T

he death of the rap artist Prodigy (Albert Johnson, half of the duo Mobb Deep) at only 42 this week, after a lifetime of suffering from sickle cell disease, was a reminder of the devastating cost of thesometimes fatal genetic disorder and of the failure to cure it.

It has been 61 years sincethe discovery of the mutation responsible for sickle cell, which affects about 100,000 people in the U.S., and 30 years since scientists found a compensatory mutation onethat keeps people from developing sickle cell despite inheriting the mutant genes. Last year, when STAT examined the lack of progress, scientists and hospital officials were frank about one reason for it: Other genetic disorders, notably cystic fibrosis, attracted piles of money that led to cures, but sickle cell strikes the wrong kind of people, including African-Americans, and so has historically been starved for funds.

The genetic mutation that causes sickle cell allowsred blood cells to cramp up in a way that impedestheir flow through blood vessels. Those who have the condition can suffer anemia, infections, fatal organ failure, tissue damage, strokes, and intense pain.

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In the last 12 months, there have been glimmers ofprogress against the disease. There are huge numbers of drug companies finally putting money into this, said Dr. Mitchell Weiss, chairman of hematology at St. Jude Childrens Research Hospital, who is developing a genome-editing approach, using CRISPR-Cas9, to cure sickle cell. As for the National Institutes of Health, the chief funder of basic biomedical research, I wouldnt say NIH is showering [sickle cell research] with money, but theyre trying to help.

Weve known for 50 years what causes sickle cell disease. Wheres the cure?

CRISPR, by making genome-editing easier than ever, is responsible for much of the hope surrounding sickle cell.

On Friday, at a meeting of the European Hematology Association in Madrid, scientists at CRISPR Therapeutics and their academic collaborators will present preliminary results of a study using it to create the compensatory mechanism that protects some sickle cell patients. Basically, that mechanism keeps the body producing fetal hemoglobin, which ordinarily vanishes soon after birth. But even in sickle cell patients, fetal hemoglobin is normal rather than deformed like adult hemoglobin. Scientists have identified several genetic routes to keeping fetal hemoglobin turned on, and even to turning it on again after the body has turned it off in infancy.

CRISPR Therapeutics does not reveal which gene it targeted, but the results were promising. Starting with blood-forming cells from both healthy volunteers and sickle cell patients, itcreated CRISPR-Cas9 molecules targeting regions of DNA involved in the fetal-to-adult hemoglobin switch. An impressive 85 percentof cellswere successfully edited, which kept fetal hemoglobin production humming. Result: Scientistsre-created genetic variants linked to high [fetal hemoglobin] levels in blood-forming cells from both healthy donors and those with sickle cell, the company said in a summary of the study. It compared how well different DNA edits increased production of fetal hemoglobin in red blood cells in lab dishes, getting 25 percent to 45 percent in the cells taken from six sickle cell patients.

The scientists then put the edited cells into lab mice, finding that they homed in on the bone marrow, as they would have to do in a patient to effect a cure. They also measured what are called off-target effects, or edits of genes that werent intended, and found none at the more than 5,000 sites deemed most likely to have them.

CRISPR Therapeutics said it had used several editing strategies to turn on production of fetal hemoglobin, underlining the accelerating progress in taking that approach to develop a cure. Weiss, for instance, is trying to turn on fetal hemoglobin by tapping into the very complicated genetics of fetal hemoglobin.

Cells have molecules that act like Victorian lamplighters: They roam the genome, turning genes on and off. One such lamplighter (in biology-speak, a transcription factor) is called BCL11A; it turns off production of fetal hemoglobin. Weiss is not targeting BCL11A itself (other scientists are considering that); rather, he is using CRISPR to disrupt where BCL11A lands. Just as a lamplighter cant turn off a light he cant reach, so BCL11A cant turn off a gene it cant reach. Expected result: Fetal hemoglobin stays on and patients have enough healthy hemoglobin to compensate for the sickled kind.

One boys cure raises hopes and questions about gene therapy for sickle cell disease

After making progress with this approach editing cells in lab dishes, Weiss said, he and his colleagueshope to launch a clinical trial in three to four years, using money raised by St. Jude but, so far, they have no commercial partner. At Boston Childrens Hospital, Dr. David Williams said he hopes to open his clinical trial, also using gene therapy to target sickle cell, this summer, and is just waiting on final safety testing of the virus that will be used to deliver the therapy.

An even more basic approach to curing sickle cell targets the causative mutation directly.The most encouraging human data so far have come from a genetic therapy being tested by Cambridge, Mass.-based Bluebird Bio. In March, the company reportedthat a boy who received the gene therapy in October 2014, when he was 13, had been able to stop taking medication that helps alleviate symptomsand has not needed to be hospitalized with a sickle cell crisis (as Prodigy was in the days before he died). Nor has hesuffered the crushing pain or bone and tissue damage that results from the inability of sickled blood cells to carry oxygen.

Bluebird uses viruses to carry the healthy hemoglobin gene into blood-making bone marrow cells taken from patients, which is the original form of gene therapy. If healthy genes insert into the DNA of enough cells, which are infused back intothe patient, the marrow makes enough healthy blood cells to cure sickle cell. With the sudden surge of activity, said Dr. Charles Abrams of the University of Pennsylvania and past president of the American Society of Hematology, people say were within 10 years of reaching the goal of a cure, and maybe less.

Sharon Begley can be reached at sharon.begley@statnews.com Follow Sharon on Twitter @sxbegle

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With a rapper's death, harsh spotlight falls on slow progress against sickle cell - STAT