primates.The study highlights the critical role of the immunogenicity of the RBD domain upon SARS-CoV-2 infection and the alternate vaccine designs that could serve as effective prophylactics against the pandemic.

Viral vector platforms within the gene therapy landscape

Throughout its 40-year history,the field of gene therapy has been marked by many transitions.It has seen great strides in combating human disease,has given hope to patients and families with limited treatment options,but has also been subject to many setbacks.Treatment of patients with this class of investigational drugs has resulted in severe adverse effects and,even in rare cases,death.At the heart of this dichotomous field are the viral-based vectors,the delivery vehicles that have allowed researchers and clinicians to develop powerful drug platforms,and have radically changed the face of medicine.Within the past 5 years,the gene therapy field has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes,these modalities range from vector-based cancer therapies,to treating monogenic diseases with life-altering outcomes.At present,the three key vector strategies are based on adenoviruses,adeno-associated viruses,and lentiviruses.They have led the way in preclinical and clinical successes in the past two decades.However,despite these successes,many challenges still limit these approaches from attaining their full potential.To review the viral vector-based gene therapy landscape,we focus on these three highly regarded vector platforms and describe mechanisms of action and their roles in treating human disease.