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Manipulating the Fabric of Life

Someone’s famous uncle once said, “With great power comes great responsibility.” Genome editing is an incredibly powerful technique with huge promise and potential for medicine, as well as many other fields including agriculture and the environment. But those wielding the power must cut through the hype, evaluate the potential, and use it wisely. Here, we talk to a selection of experts using genome editing and CRISPR/Cas9 for drug development purposes to get their views on the field. 

“A new genetic revolution.” 

“The ultimate therapy.” 

These are just two of the tantalizing phrases used by our panel when describing the technology and what it could accomplish… 

The Experts

Tirtha Chakraborty

Chief Scientific Officer, Vor Biopharma

“Vor Bio is the first ever company in the world doing allogeneic genome engineering for allogeneic hematopoietic transplants. We are focused on the treatment of hematopoietic diseases and making the hematopoietic transplant the best type of transplant on the planet.”

Rachel Haurwitz

CEO at Caribou Biosciences

“Caribou Biosciences is a genome editing company that was spun out of Jennifer Doudna’s lab at the University of California, Berkeley. Caribou has invented its own next-generation CRISPR technology, called chRDNA (CRISPR hybrid RNA-DNA), which we believe is more specific than first generation CRISPR/Cas9. The chRDNA genome-editing technology is being used to develop allogeneic cell therapies – mainly for oncology applications. Our pipeline includes CAR-T cell therapies for hematologic diseases and iPSC-derived CAR-NK (natural killer) cell therapies for solid tumors.”

Linda De Jesus

Vice President and General Manager, Global Head of Commercial at Integrated DNA Technologies (IDT)

“IDT is a biotechnology company that specializes in the manufacture and development of custom nucleic acid products. We also consider ourselves to be on the cutting edge of gene editing technologies. We’ve helped enable significant contributions in the gene editing field by providing complete CRISPR genome editing workflow solutions – from design to analysis  – through our CRISPR systems.”

Eric Rhodes

CEO at ERS Genomics

“Our founder, Emmanuelle Charpentier, won the Nobel Prize in 2020 for the discovery of CRISPR/Cas9. At ERS Genomics, we are in the business of licensing her CRISPR intellectual property for commercial use. We manage the rights outside of use in cell and gene therapy. We therefore deal with a broad cross-section of companies and industries, from basic life science research to animal health, to industrial applications.”

Why are you so excited about the potential of gene editing?

LDJ: CRISPR/cas9 is a captivating technology. In 2019, the first American patient treated with CRISPR technology for sickle cell disease achieved disease-free status. This technology's potential also extends beyond medicine; it has the power to address food crises, improve agriculture, aid drug development and pathogen detection, and offer solutions to climate change. CRISPR technology has made re-writing the code of life easy, accurate, and accessible, fueling a new genetic revolution.

TC: It is such an exciting area. Changing a fundamental aspect of biology and permanently correcting genetic messages with a level of elegance that was previously unthinkable. If diseases were created by nature, then now we have the ability to challenge them using tools presented to us by Mother Nature herself. Gene editing could be the ultimate therapy for targets that have previously been undruggable. 

RH: For me, it's about opening the door to what I think of as the third leg of the stool in the world of drug development. Today, that stool is a bit rickety with just two legs: small molecules and antibody/protein therapies. I believe the third leg is genetic medicine. Genome editing is important because if we can manipulate the genome, either ex vivo or in vivo in a variety of contexts, then we will be able to help so many different kinds of patients with different diseases.

ER: Ever since the completion of the human genome project, and in the years following, the scientific community has accumulated a massive amount of sequence data. What was initially lacking was the ability to actually manipulate that information in cells. Gene editing is the tool that allows us to utilize that information in the context of a living system to better understand pathways and how those sequences interact and are controlled. An analogy I like to make is to consider the genome a database of information; the cellular machinery is the software that runs the programs; and gene editing is a programming language we can use to manipulate the data and run programs. The introduction of CRISPR has also been a revolutionary step in making genome editing applications available to everyone, no matter what organism they may be working with.

How do we separate the hype from the reality?

LDJ: It is essential to approach CRISPR technology with critical thinking and a balanced perspective. While acknowledging its incredible potential as a powerful gene editing tool, it is equally important to recognize that the field is still in the early stages of development and faces significant challenges. Researchers worldwide are working to overcome these obstacles, and though wide-scale implementation of CRISPR applications, particularly in clinical settings, may take time, the technology continues to demonstrate hope. 

TC: The hype and excitement will help to fuel interest and further research in the field. However, we are not yet at the epicentre of precision genome engineering for most cells in the body, so while there is hype, we need to be careful about what is truly attainable with today’s technology and what is not. We still cannot get to every part of the body, even with existing delivery technologies for in vivo genome engineering. Most of the focus to date has been on the liver. How do we target the lung? Or neurons? Or even the skin? We can’t do this regularly just yet. If a delivery technology emerges that is capable of reaching every part of the body, without tissue off-target effects, then we will have a real victory. Additionally, most cells in our body do not divide. Today’s standard CRISPR/Cas platform is not very good in the precision engineering of those cells. That needs to be resolved as well, if the potential of this technology is to be fully harnessed. 

The negative side of the hype is that there are some people out there who believe we’re going to make CRISPR babies every day. If you want to change the world, you need to be cautious. We need to work very closely with regulatory authorities about what is possible and what is not, as well as to understand what the implications are when we’re working with humans rather than mice.

RH: We can all be guilty sometimes of creating hype. Scientists have pointed out that there are around 7000 monogenic genetic diseases. Wouldn't it be great if you could use CRISPR to address each of them? While certainly true at the 50,000 foot view level, I think the practical reality of how you do that becomes complex quickly. Sickle cell disease is a classic example where one mutation is shared across all patients, which opens the door to one genome editing strategy that could potentially serve the entire patient population.

In diseases like cystic fibrosis or muscular dystrophy, patients have different mutations that may require a multiplicity of different kinds of genetic medicines. And that's just the tip of the iceberg. There is definitely a lot of potential, but we have a lot of work to do.  

However, I always get worried when I talk to friends who are not in the biotech world and who base their reading on mainstream news; some of them have come to the conclusion that you can CRISPR any gene in any cell at any time. That is not reality – nor will it be anytime soon. We have to be very cautious about the kinds of promises we make to patients and to our communities about what is actually possible today, what we hope will be possible tomorrow, and what some futuristic landscape might look like. 

The reality today is that there is a fairly short list of cell types, either outside the body or inside of the body, that we can edit with high fidelity in a way that could lead to near-term clinical translation. However, there's a lot of work happening that will open the door to additional tissues and cell types in the not too distant future. 

ER: The hope has always been that once a genetic mutation leading to disease was known,  genome editing might be applied to repair the mutation and lead to a cure. But from a therapeutic reality perspective, this is not as easy as it sounds. The main challenge for gene editing remains the matter of delivery. If the mutation requires only a small portion of cells to be targeted for delivery and editing, there is a good chance that gene editing can play a role, but with most diseases this is often not the case. I frequently receive letters from desperate parents whose child has been diagnosed with a disease associated with a genetic mutation asking if CRISPR can be deployed to help their child, but often the situation would call for editing of virtually all the cells in the body and this just isn’t possible at this time. 

In the Pipeline

Vertex and CRISPR Therapeutics

These two companies have been collaborating on CRISPR/Cas9 since 2015. Their treatment for sickle cell disease (exagamglogene autotemcel; exa-cel) is being watched closely. Exa-cel is under priority review by the EMA and a rolling BLA submission has been made to the FDA. This is the closest gene-edited therapy to a potential approval.

Exa-cel is an autologous, ex vivo CRISPR/Cas9 gene edited therapy which involves editing a patient’s hematopoietic stem cells to produce high levels of fetal hemoglobin in red blood cells.

Beam Therapeutics

Beam Therapeutics is also working on treatments for sickle cell disease. The company uses base editing technologies developed at Harvard University and the Broad Institute of MIT and Harvard, and is working on a range of therapeutic candidates, including three undisclosed targets with Pfizer. Its lead programs are Beam-101 and Beam-102 – both are ex vivo gene editing therapies for sickle cell disease.

Its Beam-101 candidate produces base edits to activate fetal hemoglobin; Beam-102 edits the causative hemoglobin S point mutation to recreate a naturally occurring normal human hemoglobin variant, HbG-Makassar.

Editas Medicine

Another company with its eyes on sickle cell disease; Editas Medicine’s lead clinical program is EDIT-301, an ex vivo gene editing therapy for sickle cell disease and transfusion-dependent beta thalassemia where patient-derived CD34+ hematopoietic stem and progenitor cells are edited at the gamma globin gene promoters.

The company also has a partnership with Bristol Myers Squibb to develop ex vivo gene edited cell medicines for cancer.

What have been the biggest milestones to date?

LDJ: Since the 2012 discovery of the CRISPR-Cas9 system by Nobel laureates Jennifer Doudna and Emmanuelle Charpentier, followed by Feng Zhang's demonstration of its successful use in mammalian cells in 2013, several significant milestones have been achieved. Noteworthy achievements include (but are not limited to) the first ex vivo CRISPR therapy for sickle cell disease, the first clinical data supporting safety and efficacy in in vivo CRISPR genome editing for transthyretin amyloidosis, and the development of prime and base editing technologies for precise genome modifications.

TC: We have seen some promising genomic engineering using lentiviral and AAV vectors, but they have their limitations regarding both safety and efficacy. Using CRISPR, a much greater sophistication of genome engineering has reached the clinic and demonstrated real benefits in patients already. I am referring to the CRISPR therapeutics + Vertex programs for beta thalassemia and sickle cell disease. The in vivo editing success by Intellia Therapeutics is most impressive as well. 

Vor Bio has been working to perform allogeneic genome engineering for hematopoietic  transplants. So far, the engineered hematopoietic transplants are all autologous, and while they are wonderful, nobody has done this with healthy donor derived allogeneic cells and for malignant diseases. In the future, I really hope that engineered allo-transplants for cancer will become the standard of care.  

RH: There have been exciting early clinical datasets from a few companies – and I’m proud to say that Caribou has contributed to that! It is remarkable to think about how quickly this field has moved. It was the summer of 2012 when some of my co-founders published what has turned into a seminal manuscript in Science, demonstrating that you could reprogram the genome using Cas9 and CRISPR all-RNA guides. And here we are, not quite 11 years later, with a number of different organizations who are developing initial clinical data. We could even see the first approved CRISPR medicines sometime later this year. 

ER: Several promising CAR-T approaches for treating cancer utilize genome editing. CRISPR Therapeutics’ sickle cell and beta-thalassemia trial results indicate both safety and efficacy. Intellia’s ATTR program using a systemic delivery approach is also highly encouraging. One of our licensees recently presented data on engineering of mushrooms intended for clinical studies, opening up another important avenue of new drugs.

What are the ethical questions around gene editing? 

LDJ: Germline editing, exemplified by He Jiankui's controversial work in 2018, raises concerns about the long-term implications and unforeseen consequences of modifying the human genome. Since the twins’ genomes were modified while they were still embryos, the created genetic change can be transmitted to their children. Other ethical debates center around issues such as creating “designer babies” or non-medical genetic enhancement that could exacerbate existing social inequalities. Cultural and religious differences may also influence attitudes and ethical considerations surrounding CRISPR genome editing.

Thoughtful evaluation of ethical considerations, facilitated by collaboration among scientists, regulatory bodies, and policymakers, will be necessary to ensure responsible and informed decision-making for all, including those in underdeveloped and developing nations.

RH: Absolutely there are ethical implications – and Caribou has been involved in some of those discussions both in the US and internationally. I was one of the first industry speakers to participate in the latest iteration of the International Summit on Human Genome Editing, where academic, government and industry leaders gather to discuss advances in the technology and the responsibility the scientific and biotechnology community has in ethically implementing this technology.

This is a tremendous technology, and it comes with a tremendous responsibility to be ethical stewards for its appropriate use. For us, there is a very firm line when it comes to embryo editing. We have a company policy that we do not edit human embryos. Period. The end. We bake this into license agreements with other companies too. If you happen to buy an RNA reagent from a company like IDT, for example, you will find a document in the box that is a limited use label license that says you cannot use this reagent for human embryo editing.

TC: I agree; we are not ready for CRISPR babies. For pretty much everything else, I think there is some concern but we should not worry too much. The first people who need to understand CRISPR are the doctors who are going to allow these trials – because all of this good work will hit a brick wall if clinical investigators are not informed enough. There are still some questions about CRISPR, mostly due to lack of familiarity with a new field that has the power of making permanent genetic changes, but we must be brave. We don’t want to see patients die without therapies because we weren’t brave enough to try something new. 

ER: As with any emerging technology, there are clearly many ethical issues that need to be addressed. The CRISPR babies triggered many discussions surrounding genome editing in embryos. Here, the questions are about the long-term consequences of making permanent changes to the human gene pool. But so far, there hasn’t really been a thorough global discussion on the topic or formally adopted guidelines. We also need to consider the topic of enhancement versus therapy; CRISPR/Cas9 has the potential to go beyond treating genetic diseases and enable genetic enhancements or modifications for non-medical purposes. There are many questions about the ethics of using gene editing to enhance traits such as intelligence, athleticism, or appearance. Should CRISPR/Cas9 be used for these purposes? What are the limits and consequences?

And then what about access and equity. Could CRISPR/Cas9 exacerbate existing inequalities if it’s only available to those who can afford it?

A final area of concern I will mention is the use of gene drives. Used safely and ethically, these can be a tremendous tool, but they also represent a very clear danger if misused. Public debate, interdisciplinary discussions and involvement of stakeholders are essential in navigating these complex issues as we move forward with this genuinely revolutionary technology.

A Brief History on CRISPR

Few breakthroughs have captured the imagination like CRISPR in the field of genetic research. Short for “Clustered Regularly Interspaced Short Palindromic Repeats,” CRISPR DNA sequences were first located in Escherichia coli bacteria in 1987 (1). Yet, unbeknownst to its early investigators, the true origin and significance of this discovery would remain a phenomenon for some time. Fast forward to 1995, Francisco Mojica from the University of Alicante found similar structures in the archaeal genome of Haloferax mediterranei. Upon noticing the similarity of the elements he described in archaea with previously known DNA repeats in bacterial genomes, Mojica hypothesized that CRISPR loci include fragments of foreign DNA, and were related to the immune system of bacteria and archaea. 

Building upon Mojica’s seminal findings, subsequent research revealed that bacteria possess the ability to transcribe specific DNA elements into RNA as a responsive measure to viral infections. These RNA molecules act as guiding beacons, leading a specialized nuclease named “Cas” (short for “CRISPR-associated”) in a sophisticated defense mechanism against invading viruses. More specifically, Cas proteins precisely cleave foreign DNA, incorporating the resulting fragments into CRISPR arrays – continuous DNA stretches. Separate Cas proteins then facilitate the expression and processing of CRISPR loci, which generate CRISPR RNAs (crRNAs). crRNAs serve as guides for Cas nucleases, directing them to exogenous genetic material containing a species-specific protospacer adjacent motif (PAM). The CRISPR complex finally binds to the foreign DNA and cleaves it to destroy the invader. To date, CRISPR repeats have been identified in the majority of archaeal genomes and nearly half of the bacterial ones examined thus far.

Of all known Cas proteins, the most studied are those belonging to the system of directional cutting of foreign DNA, which includes the nuclease Cas9. CRISPR-Cas9 offers the advantage of simultaneously targeting multiple genes, eliminating the need for separate cleavage enzymes. Moreover, the system can be easily combined with customized “guide” RNA (gRNA) sequences, which are readily accessible to researchers. This understanding paved the way towards a major advancement in CRISPR genome editing technology: homology-directed repair. Enabling precise integration of donor DNA where the cut site occurred, this technique allows for activation of gene expression. Researchers have since permanently modified genes in living cells and organisms and, in the future, may be able correct mutations at precise locations in the human genome to treat genetic causes of disease.

However, the power to engineer biological systems and organisms comes with inherent ethical concerns. Editing the genomes of gametes and early embryos raises profound implications, not only for the individuals but also for future generations, since there is a potential for not just curing diseases, but also for enhancing desirable traits. As a result, the scientific community has encouraged a moratorium on human germline editing until a comprehensive understanding of the ethical implications and societal consequences is achieved. In many countries, it is illegal to genetically modify human embryos for purposes other than reproductive. 

From its humble origins, to its elucidation as a remarkable immune defense system, CRISPR has opened doors to a realm of possibilities for manipulating the fundamental aspects of life. Its applications extend across medicine and biotechnology, offering the potential to revolutionize therapeutic interventions beyond our previous expectations. As scientists continue to explore and harness the power of CRISPR, it will be crucial to strike a balance between scientific progress and the responsible consideration of ethical implications.

What are the biggest challenges facing this area of the industry?

LDJ: There are several crucial questions in the field that scientists are actively addressing. These include concerns about off-target effects, where unintended editing occurs in regions of the genome similar to the target region. Additionally, efficiently delivering CRISPR reagents in a cell type- and tissue-specific manner remains challenging. Evaluating the long-term effects and ensuring the safety of CRISPR-based therapies are also essential. Comprehensive long-term studies, both preclinical and clinical, are necessary to assess gene editing stability, potential immune responses, and any unintended consequences resulting from genome alterations.

RH: Not every underlying technology is going to be the best fit for every disease. For any given disease, we have the responsibility to figure out what is the best collection of technologies needed that could develop the right therapy.

At Caribou, we have been focused on off-the shelf cell therapies for oncology, and use our genome editing capabilities to do what we call “armoring” to enhance the cells and make sure they have sufficient antitumor activity, which is needed to rival that of today’s approved autologous CAR T therapies.

We believe that off-the-shelf has to be the answer if we want to deliver these kinds of therapies to increasingly broad patient populations. But it’s not as easy as taking a healthy T cell from a healthy donor and adding a CAR, which would be foreign to the patient’s immune system and thus rejected. We have to enhance, or armor, the cells to bridge the gap. 

ER: I think concerns remain around safety and which version of genome editing might be the safest to use in each clinical situation. Base editing and prime editing are both seen as potentially safer versions of CRISPR, but both have limitations that don’t make them as broadly applicable as the more traditional CRISPR/Cas9. 

I also believe that further discussion on the ethical concerns of genome editing must be clearly a priority. Making gene editing therapies affordable and broadly available will also be a challenge for the industry in the coming years. For my company, our goal over the next decade is to expand the use of CRISPR/Cas9. We want more companies using CRISPR/Cas9 globally and realizing its great potential.

TC: I would point to the quality of scientists as a challenge. There is not a lot of expertise in this area since the field is so new – particularly in manufacturing. High science cannot be limited to just research departments; we need people who will ask manufacturing, regulatory, and quality questions too. In many areas of drug development, there are pre-existing templates, but for genetic medicines, the lack of familiarity amongst people trained in a much more templated, traditional environment, and believing that the previously tried and tested template is going to work each time, could be a recipe for disaster. We need education across the board. We need to educate and inform patients too so they can understand the reality of these therapeutics, and to alleviate their concerns. 

What are the delivery challenges of gene edited therapeutics?

LDJ: Enhancing specificity and minimizing off-target effects are among the top priorities in ensuring the safety and reliability of CRISPR therapeutics. We need efficient delivery methods that target specific cell types or tissues. Advances in delivery methods, such as lipid nanoparticles, will enable precise delivery of CRISPR reagents to the targeted cells or tissues. Understanding the long-term effects of CRISPR-mediated therapeutics also continues to be important for clinical translation.

RH: Gene editing can be used in many ways. At my company, we are focused on cell therapies that we manufacture ex vivo – in part, largely because we can readily deliver using electroporation or other technologies to manipulate the cells at very high efficiency and in large batches. There are only so many cells that you can address in that way, such as T cells, hematopoietic stem cells, and a small number of others. To meaningfully turn the hype of in vivo genome editing into reality, we have to figure out how to deliver these reagents with high fidelity to specific organs within the body. I think this is one of the biggest bottlenecks and biggest challenges for the entire genome editing field. Some of our peers in the space have made some very exciting initial efforts and demonstrated great ability to edit cells in the liver. There is a lot that can be done in the liver, but there’s also a lot that cannot be done by targeting the liver. I hope that there are a lot of great academic institutions and companies focusing on innovating in this space because I think it's the key to the future of genome editing.

ER: The delivery method used generally depends on the target cells or tissue. Systemic delivery often uses AAV or a nanoparticle formulation. Ex vivo cell therapy can use a variety of delivery modalities, although AAV, RNA, and plasmids are commonly used. Issues related to re-treatment may also complicate this space. Not all genome editing applications may be ‘one and done,’ although that may be the goal. 

Effective delivery and continued safety will remain the biggest challenges for some time. A safety setback could impact the entire industry and because there are so many diverse clinical applications being explored, many independent groups are involved. 

Is safeguard sgRNA the key to reducing the off-target effects of gene editing, while increasing its potential applications? Find out in our article Enhancing CRISPR-Cas9

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