Gene Editing for Rare Disorders: How Promising Is It?

12 October, 2015

The ability to modify the nucleotide sequence of a genome with precision is a critical aspect of genome editing. That's been the challenge. But in the last five years great strides have been made as we’ve seen the development of TALENs, and more recently, CRISPRs. The advantage of these systems is that it has allowed a whole range of investigators—from people with moderate skills in molecular biology to make TALENS, and high school students to be able to make CRISPRs—to design nucleases that have a high probability of recognizing the desired target site in the genome.

By being able to design the guiding sequences for these nucleases, it’s possible to create double strand, and with further modification, single strand breaks at very specific sites in the genome causing the cell to activate its repair machinery. Depending on the setting, these breaks will be repaired in one of two ways:

(1) non-homologous end joining, which can result in insertions/deletions at the site of the break generally leading to inactivation of the genetic element (usually a coding gene, but it could also be any genetic element), or

(2) homologous recombination, which can lead to inactivation, activation or substitution if a piece of DNA is provided to serve as a template so that precise nucleotide changes can be inserted into the DNA.

With homologous recombination-based genome editing, a single base can be changed, or a whole set of genes can be inserted. Using homologous recombination, it’s possible to make single base pair changes, but it is also possible to insert at least 15 kilobases of additional DNA at the site of the break (thus allowing one to insert multigene cassettes into a single location in the genome).

Genome editing technology allows for the modification of the genome with precision, allowing for the use of human genetics as the target validation, both safely and efficaciously. With genome editing, that precise genetic makeup can be recreated. In addition, the genome-editing platform allows for the validation of specific targets in a way that hasn’t been done before.

The process does require the delivery of nucleases into the cells, and if homologous recombination is used, it requires the delivery of a donor vector. Sometimes that can be done using non-viral methods, but often viruses are used to transiently deliver the necessary components. Since the process is fundamentally a hit and run process, non-integrating viruses can be used to deliver the components, allowing the virus to disappear over time and leaving behind a permanent modification of the genome.

It’s likely that there will be future technological developments that will be required for this process, but at present it’s hard to anticipate what those might be. Many in the field are adopting the attitude that the tools presently at hand are worth pushing forward until the next hurdles are identified.

To learn more about how gene therapies have the potential to cure rare disorders download our free white paper: "What's Hot & What's Not in Gene Therapies for Rare Disorders."

Download White Paper