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CRISPR fix in mice may lead to muscular dystrophy therapy – Futurity: Research News

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The CRISPR gene editing technique may provide the means for lifelong correction of the genetic mutation responsible for Duchenne muscular dystrophy, a new study with mice shows.

Duchenne muscular dystrophy (DMD), a rare but devastating genetic disorder, causes muscle loss and physical impairment. Children with DMD have a gene mutation that interrupts the production of a protein known as dystrophin. Without it, muscle cells weaken and eventually die. Many children lose the ability to walk, and muscles essential for breathing and heart function ultimately stop working.

Research has shown that CRISPR can be used to edit out the mutation that causes the early death of muscle cells in an animal model, says Dongsheng Duan, professor in medical research in the molecular microbiology and immunology department at the University of Missouri School of Medicine and senior author of the paper in Molecular Therapy.

However, there is a major concern of relapse because these gene-edited muscle cells wear out over time. If we can correct the mutation in muscle stem cells, then cells regenerated from the edited stem cells will no longer carry the mutation. A one-time treatment of the muscle stem cells with CRISPR could result in continuous dystrophin expression in regenerated muscle cells.

For the study, researchers explored whether they could efficiently edit muscle stem cells from mice. They first delivered the gene editing tools to normal mouse muscle through AAV9, a virus that the US Food and Drug Administration recently approved to treat spinal muscular atrophy.

We transplanted AAV9 treated muscle into an immune-deficient mouse, says lead author Michael Nance, a MD-PhD program student in Duans lab. The transplanted muscle died first then regenerated from its stem cells. If the stem cells were successfully edited, the regenerated muscle cells should also carry the edited gene.

The researchers reasoning was correctthey found abundant edited cells in the regenerated muscle. They then tested if they could use CRISPR to edit muscle stem cells in a mouse model of DMD. Similar to what they found in normal muscle, the stem cells in the diseased muscle were also edited. Cells regenerated from these edited cells successfully produced dystrophin.

This finding suggests that CRISPR gene editing may provide a method for lifelong correction of the genetic mutation in DMD and potentially other muscle diseases, Duan says.

Our research shows that CRISPR can be used to effectively edit the stem cells responsible for muscle regeneration. The ability to treat the stem cells that are responsible for maintaining muscle growth may pave the way for a one-time treatment that can provide a source of gene-edited cells throughout a patients life.

With more study, the researchers hope this stem cell-targeted CRISPR approach may one day lead to long-lasting therapies for children with DMD.

Additional coauthors are from the University of Missouri, the National Center for Advancing Translational Sciences, Johns Hopkins School of Medicine, and Duke University. The National Institutes of Health, the Department of Defense, the Jackson Freel DMD Research Fund, Hope for Javier, and the Intramural Research Program of the National Center for Advancing Translational Sciences funded the work.

Source: University of Missouri

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CRISPR fix in mice may lead to muscular dystrophy therapy - Futurity: Research News

When You Need Stem Cells, You May Appreciate the Donor Registry – 93.1 WIBC Indianapolis

INDIANAPOLIS--Getting a diagnosis of leukemia or sickle cell disease can mean months or years of treatment, and that doesn't necessarily work. Sometimes a bone marrow or stem cell transplant is the answer and can be a cure. But, sometimes donors are hard to find.

"In any given family each child has about a 30 percent chance of having a match within their family, especially if they have siblings. The likelihood of a match becomes higher, the more siblings you have," said Dr. Jodi Skiles, who is director of the pediatric stem cell program at Riley Children's Health.

But, when the siblings aren't a match, families have to turn to the world-wide stem cell donor registry.

"There's a stem cell registry. It's called 'Be the Match', and it really is a mechanism for volunteers to sign up to be a donor," said Skiles.

LINK: Be The Match website

Brittany Pittman's daughter was nine years old when she needed a donor.

"I got the phone call when I was at work on Valentine's Day 2017, saying that she tested positive for leukemia," she said. Pittman, of Greenwood, took her daughter to Riley the next day.

"I just remember coming home. Everybody's crying. I just asked 'em like what was wrong. They didn't answer," said Alayna Pittman, 12.

"She did some rounds of IV chemo. We were eventually told that her leukemia wasn't going away with just the IV chemo, that she needed a stem cell transplant," said Pittman. "All of our family members were tested and we were not a match for Alayna."

That's when they turned to the registry. After two weeks a match was found and testing on both the donor and Alayna began. Within a month she was ready for the transplant. Alayna was in the hospital for six weeks and had to have oral chemotherapy for two years. She is considered cured, an outcome Skiles said is typical for people who get stem cell transplants.

She said leukemia, lymphoma and Sickle Cell disease are some of the most common of 40 to 50 illnesses that can be treated with stem cell transplants.

"It's a really simple process. You just have to swab the inside of your cheek and give us your information so that when we have a patient that is in need, we can search the registry to see if you happen to be a match to that patient," said Skiles.

Though it's generally tougher for minorities to find a match, when you donate, it may not necessarily be to someone in Indiana.

"The match program is a national and global program. Signing up as a potential donor in Indiana means you could be donating cells for somebody anywhere in the world."

She said http://www.BetheMatch.org is the portal to find out about donating.

PHOTOS: Chris Davis/Emmis

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When You Need Stem Cells, You May Appreciate the Donor Registry - 93.1 WIBC Indianapolis

The Week That Wasn’t: Cold Cure, Sickle Cell, Polluted Placenta – Medscape

This week you may have read headlines about a protein that's key to defeating the common cold, an Alabama man cured of a genetic disease, or pollution particles reaching the placenta. Here's why you didn't see those stories covered by Medscape Medical News.

Two teams of California researchers are making headway toward the ever-elusive cure for the common cold. The trick, it seems, is not altering the virus but altering the human cells they infect.

Research teams from Stanford and the University of California, San Francisco, found that the enzyme SETD3 is critical to viral replication. In human cell lines lacking SETD3, replication of enteroviruses was reduced 100- to 1000-fold, depending on the cell type. The researchers attempted to infect the cells with multiple types of enterovirus, including poliovirus and three types of rhinovirus, none of which were able to thrive without SETD3.

"Our results reveal a crucial role of a host protein in viral pathogenesis, and suggest targeting SETD3 as a potential mechanism for controlling viral infections," the authors write in an article published in Nature Microbiology.

This study provides a mechanistic foundation for further drug research, not yet a cure for the common cold. Scientists will need to find a way to block the part of SETD3 the virus needs without hindering the enzyme from performing its other cellular functions. Such a drug could treat the common cold and a host of other enteroviral infections, but since it doesn't yet exist, this is not must-read news for a busy clinician.

After 2 years of gene therapy at the National Institutes of Health, Lynndrick Holmes, a 29-year-old Mobile, Alabama, native born with sickle cell anemia, has been declared sickle cell free, according to news reports. He's one of seven participants in a clinical trial by bluebird bio, a Cambridge, Massachusetts, biotech firm, that finished in February. The therapy, LentiGlobin, involves removing and editing patients' stem cells using a lentiviral vector to produce an engineered form of hemoglobin (HbAT87Q) instead of the problematic S-hemoglobin.

Although Holmes' improvement illustrates the exciting promise of gene therapy for patients with sickle cell, it will take years of monitoring a large group of patients to confirm LentiGlobin as an efficacious, long-term treatment. Clinical trials are ongoing. We decided not to cover an early result from a study that involved one patient and that has not been peer reviewed for publication in the medical literature.

A new study published in Nature Communications reported that soot inhaled by people who are pregnant can make its way into but maybe not across the placenta. Research has previously connected air pollution to adverse birth outcomes, including premature birth. In this study, Belgian researchers used a scanning technique called femtosecond pulsed illumination to illuminate black carbon in placenta samples and quantify it.

They analyzed 20 samples: 10 placentas from mothers exposed to high levels of pollution, and 10 from mothers exposed to lower levels of pollution. The researchers found that higher exposure to black carbon during pregnancy corresponded to higher concentrations of black carbon in the placenta. Besides the small sample size, the study didn't show any evidence that black carbon crosses the placenta or affects the fetus. Although the study introduces an interesting methodology, it doesn't change how clinicians should counsel pregnant women, so we decided not to cover it.

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The Week That Wasn't: Cold Cure, Sickle Cell, Polluted Placenta - Medscape

Bluebird Bio reveals further encouraging data for CALD gene therapy – PMLiVE

Last year, Bluebird Bio claimed anFDA breakthrough designation for its Lenti-D gene therapy for cerebral adrenoleukodystrophy (CALD) it has now revealed additional data to support a fast-track approval.

The updated results from the biotechs phase 2/3 Starbeam study were revealed at the European Paediatric Neurology Society (EPNS) congress in Athens, Greece.

CALD is caused by progressive destruction of the myelin sheath that surrounds nerves responsible for thinking and muscle control, resulting in a relentless deterioration that typically leads to a vegetative state or death within a few years of diagnosis. The condition mostly affects young males, with the majority of patients dying before the age of ten.

The only current treatment for the disease is stem cell transplant, but it carries a significant risk from the high-dose chemotherapy used to prepare patients for the procedure. Other potential complications include graft-versus-host (GvHD) disease, when the transplanted cells recognise the recipients cells as foreign and attack them.

Bluebird's treatment works by extracting patients' stem cells and modifying them with Lenti-D. They are then infused back into the patient, where they thenhave the potential to develop into multiple cell types that can produce a functional version of the ALD protein that is lacking in CALD.

Of the patient population involved in the study, as of 25 April 2019, 15 had completed the trial and are enrolled in a long-term follow-up study, 14 are currently still on-study, and three are no longer on-study.

The primary efficacy endpoint of the study is the number of patients who are alive and free of MFDs at month 24 MFDS are the six severe disabilities commonly attributed to CALD, which have the most severe effect on a patients ability to function independently.

The study demonstrated that of those patients who have or would reach 24 months of followup and complete the study, 88% continue to be MFD-free and alive. The 14 patients currently on study have less than 24 months of follow-up and have so far shown no evidence of MFDs.

Out of the 32 treated patients, three did not or will not meet the primary efficacy endpoint, two patients withdrew from the study and one experienced rapid disease progression early, which lead to MFDs and death.

The primary safety endpoint the number of patients experiencing GvHD by month 24 was also met. According to Bluebird, no events of acute or chronic GvHD were reported posttreatment and there were no reports of graft failure, cases of insertional oncogenesis or replication competent lentivirus. There were three adverse events potentially related to treatment of Lenti-D, but these resolved using standard measures.

Lenti-D is Bluebirds lead gene therapy programme,but the company has also made significant progress with its Celgene-partnered CAR-T cancer immunotherapy programme, reporting dramatic responses with its multiple myeloma candidatebb2121 last December.

It also received approval for its gene therapy Zynteglo earlier this year. The one-time gene therapy has been approved for patients 12 years and older with transfusion-dependent -thalassaemia (TDT), and has been shown in a series of small studies to free a majority of patients from the need to have regular blood transfusions.

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Bluebird Bio reveals further encouraging data for CALD gene therapy - PMLiVE