What Do the Next 10 Years Hold for CRISPR?

Executive Summary

• The biomedical potential of CRISPR was discovered just 10 years ago, but the past decade has seen significant advances in the clinic and in the lab
• Today, developers of CRISPR-based therapies are running in vivo clinical trials in a handful of orphan diseases, as well as using CRISPR to generate novel cell therapies for hematologic malignancies
• Over the next 10 years, we expect the biomedical applications of CRISPR to accelerate:
  • A second wave of in vivo clinical trials including larger indications
  • Innovations enabling delivery of CRISPR to a greater variety of tissue
  • Expansion of the CRISPR toolkit to include base editors, prime editors, and others
  • Non-clinical advances in synthetic biology, agriculture, and research
• CRISPR developers must also confront the challenges of navigating economic headwinds, proving the safety of gene editing, and ensuring equitable access for patients
   

Introduction

Carl Zimmer recently published an article in The New York Times titled “CRISPR, 10 Years On: Learning to Rewrite the Code Of Life,” in reference to a seminal 2012 research paper from Jennifer Doudna’s lab at UC Berkely. CRISPR had of course been discovered long prior to 2012, although before then it was most notable for its implications in the manufacture of yogurt. So why was 2012 seen as the turning point for CRISPR? Because that’s the year that the biomedical potential of CRISPR was definitively demonstrated, first for its genome editing potential in bacteria, and soon after in humans and many other species. While it would be several more years until CRISPR gained broader recognition in the scientific community and subsequently the public, 2012 marked the beginning of the CRISPR revolution.

Considering that it has only been 10 years, the pace of progress for CRISPR has been astounding. In his article, Zimmer expands on the applications of CRISPR in research, medicine, and agriculture. It has also sparked controversy and urgent conversations about the ethics of genome editing. It resulted in the 2020 Nobel Prize for Professor Doudna and her collaborator. There have even been multiple iterations of CRISPR proteins: base editors, prime editors, epigenome editors, RNA editors, and others which expand on CRISPR’s capabilities and therapeutic potential.

Looking back on the progress over the last 10 years led us to reflect on what the future might hold for CRISPR. Where are the current applications of CRISPR pushing the field of medicine? Where will the next waves of CRISPR therapeutic development take place? And what are the critical challenges that must be addressed by CRISPR developers over the next decade?

Where Do Things Stand Today?

Current developers of CRISPR-based therapies are pursuing both in vivo and ex vivo applications. The initial in vivo applications have tended to focus on orphan indications, including transthyretin amyloidosis, Leber’s congenital amaurosis, and hereditary angioedema (Table 1). We recently published a white paper discussing portfolio strategy for CRISPR companies, and within our framework, these early indications share several attractive features: the genetic roots are well understood; there is an established clinical development pathway; and the disease burden is high enough to justify a riskier therapeutic approach such as CRISPR-mediated gene therapy. Early in vivo CRISPR programs have also focused on diseases originating in tissue where delivery of the CRISPR machinery is feasible, such as the eye, bloodstream, liver, and brain.

Ex vivo applications thus far have centered around using CRISPR tools to generate allogeneic, or “off-the-shelf,” cell therapies for hematologic malignancies such as non-Hodgkin’s lymphoma and multiple myeloma. The control afforded by ex vivo use of CRISPR presents fewer safety and delivery challenges compared to in vivo applications, and indeed CRISPR editing of cell therapies may be seen as a safer alternative to the untargeted viral integration-based approaches that preceded it. Beyond hematologic malignancies, CRISPR-derived cell therapies are also under study for solid tumors, sickle cell disease, and Type 1 diabetes (Table 1).

Though less flashy, the impact of CRISPR beyond the clinic shouldn’t be overlooked. CRISPR tools have allowed for the discovery and validation of novel therapeutic targets, the efficient generation of stable cell lines for manufacturing biologics, and the rapid development of in vitro diagnostics.

Table 1. Key Clinical-Stage CRISPR Programs

Where Will the Next Wave of Development Take Place?

Given CRISPR’s progress to date and immense future potential, we will be following several key trends over the next 10 years:

In Vivo Applications in Larger Indications

We expect CRISPR-based therapies to be studied in larger and more common diseases, driven by validation of the platform technology in ongoing studies, better understanding of the safety risks of in vivo editing, and increasing comfort with CRISPR-based medicine among providers and patients. Researchers and investors will also be hungry to continue pushing the boundaries of which diseases are amenable to CRISPR gene editing. This trend is evident in both the clinical and preclinical pipelines of CRISPR companies. Earlier this year, Viacyte and CRISPR Therapeutics announced their first patient dosed with a cell therapy for Type 1 diabetes, and Excision BioTherapeutics began its Phase I trial in patients with HIV. Preclinically, Verve Therapeutics is studying a cure for familial hypercholesterolemia. Each of the above diseases affects more than 1MM Americans.

Broader Ability to Deliver CRISPR In Vivo

The large size of the CRISPR/Cas9 system poses a challenge for therapeutic delivery, and as a result, the initial wave of indications has focused on tissue that can be targeted by systemic infusion (liver, bloodstream) or localized injection (eye, brain). Developing novel delivery approaches for reaching a greater variety of tissue is a top priority for researchers in both academia and industry – for example, by shrinking the CRISPR system so it can be delivered via viral vectors, or by direct delivery of CRISPR protein and RNA encased in lipid nanoparticles. Given the high amount of activity in the field of delivery, we expect to see advances that broaden the potential use of CRISPR to patients who can’t be addressed by current delivery technology.

Clinical Validation of Alternative CRISPR Approaches

We have already seen preliminary data readouts for both in vivo and ex vivo clinical studies utilizing the original CRISPR system with its DNA double-strand cutting capabilities, with more data eagerly anticipated in the coming months and years. Over the next decade, we expect to see clinical validation of the next generation of CRISPR-based tools – base editors, prime editors, epigenome editors, RNA editors, and others – which are just beginning to approach the clinic. Whereas the original CRISPR system is best suited for disruption of toxic genes, the modified CRISPR systems may be able to restore damaged DNA, integrate missing genes, or regulate gene expression without making permanent DNA changes. More novel approaches may yet emerge. This expanded CRISPR toolkit may represent a safer alternative to the first generation of CRISPR therapies, while also expanding the list of targetable genetic diseases.

Developers of alt-CRISPR approaches are pursuing a similar early portfolio strategy to their peers – for example, Beam’s pipeline for base editor targets includes a number of inherited retinal, blood, and metabolic disorders. Clinical proof-of-concept for base editing would open the door to potentially treating the thousands of diseases caused by loss-of-function mutations, far too many for a single company to pursue. But compared to the original CRISPR system, intellectual property ownership for alt-CRISPR proteins is more straightforward, raising the barriers to entry for would-be competitors. Companies will respond by developing their own novel systems if they have the capabilities – as Intellia has done – or licensing the technology from the originator for specific diseases or even entire therapeutic areas, as Beam has done with Verve and Apellis.

Given the emergence of next-gen CRISPR tools, it’s tempting to ask which technology will ‘win’ in terms of superior efficacy, safety, etc.? First, perhaps the only sure thing is that we won’t be able to answer this question within the next decade, as doing so will require multiple mature clinical datasets for each technology. Second, rather than one technology coming to predominate, we anticipate that the CRISPR tools will occupy distinct or even partially overlapping domains where each is well suited. The urgency of betting on the ‘right’ CRISPR platform is most acute for platform companies, whereas Big Pharma has shown a willingness to partner with or acquire a range of gene editing technologies provided the underlying data is compelling. Therefore, the more apt question is, “which CRISPR technology is most appropriate for my specific situation?”

Continuing Development Outside the Clinic

We also expect the non-therapeutic use of CRISPR to continue accelerating over the next 10 years. Top applications to watch include:

• In agriculture, CRISPR is being used to generate crops and other plants with properties that make them more resilient to the effects of climate change.
• CRISPR has become a mainstay of the synthetic biology industry, a rapidly growing field that appears poised to impact nearly every aspect of our lives.
• Prior to the clinic, research tools developed through the use of CRISPR will benefit the life sciences researchers who test the safety and efficacy of drug candidates prior to studies in humans.

What Are the Biggest Upcoming Challenges?

Developers of CRISPR-based therapies will have to confront a number of serious obstacles in the coming decade:

• The top near-term challenge is the current economic headwind, which appears to be strengthening. While the downturn is affecting all companies – biotech or not – the market conditions are having an acute impact on CRISPR companies, given their early stage and nascent technology. The next several years will pose challenges for CRISPR companies that have insufficient runway to carry through to the next value inflection point – say, a proof-of-concept or pivotal trial readout. Many companies will adapt by curtailing their activities and doubling down on their core programs with the highest likelihood of success. Some will also find themselves to be attractive acquisition targets for competitors or strategic investors. Compared to today, the landscape of CRISPR companies is likely to look vastly different 10 years from now.
• Even compared to traditional gene therapies, CRISPR poses unique safety, dosing, and ethical challenges due to the permanent and error-prone nature of the DNA modifications. Scrutiny is high, especially in light of the recent spate of deaths in clinical trials of traditional gene therapies and fears of unethical use of CRISPR by rogue scientists. Key stakeholders such as physicians, patients, regulators, and payers will be closely following the trial results, and the clinical profile emerging from early programs – strength and durability of response, long-term safety – will be instrumental in determining the future place of CRISPR in medicine.
• Clinical-stage CRISPR companies should already be preparing to navigate the market access challenges that await the first wave of approvals. CRISPR therapies are expected to have similar features to traditional gene therapies – high upfront costs, the need for specialized training and equipment among administering physicians, manufacturing constraints – and will likely face similar market access barriers. The question of market access will become more urgent if and when CRISPR therapies are approved for non-orphan indications. Where multiple therapeutic approaches may apply, developers will need a compelling argument for why (and in which patients) CRISPR is superior to other modalities that carry less risk. There is no consensus today on the optimal path to commercializing gene therapies, and negotiating these challenges will be key to ensuring broad and equitable access to cutting-edge treatment for all patients.

Conclusion

The CRISPR system evolved over millions of years out of the need for precision: bacterial cells needed a way to recognize and destroy the DNA of viral invaders. In the last 10 years, researchers have been hard at work harnessing the precision of CRISPR, and in the process have revolutionized biomedical research and suggested potential cures for intractable genetic diseases. Over the next 10 years, we eagerly await the results of the first generation of CRISPR-based therapies and the exciting new avenues that arise from ongoing studies.