Tag: CRISPR

Nobel Prize in Chemistry 2020 for CRISPR-Cas9 Genetic Scissors

On 7 October 2020, the Royal Swedish Academy of Sciences awarded the Nobel Prize in Chemistry 2020 to Emmanuelle Charpentier and Jennifer A. Doudna for the development of a method for genome editing.  Currently Emmanuelle Charpentier works at the Max Planck Unit for the Science of Pathogens in Berlin, Germany, and Jennifer A. Doudna at the University of California, Berkeley, USA.

Emmanuelle Charpentier and Jennifer A. Doudna; the Awardees for their development of CRISPR-Cas9
Emanuelle Charpentier [1] and Jennifer A. Doudna [2]

Charpentier and team published their initial discovery on bacterial genome editing in 2011[3]. In collaboration with Doudna, they were able to establish and simplify the method[4]. Their discovery and further developments of the CRISPR-Cas9 genetic scissors made one of most powerful technologies for genome editing widely accessible. In essence, Cas9-RNA mediates site-specific genome engineering in the genome of human cells, or other eukaryotes. One of the applications for in-vivo human gene therapy is that the Cas-9 enzyme can be used to reverse undesirable mutations[5], making it possible to treat a wide variety of diseases, including previously untreatable monogenic diseases. Overall, CRISPR-Cas9 technology has a highly transformative potential that is expected to have an impacts on various important megatrends in biotechnology and medicine bringing great benefits to mankind (figure 1).

Current and potential applications of CRISPR-Cas9
Figure 1: Current and potential applications  of CRISPR-Cas9 genome editing. Adapted from [6].

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References

[1] https://en.wikipedia.org/wiki/Jennifer_Doudna

[2] https://en.wikipedia.org/wiki/Emmanuelle_Charpentier

[3] Deltcheva, E. et al. 2011. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature 471(7340):602-7.

[4] Jinek, M., J.A. Doudna, E. Charpentier et al. 2012. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816-21.

[5] https://supertrends.com/first-in-vivo-crispr-medicine/

[6] Doudna, J.A. and E. Charpentier 2014. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science 346(6213):1258096.

What are genome editing and CRISPR-Cas9?

Genome editing (also called gene editing) is a set of technologies that enable scientists to change the genetic code in the living cells of an organism. They make it possible to make specific changes to a particular location in the genome in a controlled way. One of the approaches is known as CRISPR-Cas9.

The “Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9”, or CRISPR-Cas9 for short, was discovered by a team of CRISPR pioneers led by biochemists Emmanuelle Charpentier from France and Jennifer Doudna from the US. CRISPR-Cas9 is a genome editing system that occurs naturally in bacteria, which use it to protect themselves against viruses.

CRISPR-Cas9 applications in humans

An adapted CRISPR-Cas9 system can act also on the genome of higher organisms, including humans. Researchers generate a small piece of ribonucleic acid (RNA) with a short guiding sequence that attaches to a specific target sequence of DNA in a genome. The Cas9 enzyme is also bound to the RNA. As in bacteria, modified RNA is used to recognize a target DNA sequence, and the Cas9 enzyme cuts the deoxyribonucleic acid (DNA) at the intended location. Enzymes other than Cas9 may also be used for this process. After the target DNA is cut out, researchers make use of the DNA repair machinery of the cell in order to introduce changes in the DNA by replacing an existing segment with the desired DNA sequence.

Most of the applications in humans are limited to somatic cells, which are cells other than egg and sperm cells. Although changes in the germline would be passed on to the next generation, germline modifications are forbidden in most countries.

Relevance for science

This approach creates a pathway to cures for unwanted changes in human genes. The approach is being explored in a wide variety of diseases, in particular previously untreatable single-gene disorders (monogenic diseases), such as Leber congenital amaurosis 10, which causes blindness.


Genome editing is already used in human clinical trials. Interested in what will happen next? We have asked experts and the Supertrends community for their opinion. Simply search for “gene therapy” in the Supertrends Pro app to see their predictions for future breakthroughs in this field. Not an app user yet? Visit the Supertrends Pro – page to learn about your benefits and request a trial – for free!

© 2020 Supertrends

First in vivo CRISPR medicine administered to patients in clinical trial

On 4 March 2020, the collaborating companies Allergan plc and Editas Medicine, Inc. announced the dosing of the first patient with the CRISPR-based medicine AGN-151587 (EDIT-101) in a phase 1/2 clinical trial (BRILLIANCE trial).[1]  

Treatment for Leber Congenital Amaurosis 10

AGN-151587 (EDIT-101) is an experimental CRISPR-based medicine currently under development. The medicine is delivered via sub-retinal injection under development for the treatment of Leber congenital amaurosis 10 (LCA10). LCA is inherited form of blindness caused by mutations in the gene coding for the protein 290 (CEP290).[2]

Leber congenital amaurosis (LCA) is a group of inherited retinal degenerative disorders caused by mutations in a growing group of genes. The most commonly affected genes are CEP290, GUCY2D, CRB1, RPE65, RDH12, RPGRIP1, and AIPL1.[3] LCA is associated with severe visual impairment within the first year of life and is the most common cause of inherited childhood blindness. The prevalence of LCA is between 1/50,000 and 1/33,000 live births and accounts for 5 percent of all retinal dystrophies and 20 percent of blindness in school-age children.[4] The most common form of the disease, LCA10, is caused by mutations in the CEP290 gene and is the cause of disease in approximately 15-20 percent of all LCA patients.[3]  

The BRILLIANCE clinical trial

The BRILLIANCE clinical trial is a Phase 1/2 study to evaluate the safety, tolerability, and efficacy of AGN-151587 in approximately 18 patients diagnosed with LCA10. Additional patient enrollment to the BRILLIANCE Clinical Trial is ongoing. Up to five cohorts of patients across three dose levels are planned to be enrolled in the open label, multi-center clinical trial. Both adult and pediatric patients (ages 3-17) with a range of baseline visual acuity assessments are eligible for enrollment. Patients will receive a single administration of AGN-151587 via subretinal injection in one eye. Additional details can be found on clinicaltrials.gov.[4]

Cynthia Collins, president and CEO of Editas Medicine, commented on the groundbreaking nature of the treatment:


“This dosing is a truly historic event – for science, for medicine, and most importantly for people living with this eye disease. The first patient dosed in the BRILLIANCE clinical trial marks a significant milestone toward delivering on the promise and potential of CRISPR medicines to durably treat devastating diseases such as LCA10. We look forward to sharing future updates from this clinical trial and our ocular program”[1] Cynthia Collins, president and CEO of Editas Medicine


Mark Pennesi, M.D., Ph.D., Associate Professor of Ophthalmology, Kenneth C. Swan Endowed Professor, Division Chief, Paul H. Casey Ophthalmic Genetics, Casey Eye Institute, Oregon Health & Science University, Principal Investigator and enrolling physician of the first patient treated with AGN-151587, said:


“Our first treatment in this clinical trial is an important step toward bringing new and promising treatments to patients with disease-causing gene mutations. OHSU is honored to be involved in this effort to address previously untreatable diseases such as Leber congenital amaurosis 10”[1] Mark Pennesi


In summary, the study represents a key milestone in gene therapy and has the potential to serve as clinical proof of concept for in vivo administered CRISPR-based medicines.


Are you interested in other milestones regarding gene therapy? Simply search for “gene therapy” in the Supertrends Pro app to see our expert- and crowdsourced predictions for future breakthroughs in this field. Not an app user yet? Visit the Supertrends Pro – page to learn about your benefits and request a trial – for free!

© 2020 Supertrends

References 

[1] https://ir.editasmedicine.com/news-releases/news-release-details/allergan-and-editas-medicine-announce-dosing-first-patient

[2] https://www.omim.org/entry/611755

[3] Kondkar AA and Abu-Amero KK. Leber congenital amaurosis: Current genetic basis, scope for genetic testing and personalized medicine. Exp Eye Res. 2019 Dec;189:107834. doi: 10.1016/j.exer.2019.107834. Epub 2019 Oct 19.

[4] https://www.orpha.net (Orpha#: 65)

[5] www.clinicaltrials.gov (NCT#03872479) 

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