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Genome Editing: An Introduction

March 24, 2020


Written by: Ismail Ismailoglu, PhD Ivana Yeow, PhD

Key takeaways:

  • After focusing efforts on protein and more recently RNA targets, the bio-pharmaceutical industry is now getting ready to modify DNA with genome editing, the final piece of the central dogma of molecular biology
  • While genome editing technologies were being developed for many years, it is only now that we are seeing this being translated into clinical use
  • With more and more companies looking to commercialize genome editing, the key players to look out for include Sangamo, Cellectis, bluebird bio, Editas Medicine, CRISPR Therapeutics, and Intellia Therapeutics

CBPartners take: Genome editing is still a few years away from the clinic, but presents an immense opportunity for the future of the pharmaceutical industry.

A powerful new tool for making precise alterations to the genome

With the recent launches of ZOLGENSMA® (Onasemnogene abeparvovec) and ZYNTEGLO® as well as more assets in the pipeline, the gene therapy field has been gathering steam over the last few years. Amongst the news of these exciting products you might have also heard about genome editing, a technology that has only recently entered clinical trials. While the two approaches are related, genome editing has been lauded by some as the next paradigm shifting technology in life sciences, due to its precision and versatility. Members of the Cell and Gene Therapy Center of Excellence have been keeping an eye on this emerging field, as biotech and pharma companies start to move through clinical trials. In this blog post, we would like to provide you with a primer on the technology, its applications, and a look at some of the major players in the landscape.

The central dogma of molecular biology explains life through the interaction of three types of molecules: DNA, RNA, and protein. Of the three, scientists first learned how to target proteins to modify the course of a disease, altering protein function with small molecules (e.g., imatinib / GLEEVEC®) and then with antibodies (e.g., adalimumab / HUMIRA®). RNA-based therapies entered the landscape more recently. We now have a few approved products – and many more in the pipeline – that can manipulate their targeted RNAs in different ways to achieve desired outcomes at the protein level (e.g., nusinersen / SPINRAZA®, patisiran / ONPATTRO®). Genome editing targets the final and the most stable player in the central dogma, the DNA, potentially allowing treatment of a disease at its source.

The development of genome editing technologies

CRISPR technology, a tool used by researchers to easily alter DNA sequences and modify gene function, operates with versatility and relative simplicity. It has recently captured the headlines and brought genome editing into focus for many us, while related approaches (e.g., ZFNs, TALENs, megaTALs) have been around for many years. At its core, all genome editing technologies rely on making a “cut” (i.e., a break) at a precise location in the stable backbone of the DNA. This intentional “damage” kicks off a rapid cellular response to repair. Changes to the code then can be introduced by providing a “repair template” carrying the desired letters or simply letting the erratic cellular repair mechanisms delete a few bases on each side of the break. Successfully edited cells will start producing RNA and/or proteins according to the new code and faithfully copy and pass it along to daughter cells when they divide.

Mechanisms, advances, and prospects of genome editing

Genome editing has several advantages when compared to recently launched (e.g., ® (voretigene neparvovec), ZOLGENSMA® (onasemnogene abeparvovec) that introduce new genetic code into cells:

  • Ability to edit larger genes: Due to the carrying capacity of the gene therapy vectors, addressing issues with large genes is not straightforward, particularly with the current methods available. Genome editing, on the other hand, only requires the introduction of a shorter “repair template” rather than the whole sequence, thus allowing treatment using current vectors.
  • Precise control of expression: Current gene therapies allow limited control on the expression of the introduced sequence, while with genome editing technology, the corrected sequence remains within the context of the genome and thus expression can be controlled through regular cellular mechanisms. However, this advantage can become a vulnerability in cases where the high-level expression of a gene is necessary.
  • Precise targeting: Editing an be seen to have an advantage vs. integrating vectors (e.g., lentiviruses) due to more precise targeting, but an argument can still be made for the safety of non-integrating vectors (e.g., AAVs) that leave the genome intact and avoid introducing any dangerous breaks.

Knowing the power of the technology, it is not hard to dream of applications targeting human disease. Proposed therapeutic areas for the technology cover a broad spectrum including rare genetic disorders (e.g., cystic fibrosis, Huntington’s disease, beta-thalassemia), oncology through modification of CAR T cell therapies, and even common conditions such as hypercholesterolemia. As the challenges in human applications continue to evolve, initial efforts largely focus on “easier” target diseases where editing can be achieved outside the body (e.g., hematologic disorders), and those that require a low number of cells to be edited (e.g., retinal disorders).

Biotech companies and their role with genome editing

Among the older technologies, ZFN (zinc finger nuclease) is largely controlled by the biotech company Sangamo, while Cellectis and bluebird bio lead the charge using the similar TALEN (transcription activator-like effector nucleases) and megaTAL technologies respectively.

Sangamo Therapeutics, founded in 1995, has two Phase II ZFN-based assets, targeting beta-thalassemia and sickle cell disease with their partners Bioverativ / Sanofi, while their wholly-owned MPSII treatment aims to eliminate the need for enzyme replacement therapy by expressing the missing enzyme from edited liver cells instead. The company has also recently signed a deal with Kite Therapeutics (owned by Gilead) to develop off-the-shelf and modified autologous CAR T therapies. Indicating their aspirations for the ZFNs beyond genome editing, Sangamo also entered an agreement with Biogen, where they would develop ZFN-based tools that can repress or activate genes to address neurodegenerative disease, such as Alzheimer’s or Parkinson’s.

Cellectis, founded in 1999 and headquartered in France, has chosen to focus specifically on the editing of CAR T cells to advance a portfolio centered around off-the-shelf oncology cell therapies. The company partners with Allogene Therapeutics, a recent spin-off from Pfizer, on a number of assets. Maintaining the oncology focus, Cellectis also entered a licensing agreement with Iovance Biotherapeutics. The goal of the collaboration is to use genome editing to improve Iovance’s TIL (tumor infiltrating lymphocyte) products in development.

As they get ready to launch their beta-thalassemia gene therapy ZYNTEGLO in the EU and push towards the finish line with their leading CAR T asset together with their partner BMS, genome editing can be seen as a side endeavor for the USA-based bluebird bio. However, the company recently entered a three-year collaboration agreement with Novo Nordisk, to use their megaTAL platform to develop treatments for haemophilia.

The future of genome editing technologies

When it comes to the youngest kid on the block, CRISPR, the world is murkier. Against the background of a seemingly never-ending patent battle, there are three leading companies currently moving forward to commercialize the technology.

  1. Editas Medicine
  2. CRISPR Therapeutics
  3. Intellia Therapeutics

There’s CRISPR Therapeutics and their Vertex-partnered, beta-thalassemia, and sickle cell disease asset. Editas, with the Allergan-partnered LCA treatment got to the clinic first; but Intellia is not far behind and is expected to launch a clinical trial with Regeneron in 2020. As with the more established genome editing companies, all three CRISPR leaders are also getting ready to explore the CAR T cell therapy world. Editas is partnered with BMS (established during the Juno years) and Intellia is working with Novartis in these efforts, while CRISPR Therapeutics have chosen to fully own their assets.

If the volume of pharma and biotech investment in genome editing is any indicator, the future for the technology is bright. The CBPartners team will continue to follow this topic as the technology improves, new targets are identified, and clinical trial outcomes are revealed. In the meantime, if you have any questions on the future of this exciting technology, please do not hesitate to reach out to us.


If you are interested in reading more about the Cell & Gene Therapy landscape, read related posts in the Center of Excellence team’s thought leadership channelor find out more about the work we do.

If you’re interested in finding out more about CBPartners’ work in this landscape, please contact Julia Pikus, Principal (Julia.pikus@cbpartners.com) and Ismail Ismailoglu, Senior Manager (ismail.ismailoglu@cbpartners.com), co-founders of the CBPartners Center of Excellence.