The gene-editing capabilities of CRISPR have been the source of hope and hype ever since the demonstration nearly a decade ago. CRISPR’s tri-fold promise as a simpler, cheaper, and more precise gene-editing technology opened up huge new regions of possibility in synthetic biology and biotechnology. It didn’t take long for CRISPR to significantly impact bench-science and lab-work, but the anticipated clinical applications of the tech have been slower to arrive.
The latest press release from Intellia Therapeutics, a Massachusetts-based biotechnology company, is a significant step toward the clinic for these therapies, with the company announcing that its NTLA-5001 T cell therapy had gained orphan-drug designation from the FDA as a potential treatment for acute myeloid leukemia (AML). While the orphan-drug designation is significant for Intellia from a business-perspective (Intellia’s share-price has risen 8.4% as of this moment on the back of the announcement), what we’re focused on here is another milestone towards developing platforms that allow the safe and effective use of cell and gene therapies in humans.
To understand this, we need to look closer at what Intellia are aiming to do, and what they’ve done so far.
At its core, Intellia wants to fully unlock the potential of CRISPR/Cas9 to enable clinical genomic editing. This means refining both the CRISPR/Cas9 system, and its supporting technologies to
a) deliver the enzyme to the right cells
b) edit the genome precisely (and maybe the epigenome someday too?)
c) minimise side-effects and off-target effects
To this end, Intellia has two functioning arms to its tech stack: one focusing on curing genetic diseases by delivering CRISPR in vivo, and the second focused on ex vivo, CRISPR-engineered cell therapies for cancers and auto-immune diseases.
The in vivo arm aims to deliver CRISPR directly into the body, where it needs to enter cells and directly edit the patient’s genome. Intellia’s approach here is unique, because instead of directly injecting the CRISPR/Cas9 protein into the body, the company delivers the mRNA template for the Cas9 enzyme, plus a “guide”-RNA which helps the Cas9 find the right spot in the genome and make the right edit.
The company achieves this using a similar lipid nanoparticle-based mRNA delivery mechanism to that of the mRNA-based COVID-19 vaccines, like Pfizer or Moderna. Lipid nanoparticles (LNP) are a crucial part of the tech stack because free mRNA is rapidly degraded in the body, whereas the lipid-bound form is stable. Not only that, but on their own, hydrophobic, negatively charged nucleic acids (such as mRNA) cannot pass through cell-membranes, which is a problem if you want to edit the genome tucked away inside the cell nucleus. Lipid nanoparticles again solve this by packaging the mRNA in such a way that they can be endocytosed by cells, and their contents released once inside.
Once inside, this arm of the tech stack allows Intellia to silence or remove disease-causing genes, or insert genes whose absence causes disease.
Intellia recently released preliminary data from its phase 1 clinical trial on human patients receiving their gene therapy for transthyretin (ATTR) amyloidosis, showing that their therapy could significantly lower the level of the problematic serum transthyretin protein that characterises the disease.
This is a major milestone for in-vivo gene therapies, because the platform (at least in theory) is extensible to other pathologies – a key advantage of CRISPR-based therapies!
The second arm of CRISPR tech that Intellia has been developing takes us back to where we began this article: Intellia gaining orphan-disease designation for its T cell therapy.
The aim here is to isolate and extract the functional cell-type of interest (which is often an immune cell like a T lymphocyte) and use CRISPR to engineer novel properties of the cell by altering its genome. The alterations in the case of the AML drug specifically aim to engineer the T cell receptor (TCR) to enhance the immune cells’ targeting of the WT1 antigen (a common antigen expressed in several haematologic tumours, including AML). After successful genome editing to create these enhanced T cells, the cells are reinfused back into the patient (much like a regular blood transfusion would deliver standard red blood cells).
In doing this, Intellia is paving both the technological and regulatory path that will bring CRISPR (and by extension gene-editing) into the mainstream. From a regulatory perspective, creating precedent for FDA approval of gene editing therapies is crucial to ensure research spending continues, while technological development in the space makes it easier to test and apply ever bolder gene-editing ideas.
While it hasn’t traditionally been seen as a longevity intervention, gene therapies have quietly but increasingly become a part of the landscape of longevity biotech therapies (see e.g. Rejuvenate Bio). In part, the reasons to suspect that gene therapy might be underrated as an anti-aging therapy come from noticing trends and differences in the genomes and transcriptomes of long and short-lived animals, with a general trend for the genomes of long-lived animals to enable increased DNA maintenance and repair, ubiquitination (assists with protein degradation), immune-regulation, and mitochondrial function. Even simpler than this, mice engineered to have extra copies of p53 – a key gene regulating and preventing cancer formation – also have significantly longer lifespan due to p53’s ability to mitigate age-associated DNA damage.
For fun, let’s look at two more promising uses of gene therapy in ageing (both in mice).
Right now Intellia is focusing on near-term targets for gene and cell therapies, such as cancer, or rare disease-indications, such as amyloidosis, but success there paves the way for human analogues of the mouse work done above!
Intellia’s tech is important not just for what it achieves for patients today, but also because Intellia and other innovators push the frontier of what we can imagine is (safely) possible with CRISPR when it comes to ageing and longevity.
Of course, no milestone in biotech is ever without its caveats, and there are still several steps ahead for Intellia and other gene and cell therapy companies. There are still significant technical and regulatory risks to be faced, but companies like Intellia are tackling these challenges head-on.
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