2023 Gene Therapy Mini-Series
2023 Gene Therapy Mini-SeriesSince the discovery of the structure of DNA and its transcription, it has been a scientific dream to treat monogenic disorders by rewriting and correcting the genetic code. Development of recombinant DNA technology and DNA sequencing in the 1970s laid the foundation for gene-insertion therapies, with the goal to deliver a healthy functioning copy of the mutated gene in patients. Development of retrovirus and adenovirus delivery vectors in the 1980s led to the first gene-therapy treatment of a patient with adenosine deaminase–deficient severe combined immune-deficiency in 1990.
CRISPR-Cas9 base editors and their current role in human therapeuticsConsistent progress has been made to create more efficient and useful CRISPR-Cas9-based molecular toolsfor genomic modification.
CRISPR/Cas9-mediated gene editing. A promising strategy in hematological disordersThe clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has revolutionized the gene editing field, making it possible to interrupt, insert or replace a sequence of interest with high precision in the human genome. Its easy design and wide applicability open up a variety of therapeutic alternatives for the treatment of genetic diseases. Indeed, very promising approaches for the correction of hematological disorders have been developed in the recent years, based on the self-renewal and multipotent differentiation properties of hematopoietic stem and progenitor cells, which make this cell subset the ideal target for gene therapy purposes.
Editing human hematopoietic stem cells: advances and challengesGenome editing of hematopoietic stem and progenitor cells is being developed for the treatment of several inherited disorders of the hematopoietic system. The adaptation of CRISPR-Cas9-based technologies to make precise changes to the genome, and developments in altering the specificity and efficiency, and improving the delivery of nucleases to target cells have led to several breakthroughs. Many clinical trials are ongoing, and several pre-clinical models have been reported that would allow these genetic therapies to one day offer a potential cure to patients with diseases where limited options currently exist.
Boosters for adeno-associated virus (AAV) vector (r)evolutionAdeno-associated virus (AAV) is one of the most exciting and most versatile templates for engineering of gene-delivery vectors for use in human gene therapy, owing to the existence of numerous naturally occurring capsid variants and their amenability to directed molecular evolution. As a result, the field has witnessed an explosion of novel “designer” AAV capsids and ensuing vectors over the last two decades, which have been isolated from comprehensive capsid libraries generated through technologies such as DNA shuffling or peptide display, and stratified under stringent positive and/or negative selection pressures.