Advancements in Vaccine Technology and Nucleic Acid-Based Therapies Quiz

Advancements in Vaccine Technology and Nucleic Acid-Based Therapies

• Lactobacillus salivarius has been engineered to immunize against Johne’s disease in cattle.
• Adjuvants are materials that enhance the immune response to an antigen, facilitating the administration of reduced quantities of antigen to achieve an adequate immunological response.
• Aluminium-based products are routinely used as adjuvants in human medicine due to safety reasons.
• An ideal adjuvant should be safe, effective, non-pyrogenic, chemically defined, effective in infants/young children, yield stable formulation with the antigen, be biodegradable, and non-immunogenic itself.
• Nucleic acid-based therapeutics include Gene Therapy, Antisense Technology, RNAi, Ribozymes, Aptamers, and CRISPR genome editing technology.
• Only a handful of nucleic-acid based products have gained regulatory approval, while hundreds of protein-based biopharmaceuticals have been approved by early 2020.
• Gene therapy aims to introduce a stable gene into the genetic complement of a cell to achieve a therapeutic goal.
• Two-thirds of all gene therapy trials aim to treat cancer, and 1,200 different clinical studies have been undertaken worldwide.
• ~62% of gene therapy trials are in the early stage, and only some 2.2% of all trials reach Phase III.
• Gene therapy has significant associated risks, and only a handful of studies have revealed a therapeutic benefit to the patient.
• Gene therapy protocols may entail cell-based delivery or direct delivery, with in vitro approaches being the most commonly adopted protocol to date.
• In situ, direct injection/administration of the gene-containing vector to the target cell in situ into the immediate vicinity of the target cells in the body, and in vivo approaches, entails the development of vectors capable of recognizing specific cell types.

Gene Therapy Vectors: Viral and Non-Viral Delivery Systems

• Retroviral vectors are used in ~24% of gene therapy trials, but they are labile and can only infect dividing cells, and can activate oncogenes.
• Adenoviral vectors have a large dsDNA genome, but prompt a strong immune response, limiting their efficacy in repeat administration.
• Adeno-associated virus vectors are small and can only replicate in the presence of co-infecting adenovirus, but they can integrate into the host genome and facilitate long-term expression.
• Non-viral-based gene delivery methods have low/non-immunogenicity and do not integrate into the host genome, but have low transfection rates.
• Naked plasmid DNA was the first non-viral-based system used in gene therapy, with low transfection rates and no integration into the host genome.
• DNA coated on gold beads propelled into the epidermis with a gene gun can be expressed in the animal's skin, and can result in effective immunization.
• Modern non-viral-based systems use carrier molecules such as cationic lipids and poly-lysine chains to stabilize and protect DNA, and target it to specific cell types.
• Over 4,000 genetic diseases have been characterized, but progress in gene therapy is slow due to the limited number of identified genes, unsatisfactory gene-delivery vectors, complex diseases, problematic regulation of trans gene expression levels, and limited patient populations.
• Gene therapy has potential as a therapeutic option for genetic diseases, but there are several challenges that need to be addressed to achieve success.
• The cost of drug development may be a barrier for companies developing gene therapies for limited patient populations.
• Gene therapy research is ongoing, and new delivery systems and approaches are being developed to overcome the challenges and limitations of current gene therapy methods.
• The use of gene therapy in clinical practice is still limited, but it has the potential to revolutionize the treatment and cure of genetic diseases.

Advances in Nucleic Acid-Based Therapies

• Over 4,000 genetic diseases have been characterized, but the application of gene therapy has made little impact in practice due to various challenges.
• Antisense technology is a nucleic-acid-based approach to down-regulate the expression of gene products by generating short, single-stranded stretches of nucleic acids with a specific sequence.
• Antisense oligonucleotides are being assessed as therapeutic agents in the treatment of cancer and viral infections.
• Antisense oligos display desirable characteristics, including specificity, low toxicity, and ease of manufacture.
• Vitravene (fomivirsen) is the first antisense product approved by the FDA for the treatment of cytomegalovirus retinitis in AIDS patients but was later withdrawn from the EU market due to poor sales.
• Vitravene is a 21-nucleotide phosphonothioate based product administered via direct injection into the eye.
• RNA interference (RNAi) is an innate cellular process that achieves silencing of selected genes via an antisense mechanism.
• RNAi represents a sequence-specific post-translational mechanism of gene expression induced ultimately by dsRNA.
• The siRNA is incorporated into a multi-subunit effect or complex known as an RNA-induced silencing complex (RISC).
• The first clinical trial based on siRNA was reported in 2010, demonstrating its efficacy when administered systemically to patients with skin cancer melanoma.
• Both antisense technology and RNAi hold potential as therapeutic agents for various diseases.
• Further research and development are needed to overcome the challenges and optimize the therapeutic potential of nucleic acid-based therapies.