If you have read a newspaper lately, there is a good chance you have heard about CRISPR-Cas9, the versatile gene editing technology. Over the past several months, legal battles over intellectual property, ethical concerns over editing of the human germline, jaw-dropping partnerships with pharma, and talk of IPOs have crescendoed to a steady roar, reaching beyond the biotech community and into the popular press.
Yet amid all the noise about CRISPR, there remain several major technical challenges that scientists at the leading CRISPR companies—Editas Medicine, CRISPR Therapeutics, and Intellia Therapeutics—are working furiously to address. Their success will determine whether CRISPR lives up to its hype and, crucially, whether patients with severe, intractable genetic diseases will benefit.
With any novel technology like CRISPR, there exist uncertainties about safety. Safety is an even greater uncertainty in this case because of prior experience from the closely related field of gene therapy. Gene therapy involves providing a functional copy of a gene to diseased cells, while gene editing involves editing the existing genome in those cells. In 1999, Jesse Gelsinger, a patient with Ornithine Transcarbamylase Deficiency, tragically died from an immune response to the viral shell used to deliver an experimental gene therapy. Separately, in 2002, the first of several gene therapy-treated children developed deadly leukemia caused by insertion of a therapeutic gene into a cell’s DNA in a way that turned on one of the cell’s pro-cancer genes. After these adverse events and the subsequent shutdown of multiple clinical trials, the excitement over gene therapy came crashing down.
Today, scientific and business leaders in gene editing are hoping to avoid the early missteps that set the field of gene therapy back by several years. One of the greatest concerns is the possibility of off-target activity—where CRISPR edits unintended genes and may produce carcinogenic mutations. Editas Medicine, in its S-1 disclosure to the SEC, acknowledged that its researchers “cannot be certain that off-target editing will not occur in any of [their] planned or future clinical studies.”
Yet the pressures on the leading CRISPR companies are tremendous, pushing companies to commercialize their technologies within the next few years. John Leonard, chief medical officer of Intellia Therapeutics, likens the competition to a “footrace” in which none of the major companies has a clear lead. Ali Behbahani, a board member at CRISPR Therapeutics and partner at New Enterprise Associates, states that the “time pressures” might push some companies to move to the clinic before the technology is ready. Katrine Bosley, CEO of Editas, has committed her company to human trials of CRISPR by 2017.
Adding to the time pressure are the expectations of investors. Editas Medicine filed an S-1 with the SEC this month in preparation for an IPO, and Intellia Therapeutics appears close behind, recently bringing on “crossover” investors like Fidelity that typically invest in private companies shortly before they go public. Public investors tend to demand rapid results. Only CRISPR Therapeutics has taken a funding approach that seems to rely primarily on private investment, recently signing a deal with Bayer worth $335 million, following a $105 million deal with Vertex.
All three companies are devising means to overcome some of the safety challenges with CRISPR. Feng Zhang, a scientific founder of Editas Medicine, has worked on creating a modified Cas9 enzyme that more reliably targets the desired location on the DNA sequence.
Leonard says that Intellia has focused on improving the guide RNA that directs the Cas9 to the site of action. “We’ve demonstrated that there are very good guides that are completely clean,” he says.
Simeon George, a board member of CRISPR Therapeutics and partner at SR One, says that CRISPR Therapeutics has been devoting considerable energy to honing computer algorithms that will identify areas of potential off-target activity. “This is something that is going to differentiate us,” he says.
Another major challenge facing these companies is regulatory approval. The FDA will be taking a close look at any applications to test the therapy in humans. All the companies are hoping to benefit from the precedent set by companies that have been successful in related fields. Sangamo BioSciences has a Phase 2 trial and two Phase 1 trials in humans underway using Zinc Finger Proteins (ZFPs), another approach to gene editing that was discovered before CRISPR but is generally seen as more cumbersome and less versatile. Reassuringly, Sangamo has not reported any major adverse events in these studies.
Which patients are likely to be the first beneficiaries of CRISPR? Leonard says that he “divides the world into cells you can take outside the body and those you can’t.” For example, blood cells can be removed from the patient, treated with CRISPR, and then infused back into the patient. This approach has lower risk of adverse effects because only blood cells will receive the therapy and those cells can be studied carefully before being infused. Patients with sickle cell disease and other genetic diseases of hemoglobin may be the first to receive treatment. “Sickle cell disease is one of the ex vivo [outside the body] applications that we are most excited about,” says George.
Another application outside the body is in CAR-T cells, white blood cells that are engineered to fight cancer. CRISPR could permit CAR-T cells from one donor to be given to many different patients, or improve the safety of the CAR-T cells, says Leonard. Intellia has entered a partnership with Novartis to pursue these possibilities.
Editas has taken the ambitious approach of focusing primarily on treatments inside the body. The company’s lead program will be in Leber congenital amaurosis, a rare congenital cause of blindness. That therapy would be injected directly into the eye to treat defective cells in the retina.
Ultimately, all three companies hope to have therapies both for use inside and outside the body. CRISPR Therapeutics is pursuing therapies for cystic fibrosis with Vertex, and its deal with Bayer is explicitly intended for the development of systemic therapies. Intellia has created two divisions, one dealing with therapies inside the body and the other for therapies outside the body. In its S-1, Editas identified programs in hemoglobin diseases, CAR-T, muscular dystrophy, and cystic fibrosis, among others.