First U.S. Company-Sponsored CRISPR/Cas9 Clinical Trial Launches
Vertex Pharmaceuticals and CRISPR Therapeutics jointly launched the first U.S.-company-sponsored clinical trial of this gene-editing technology, to test it in patients with beta thalassemia, a rare blood disorder cause by a mutation that reduces the amount of hemoglobin the body can produce. The announcement surprised some because Editas Medicine’s experimental CRISPR/Cas9 treatment for a rare form of blindness was generally expected to be the first studied in the clinic.
The Phase 1/2 clinical trial will be conducted at a hospital in Regensburg, Germany. The gene-editing therapy, CTX001, is intended to treat both beta thalassemia and sickle cell disease, and uses an interesting approach. Instead of correcting the disease-causing mutation, it targets a region of DNA that normally halts production of “fetal hemoglobin,” found in newborns but later replaced by adult hemoglobin. Fetal hemoglobin, however, can function in adults. For the treatment, blood cells will be taken from a patient and edited to restore production of fetal hemoglobin, with the goal of providing enough to normalize blood oxygen levels.
In other CRISPR news, scientists used the technology to successfully treat Duchenne muscular dystrophy (DMD) in a dog model of the disease, the first time success has been shown in large animals.
EC Approves Two CAR-T Therapies
The European Commission recently approved Novartis’s Kymriah (tisagenlecleucel) and Gilead’s Yescarta (axicabtagene ciloleucel) for treating certain blood cancers. Both are chimeric antigen receptor T-cell (CAR-T) therapies, a new class of therapies that many experts hail as a breakthrough in cancer treatment but are costly. Indeed, one day after the EC approved Yescarta, UK’s NICE rejected it because it considered the treatment too costly for coverage by the National Health Service; however, after negotiating a deal with Novartis, NHS approved Kymriah. Approved by FDA in 2017, Kymriah and Yescarta cost up to $475,000 and $375,000 per year, respectively.
CAR-T therapy is considered by many to be so promising that it may become the “fifth pillar” in cancer treatment (the other four being surgery, radiation, chemotherapy and targeted therapy). In CAR-T therapy, some of a patient’s own T-cells are removed and DNA is introduced in them to produce receptors (CARs) on their surface that recognize antigens on tumor cells. The re-engineered T-cells are then multiplied and, when there are enough, infused back into the patient.
Hopes and Fears for First-of-its-kind Stem Cell Trial for Heart Failure
In early 2019, cardiac surgeons in Osaka, Japan will implant sheets of 100 million stem-cell-derived heart muscle cells (cardiomyocytes) into the hearts of three patients with advanced heart failure, marking the first clinical use of induced pluripotent stem cells (IPSCs) for damaged hearts, and the second clinical use of IPSCs overall (the first was for treatment of macular degeneration, also performed in Japan). While many experts are hopeful about IPSC potential, a number have expressed concerns about this trial, including:
- The need for open-heart surgery to implant the cell sheets, rather than the less-invasive approach of injecting cells into the heart
- Whether the IPSCs actually integrate into the heart muscle or simply secrete factors that stimulate growth of existing hearts cells
- The additional stress of months of immunosuppression therapy to prevent tissue rejection, since the IPSCs are not autologous (from the patients themselves)
- The foreign IPSCs might generate tumors
Nonetheless, given that current treatments for heart failure are limited in number and effectiveness, many remain excited about the study and, at a minimum, the new information it will bring.
FDA Investigating Possible Cancer Risk with Blood Pressure Drug Class
FDA recently announced it was investigating the angiotensin II receptor blocker (ARB) class to see if they contain an impurity linked to cancer: NDMA (N-Nitrosodimethylamine). The announcement follows an investigation in July showing products containing the ARB valsartan (Diovan) contained NDMA, prompting FDA to call for an initial voluntary recall. Generally recognized as a possible carcinogen, NMDA is a by-product of various industrial processes and can be found at low levels in certain foods.
Hospitals to Start a Drug Company
Fed up with high drug prices and shortages, a group of about 500 hospitals are launching their own, first-of-its kind non-profit generic drug company, Civica Rx. While the company hasn’t disclosed the drugs’ names, they include generic pills, patches and injectables for treating heart conditions, infections and pain – at about a 20 percent reduction in prices. The first Civica Rx drug may be available early next year.
Brain Benefits of Exercise in a Bottle?
Decreasing the risk of age-related dementia is among the many recognized benefits of exercise, but scientists have been unsure of the mechanism(s) involved. A report in the September 6 issue of Science offers some insights. Researchers showed that mice with a severe genetic form of Alzheimer’s disease and who exercised grew new brain neurons and improved cognitive function. They tried to duplicate the effect by stimulating neurogenesis, but found that the resulting new neurons didn’t survive for long, so there was no cognitive improvement. However, they were able to show similar improvements to exercise when they stimulated neurogenesis and also increased levels of a nerve-growth factor in the body called brain-derived neurotrophic factor (BDNF). The findings have implications for new, potential avenues for human research on Alzheimer’s, which so far has been almost myopically focused on amyloid.
Weight Gain Reduces Brain Function
Somewhat on the flipside, another study in mice explored how obesity causes cognitive decline. The study showed that, after 12 weeks on a high-fat diet, the mice weighed about 40 percent more than their normal-weight counterparts, and performed worse on escaping mazes and on mousy memory tests. The researchers also found changes in the fat mice’s brain hippocampus regions: increased microglial immune cell activation, which is thought to reduce the number of dendritic spines, which are important for learning and memory. Perhaps most encouraging: Pharmacologic inhibition of microglial cells prevented dendritic spine loss and maintained cognition and learning.