Nucleic Acid therapeutics Flashcards
What are some examples of nucleic acid-based therapeutics that have gained regulatory approval?
Gendicine (approved only in China) - a gene therapy product
Glybera (approved in Europe in 2012, withdrawn in 2017) - a gene therapy product
Vitravene - the first antisense-based product approved by the FDA
Macugen - an aptamer
Kynamro - an oligonucleotide
Eteplirsen - an oligonucleotide
Defitelio - an oligonucleotide
Spinraza - an oligonucleotide
How does the number of nucleic acid-based products approved compare to protein-based biopharmaceuticals?
By the early 2020s, only a handful of nucleic acid-based products had gained regulatory approval, while hundreds of protein-based biopharmaceuticals had been approved.
What is THPdb?
THPdb is a manually curated repository of FDA approved therapeutic proteins. It provides comprehensive information on FDA approved therapeutic peptides, proteins, and their drug variants.
What are some current developments in nucleic acid-based therapeutics?
Current developments include gene therapy, antisense technology, RNA interference (RNAi), ribozymes, aptamers, and CRISPR genome editing technology.
Can you provide an example of a gene therapy product?
Gendicine is an example of a gene therapy product that has gained regulatory approval, although it is approved only in China.
What was the first antisense-based product approved by the FDA?
Vitravene was the first antisense-based product approved by the FDA.
What is the fundamental principle of gene therapy?
The fundamental principle of gene therapy is the stable introduction of a gene into the genetic complement of a cell to achieve a therapeutic goal.
Which disease category has been the focus of the majority of gene therapy trials?
Two-thirds of all gene therapy trials conducted to date aim to treat cancer.
Where are the majority of gene therapy trials conducted?
Approximately 67% of gene therapy trials are being conducted in the United States, with the remaining trials being conducted in Europe, mainly in the UK and Germany.
What percentage of gene therapy trials reach Phase III?
Only about 2.2% of all gene therapy trials reach Phase III.
What are the two basic approaches to gene therapy?
The two basic approaches to gene therapy are cell-based delivery (in vitro approach) and direct delivery (in vivo approach).
What is the in vitro approach in gene therapy?
The in vitro approach involves removing target cells from the body, culturing them in vitro, and incubating them with the vector containing the desired gene(s) before reintroduction into the body.
What is the in situ approach in gene therapy?
The in situ approach involves the direct injection or administration of the gene-containing vector to the target cells in the immediate vicinity within the body.
What is the in vivo approach in gene therapy?
The in vivo approach focuses on developing vectors capable of recognizing specific cell types and delivering genes directly to those cells in the body.
What are the advantages of using retroviral vectors in gene therapy?
Retroviral vectors can integrate into the host cell genome, allowing for long-term expression of the transferred genetic material.
What are the disadvantages of retroviral vectors?
Retroviral vectors are labile and can be damaged during purification and concentration steps. They can only infect dividing cells, limiting their target range. There is also a risk of disrupting essential genes or activating proto-oncogenes, potentially leading to cancer.
How do adenovirus vectors differ from retroviral vectors?
Adenovirus vectors have a larger dsDNA genome and do not integrate into the host cell DNA. However, they prompt a strong immune response, limiting their efficacy in repeat administrations.
What are the characteristics of adeno-associated virus (AAV) vectors?
AAV vectors are small ssDNA viruses that require co-infection with adenovirus for replication. They can introduce relatively small genes into non-dividing cells and facilitate long-term expression of the transferred genetic material. AAV vectors can integrate into the recipient cell genome.
What are the advantages of using non-viral vectors in gene therapy?
Non-viral vectors have low or non-immunogenicity and do not integrate into the host genome, minimizing the potential for disrupting essential genes or activating host oncogenes.
What was the initial approach for non-viral gene delivery?
The initial approach involved administering naked plasmid DNA, which was shown to be expressed in mouse muscle cells after injection. However, the transfection rate was low, and the DNA was not integrated into the host cell’s chromosome.
How can DNA be delivered using a gene gun?
DNA can be coated on microscopic gold beads and propelled into the epidermis of test animals using a gene gun. This method has been shown to result in gene expression in the animal’s skin.
What are the commonly used carrier molecules in non-viral gene delivery?
Cationic lipids and polylysine chains are commonly used carrier molecules. Cationic lipids can form vesicles or liposomes that interact with DNA, providing physical protection to the therapeutic gene.
What is the challenge in the formation of lipoplexes for gene delivery?
The process of lipoplex formation is not easily controlled, and different batches made under seemingly identical conditions may not be structurally identical.
Why has the application of gene therapy to treat genetic diseases made little impact in practice?
The slow progress in gene therapy for genetic diseases can be attributed to factors such as a modest number of identified and studied disease-causing genes, unsatisfactory gene-delivery vectors, complexity of some genetic diseases affecting multiple organs/cell types, problematic regulation of transgene expression levels, and limited patient populations for cost recovery.
Which two genetic diseases were among the earliest targets for gene therapy?
The two earliest genetic diseases targeted for gene therapy were SCID (bubble baby syndrome) and Cystic Fibrosis.
How does a lack of adenosine deaminase (ADA) activity contribute to SCID?
One form of SCID is caused by a lack of ADA activity, which plays a central role in the degradation of purine nucleosides. The deficiency leads to B- and T-cell dysfunction, resulting in a compromised immune system.
