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Artwork by Alba Llach Pou


CRISPR-Cas9 wins its first battle against rare genetic diseases

Ten years after its discovery, the groundbreaking gene editing technology shows encouraging preliminary results in patients for the treatment of a deadly genetic disease


I was starting my bachelor’s in biology when CRISPR was first discovered and characterized by Prof Emmanuel Charpentier (PhD training done at Institut Pasteur) and Prof Jennifer Doudna. Almost 10 years later they received the Nobel prize for their discovery and I use it in lab every day​​. Inspiring both optimistic and alarming headlines in mainstream media, CRISPR quickly became a familiar tool in biological labs. CRISPR technology’s impact on how we do research is so profound that it is easy to forget that the medical applications of gene editing are still in their infancy. For this reason I wanted to share an exciting landmark trial that brings the research field one step closer to its goal of helping patients.

Transthyretin is a protein secreted by liver cells to help transport hormones and vitamins through our body. Unfortunately, for the 50000 patients suffering from Transthyretin Amyloidosis a genetic mutation turns transthyretin into a slow killer, causing deadly organ damage and debilitating symptoms. A recent clinical trial demonstrated the successful targeting of the transthyretin gene using CRISPR, a cutting edge gene editing technology.

Seek and destroy

Like every protein produced by our body, all the necessary information for the synthesis of transthyretin is contained in a gene encoded in the DNA of our cells. In rare cases, this gene can carry a specific mutation, often inherited from a parent, leading to a change in the protein structure. This causes the protein to aggregate in the blood and slowly accumulate in the nervous system and heart, leading to progressive loss of limb sensation and eventual dementia and heart failure. Although treatments exist to stabilize the protein and/or reduce its production, Transthyretin Amyloidosis is still incurable.

Due to the genetic origin of the disease, an international collaboration between researchers from public universities and biotechnology companies reasoned that disrupting the mutated transthyretin gene in liver cells could potentially block its protein production permanently, effectively curing the disease 1.

This is where CRISPR comes into play. Often described as a pair of molecular scissors, CRISPR consists of an enzyme called Cas9, paired with a small molecule called guide RNA, which together scan along the cellular DNA and cut the DNA at a specific site. As the guide RNA molecule is, like DNA, composed of a sequence of molecular “letters”, it can be used by Cas9 as a searching head to find the sequence match on the DNA of the target gene. CRISPR thus acts like the search function of a text editing software that finds a predefined phrase in the giant document that is our genome and then breaks the text only at this specific site. Researchers can thus easily repurpose CRISPR technology to cut any gene in a human cell by simply changing the guide RNA sequence, which is often enough to disrupt the gene’s activity.

The delivery challenge

CRISPR technology has been routinely used in cultured cells for the past 10 years in labs around the globe. More recently, it has allowed for successful genetic surgery in cells taken from patients with sickle cell disease. The edited cells were then reinjected into the patients after ensuring that the procedure went smoothly.

Directly targeting cells within a patient however, proves to be a lot more challenging. Researchers indeed had to make sure that both Cas9 and the guide RNA were delivered to as many cells as possible in the right organ and that, once there, they would behave similarly to what they see in the lab. Thankfully, liver cells routinely absorb molecules from the bloodstream as part of their normal function. The researchers thus packaged their guide RNA and a messenger RNA containing the information for the production of the Cas9 enzyme in lipid droplets, a strategy similar to that used in mRNA vaccines. The lipid droplets were directly injected into the bloodstream of patients where they acted as Trojan horses which were recognized by blood transport proteins, allowing for liver cell internalization. These liver cells then used the messenger RNA to produce the Cas9 enzyme themselves, which then paired with its accompanying guide RNA to target the transthyretin gene, destroying resultant protein synthesis.

A one-time treatment with long-term effects

All six patients enrolled in the study showed decreased circulating transthyretin levels 28 days after a single injection, with an average reduction of 87% for the highest drug dose. These results are very encouraging, and although it is too early to observe any impact on disease progression, it is expected that the effect will be permanent with treated liver cells passing on the disrupted transthyretin gene during cell division.

The research team will continue the trial with higher doses in the hope of obtaining a full suppression of the protein expression, resulting in long-term recovery for patients. Interestingly, the full deletion of the gene in mice only led to decreased blood levels of the hormones normally transported by transthyretin with no negative effect on their health. The impact in humans however, is still unknown and some studies suggest that transthyretin could play a protective role in the brain 2. A last goal of the trial will thus be to evaluate if potential adverse effects appear above a certain dose that could outweigh the benefits of the treatment.

This last point highlights the difficulty for researchers to predict the effect of disrupting a gene in the human body where it can have various functions in different organs. Consequently, research is currently ongoing to develop more subtle versions of the CRISPR system that could precisely correct genetic mutations without leaving any genetic scar and impacting the expression of the gene.


1. Gillmore et al. (2021) CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N. Engl. J. Med.

2. Liz et al. (2020) A Narrative Review of the Role of Transthyretin in Health and Disease. Neurology and Therapy.

Additional information

1. Biologist Explains One Concept in 5 Levels of Difficulty - CRISPR | WIRED

2. Can CRISPR cure Sickle-cell Disease? | NATURE VIDEO

3. CRISPR gene therapy shows promise against blood diseases | NATURE NEWS

4. Editas Early Data for CRISPR Therapy EDIT-101 Shows Efficacy “Signals” in Two Patients | GEN

5. Genetic Engineering Will Change Everything Forever – CRISPR | KURZGESAGT

6. Emmanuelle Charpentier – Graduation Ceremony 2020 | Institut Pasteur

This article was specialist edited by Dr. David Bikard and copy edited by Maureen Wentling. This article results from a collaboration with ComSciCon France, a workshop on Scientific communication for PhD students.


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