Since the human genome was first mapped in 2000, scientists have identified the individual genes responsible for 4,300 genetic disorders, many of which can drastically affect an individual’s quality of life or reduce life expectancy. The Centers for Disease Control and Prevention reports that genomics play a role in nine of the ten leading causes of death in the United States, most notably chronic conditions such as cancer, diabetes and heart disease.
The development in 2012 of CRISPR/Cas9 as a genome editing tool by one of Intellia’s founders, Jennifer Doudna, has triggered an unprecedented volume of scientific research. This work is rapidly advancing our understanding of how this technology could revolutionize genome editing, harnessing a natural biological pathway and leading to the development of new class of therapeutic options for patients with many chronic diseases.
The Ideal Genome Editing Technology
CRISPR/Cas9 technology makes possible genome editing – the precise and targeted modification of the genetic material of cells. Genome editing works by using an enzyme to make a cut at a particular sequence in the genome, followed by the deletion, repair or insertion of genetic material at the cut site, facilitated by the cell’s natural DNA repair mechanisms.
“CRISPR-Cas9 gives scientists the power to remove or add genetic material at will… This is a true breakthrough, the implications of which we are just beginning to imagine.”
Mary-Claire King, a geneticist and the discoverer of the BRCA1 cancer gene
CRISPR/Cas9 genome editing has the potential to treat a broad range of diseases that are not adequately addressed by more traditional therapies based small molecules or biologics. Given its permanent effects on the target DNA, genome editing could potentially cure a disease with a single treatment course, instead of the multi-treatment or chronic dosing regimens often seen with traditional therapies, which typically have transient effects and may require life-long treatment.
Additionally, unlike gene therapy, which typically involves introducing a copy of a gene into a patient’s cells, genome editing has the potential to make permanent, precise changes at the cellular level, repairing the underlying genetic mutation. This attribute may provide a significant competitive edge over gene therapy, more closely mimicking the body’s own repair system while also addressing a broader spectrum of diseases.
Attributes and Therapeutic Potential
Unlike more complex and costly earlier-generation genome editing technologies, such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), the CRISPR/Cas9 system is simple. CRISPR/Cas9’s potential stems from its selectivity, simplicity of use, broad applicability, ability to scale and optimize at speed, and multifunctional programmability.
KEY ENABLING ATTRIBUTES TO BECOME NEXT BIG DRUG CLASS
- High potency (cleavage efficiency) and specificity
- Broad applicability to both in vivo and ex vivo applications
- Simple editing tools (guide RNA plus protein) allow unprecedented ability to scale and optimize at speed
- Potential one-time curative treatment
BROADEST POTENTIAL TO MODULATE GENES
- Ability to target multiple DNA sites simultaneously
- Multiplexing potential to address polygenic of complex genetic disorders
- Multifunctional programmability: knockout, insert or repair genes
How It Works
There are two main components to the CRISPR/Cas9 genome editing system:
- The Cas9 protein, which act like a pair of “molecular scissors” that initiates the natural cellular repair process to knockout, repair or insert a gene.
- The guide RNA sequence that recognizes and directs the Cas9 to a specific target DNA sequence.