CRISPR enters first human clinical trials
Conventional gene therapies have been used in the past in attempts to correct genetic deficiencies. However, most of these trials have not been successful and either didn't halt disease progression or resulted in severe side effects. CRISPR promises to be a more targeted and hence more secure approach but even CRISPR sometimes goes to the wrong spot in the genome, resulting in so-called off-target editing. Thus, a certain risk for detrimental changes in the patient's genome remain - even with a tool as precise as CRISPR.
There is also the issue of delivering the CRISPR/Cas9 complex to the right cell types. Delivery is less of a problem in trials to treat blood disorders since blood cells can be safely removed from the patient's body, genetically altered in vitro, and then injected back into the patient. That is why some of the initial trials are attempting to treat myeloma or blood disorders (see ClinicalTrials.gov for an overview of running CRISPR trials).
Currently, a trial sponsored by Vertex Pharmaceuticals is under way for the blood disorder beta-thalassemia. The therapy aims to fix a genetic defect in hemoglobin by reactivating a gene for fetal hemoglobin, which is usually shut off after birth. However, people who have a genetic variant that causes fetal hemoglobin to be produced throughout life and who have also inherited a beta-thalassemia mutation show no symptoms. The Vertex trial aims to show that reactivating the fetal hemoglobin gene will reduce or eliminate the symptoms of the disease. In another trial University of Pennsylvania researchers have given two people with recurring cancers a CRISPR/Cas9 therapy. One person has multiple myeloma; the other, sarcoma. As part of an ongoing trial, both received reprogrammed T cells targeting the cancer cells.
Still, many genetic diseases affect the whole body or organs that can’t be removed and edited in a lab and no one knows whether CRISPR will work well in such cases. An organ which is easily accessible to CRISPR-based modifications is the human eye. A study sponsored by the Cambridge, Massachusetts-based company Editas Medicine, which is currently recruiting, aims to reverse a mutation in the CEP290 gene causing an inherited type of blindness called Leber congenital amaurosis 10. There already is an approved gene therapy for Leber congenital amaurosis which treats a defect in a different gene called RPE65. Whereas RPE65 is small enough to fit into a viral vector and can thus be delivered rather easily, CEP290 is too big for viral shuttles. This where CRISPR/Cas9 comes in since its components easily fit into most viral vectors. Editas, working together with the global pharmaceutical company Allergan, is now starting a clinical trial in which two guide RNAs will lead Cas9 to make suitable changes in the patient's genome. Preclinical trials were promising, editing up to 60% of retinal cells in mice and up to 28% in monkeys.
In May, the FDA approved Zolgensma, a gene therapy for children with spinal muscular atrophy caused by a mutation that disables the SMN1 gene. Children with the genetic disease often die because the muscles that control breathing fail. Despite the fact that there may have been problems with data manipulation during animal testing, the therapy stays on the market due to its enormous effectiveness. When it comes to CRISPR-based gene editing, researchers are hoping for similar happy endings even though it may still be a long way until the first CRISPR gene therapy will hit the market.