• Specificity and safety data still unknown
• In vivo milestones further off than ex vivo
• Discovery of new applications continues
The quest to develop and commercialise a CRISPR therapy will likely involve numerous stages of scientific and regulatory hurdles for developers as they race to dose the first human, agreed industry experts.
Sichuan University's West China Hospital's recent milestone of achieving the world's first CRISPR trial approval in lung cancer last month is merely one short leg of a tough R&D marathon, and does not necessarily guarantee any solid lead, said CRISPR experts. Biotechs such as Intellia (NASDAQ: NTLA), Editas (NASDAQ: EDIT), and CRISPR Therapeutics are some of the names in the CRISPR race.
Rodolphe Barrangou, Associate Professor, Food, Bioprocessing and Nutrition Sciences, North Caroline State University, and co-founder of Intellia, said coming years will see a series of milestone achievements from CRISPR developers, beyond being first to enter the clinic or receive approval, with some indications and organs proving harder to target or more commercially relevant than others. Additionally, the first organisation to receive trial approval will not necessarily be the first to dose a patient or finish a trial, so for now no therapy has a clear lead, said Barrangou.
The gene editing tool CRISPR - clustered regularly interspaced short palindromic repeats - was harnessed for genome editing three years ago using the RNA-guided DNA endonuclease Cas9. It will prove extremely important because it targets gene deletion and correction in genetic diseases more easily and affordably than earlier methods like zinc finger nuclease (ZFN) and transcription activator-like effector nucleases (TALENS), agreed experts, including Michael Deines, general manager, Dharmacon, a business unit of GE Healthcare (NYSE: GE) which develops preclinical CRISPR tools. The initial focus of therapeutics companies will be on diseases with known single mutations, such as sickle cell anaemia, beta thalassemia, cystic fibrosis, and HIV, said Deines.
One hurdle for RAC approval is that the scientific community does not yet understand the specificity of CRISPR, said Dean Anthony Lee, director of cellular therapy at Ohio State University Comprehensive Cancer Center, and an ad hoc member of the NIH Recombinant DNA Advisory Committee (RAC), which assesses the risk-benefit balance of US gene therapy trials before the FDA's decision. The general belief - yet to be confirmed in studies - is that CRISPR has greater potential to interrupt unintended genes than ZFN and TALENs, he said.
Lee said RAC and national regulators, for now, are minimising the risks raised by CRISPR's lack of specificity by limiting the types of modifications allowed. Experts agreed potential uses of CRISPR in humans range from the least risky intervention, ex vivo modification of selected cells outside the body, to the more risky in vivo editing via injecting a vector that would carry CRISPR to every or many cells in the body, modifying all organs.
RAC gave approval to the University of Pennsylvania (UPenn) on 21 June for the first kind of trial, selectively modifying T-cells outside the body to target the programmed cell death protein (PD-1) receptor and the alpha and beta chains of the T cell receptor (TCR), said Lee. He said the RAC felt more comfortable approving ex vivo editing for its first in human CRISPR study, because there is reduced potential for unintended modifications. RAC and FDA approval of in vivo editing will be a "bigger leap," he said, and committees will need to see more data on off-target effects, either ex vivo studies like UPenn's or very vigorous in vivo animal studies.
Barrangou said CRISPR is not a race to get the first therapy in humans and approved, but several races, with some areas of the body harder to access than others.
Delivering CRISPR therapies is not only a regulatory hurdle but a practical one, as the delivery of CRISPR systems will need to be customised on an organ-by-organ basis, said Barrangou and Thomas Barnes, CSO, Intellia. Barrangou said ex vivo CRISPR modification is easier to deliver to patients, and this is where companies will make the first achievements. It will be easier to develop CRISPR therapies administered directly to the affected organ for instance, muscular dystrophy therapies could be delivered by intramuscular injection; or anaemia therapies could be injected into the bloodstream; compared to harder to access areas, like the brain or liver, he said.
However, some companies are addressing these harder to access organs and/or more difficult in vivo delivery. Editas announced last week its in vivo CRISPR-mediated therapy for Leber congenital amaurosis, a form of blindness, is on track to enter the clinic in 2017. Barnes added Intellia -- in a partnership with Regeneron (NASDAQ: REGN) -- is developing an in vivo liver-targeting delivery system, encapsulating the CRISPR cargo inside a lipid nanoparticle (LNP) which is scavenged by the liver.
It would behoove all companies to diversify their portfolio in terms of range, accessibility and therapeutic impact, Barrangou said. The higher barriers to entry for some indications will mean companies addressing these areas will have more market command with less competition, he said.
Deines said CRISPR's potential for adaptability to different types of genome editing will prove the biggest challenge for researchers keeping up with the rate of improvements and discoveries around the technology itself. Barnes and Lee confirmed that while upcoming CRISPR trials are focused on deleting a gene, CRISPR could in future allow scientists to splice back in the corrected bases, a harder process. Deines added pharma companies may use CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) for future therapies: methods of turning up or down the amount of gene present instead of changing the DNA sequence to switch off a gene. Lee added future ethics committees will also be challenged when presented with a trial which plans to edit genes in ways that are heritable - unlike the UPenn study - as these changes will impact future generations.
Sichuan University's West China Hospital received approval from its hospital's review board to use CRISPR-Cas9 for ex vivo gene editing in patients with lung cancer, and plan to begin the intervention this month, as reported in July by Nature. Prior to this announcement, no trial had received full approval for therapeutic human use of CRISPR, said Barrangou, although CRISPR is already used in preclinical R&D, and in non-therapeutic human embryonic research, by the UK's Francis Crick Institute.
Lee confirmed the UPenn study has not yet received FDA approval, and is the only trial of CRISPR in humans reviewed so far by RAC. Barnes added the first programme out of Intellia's collaboration with Novartis (VTX:NOVN) - an ex vivo hematopoietic stem cell (HSC) product - will file an IND in 2018, and a second ex vivo Novartis collaboration on T-cells will enter the clinic afterwards. CRISPR Therapeutics announced a collaboration in June with Illkirch-Graffenstaden, France-based Anagenesis Biotechnologies to use Paraxial Mesoderm Multipotent Cells (P2MCs) in musculoskeletal diseases.
CRISPR Therapeutics and Editas declined to speak to this news service about the progress of their pipelines.