For decades, researchers, some physicians, and a few patients have had visions of treatments that would go in and fix diseases at the genetic level. Last year, those dreams took on some reality as Kymriah and Yescarta became the first FDA-approved gene therapy treatments.
But there’s a catch: Are they really gene therapy?
For a long time, gene therapy has been viewed as therapy that would fix or replace a specific aberrant gene causing an inherited condition or sparking a disease.
By that definition, Kymriah and Yescarta are not, strictly speaking, gene therapy.
Novartis’s Kymriah, approved in August 2017, is indicated for the treatment of acute lymphoblastic leukemia in people up to age 25. Yescarta, which was approved in October, is indicated for treatment of adults with relapsed or refractory non-Hodgkin’s lymphoma. As products with very limited clinical trial results behind them, both are currently reserved for the last resort situations after two or more tries with more conventional treatment have failed to control the person’s cancer.
Kymriah and Yescarta are produced in a similar fashion. Both involve harvesting the patient’s own T cells and genetically engineering those cells to add a specific synthetic receptor to their surface. That receptor has the ability to recognize an antigen on cancerous B cells. In this way, T cells, which ordinarily focus in on invasive microorganisms, are manipulated so they turn their disease-fighting attention on cancer cells.
The synthetic receptor on the T cells is called a chimeric antigen receptor, which gets shortened to CAR. Kymriah and Yescarta are talked about as CAR T-cell or CAR-T treatment.
CAR-T therapy involves some genetic engineering that is amazing; the culmination of work that began decades ago. But CAR T-cell therapy is not the classic form of gene therapy. Some refer to it as gene transfer that infuses copies of a normal gene or a modified gene into a genome in a more or less random fashion. For many in the field of gene therapy, the holy grail has been gene editing, which might be thought of as gene replacement surgery: A precise location in the genome is identified, and a healthy gene is inserted to replace an aberrant gene or one that is missing.
One major difference between gene editing and gene transfer is that gene editing is seen as a one-time treatment. If the hopes for gene editing pan out, the healthy gene will be inserted and be expressed in a normal, healthy way like it was there all along. By contrast, CAR-T treatment may not create a permanent change to the genome. There is a distinct possibility that CAR-T treatment could require a second round of treatment.
Gene editing may be considered a higher form of gene therapy, but gene transfer is crossing the FDA approval finish line sooner, a not-minor advantage. A case point is the approval in December of Spark Therapeutics’s Luxturna, which treats a form of inherited blindness.
Gene editing is still in the experimental stage and has a way to go before FDA approval. Yet it took a step forward in November when Sangamo Therapeutics in Richmond, Calif., announced the first-ever patient to receive in vivo genome editing therapy. The treatment, which has the investigational name of SB-913, is for a condition called mucopolysaccharidosis type II, or Hunter’s syndrome. The first person to receive it was a 44-year-old man treated at the University of California–San Francisco’s Benioff Children’s Hospital Oakland.
In Hunter’s syndrome, a faulty gene fails to make enough of an enzyme called iduronate-2-sulfatase. Normal levels of the enzyme prevent the buildup of toxic carbohydrates in cells. Patients with Hunter’s syndrome endure worsening damage to the heart, bones, and lungs. The company says many die of airway obstruction, upper respiratory infection, or heart failure before they reach the age of 20. Hunter’s syndrome affects approximately one in every 100,000 to 170,000 people.
Gene editing can also be done ex vivo, which means cells are harvested from a patient, edited in the lab, and then transferred back to the patient.
Gene editing relies upon highly precise technology to accurately identify the exact location of the gene that is being targeted for repair, then opening up the genome and inserting the new therapeutic gene. Currently, the CAR-based gene therapies insert genes randomly into the genome.
Sangamo Therapeutics is working on two other gene-editing candidates, one for MPS I, which is also known as Hurler’s syndrome, and another for hemophilia B. All three have received FDA fast track and orphan drug designations.
Gene editing is newer and not as thoroughly proven as gene transfer strategies. Much of the work in gene editing involves validating the accuracy of the competing platforms that are used to edit the genome and insert a therapeutic gene. These competing platforms have complex names and are better known by their acronyms: ZFN, which stands for zinc finger nuclease; TALEN, which stands for transcription activator-like effector nuclease; and CRISPR, the acronym for clustered regularly interspaced short palindromic repeats-associated nuclease Cas9.
These platforms create a nuclease, an enzyme that cleaves to the genome. The key to success is for the nuclease to home in on the precise spot in the genome where the new gene is needed. Off-target location errors could have a devastating clinical effect.
ZFN was the first of these platforms to be developed. It was discovered in 1985 and first applied in 1994. Sangamo used ZFN in its first-ever in vivo gene edit of the Hunter’s syndrome patient. ZFN, though, is currently being upstaged by CRISPR, which was discovered in 2010. CRISPR is still in the pre-clinical validation phase for the correction of genetic diseases, says Helen Heslop, MD, president of the American Society of Gene and Cell Therapy. It offers a simpler approach to gene editing than the ZFN platform. The drawback might be that it’s not as specific as ZFN in targeting gene locations.
In November 2017, the Senate Health Education, Labor, and Pensions (HELP) Committee held a hearing about CRISPR and a wide range of gene editing issues. The committee chair, Sen. Lamar Alexander, commented that CRISPR poses a national security concern and that it was included on a 2016 list of weapons of mass destruction and proliferation by James Clapper, former director of national intelligence.
Testimony from others highlighted the potential of gene editing to provide one-shot cures of many inherited and acquired diseases. There was little discussion of how the science of gene editing may be ahead of the policy, social, and regulatory frameworks to deal with issues such as germline editing to create designer babies, or the need for updated safety and approval guidelines from the FDA.
The next step in gene editing is for the clinical trials to move to Phase 3 trials and then on to final approval. An article published in April 2017 in Acta Pharmacologica Sinica reviewed current Phase 1/2 clinical trials worldwide. In this country, the most common target was the CCR5 gene in HIV. In China, a number of phase 1 clinical trials are targeting the PDCD1 gene found in several cancers.