Early results boost hopes for historic gene editing attempt
By MARILYNN MARCHIONE
AP Chief Medical Writer
Wednesday, September 5
PHOENIX (AP) — Early, partial results from a historic gene editing study give encouraging signs that the treatment may be safe and having at least some of its hoped-for effect, but it’s too soon to know whether it ultimately will succeed.
The results announced Wednesday are from the first human test of gene editing in the body, an attempt to permanently change someone’s DNA to cure a disease — in this case, a genetic disorder called Hunter syndrome that often kills people in their teens.
In two patients who got a medium dose of the treatment, urine levels of large sugar compounds that are hallmarks of Hunter syndrome had fallen by half, on average, four months later — a possible sign the treatment is working. Two others who got a low dose have seen little change in these sugars so far.
There’s no way to know yet whether the change in the middle-dose patients is due to the gene editing or something else, but the fact their sugars have declined consistently since treatment suggests it might be.
“I cannot absolutely say it’s a treatment effect” but the drop is “really encouraging,” said the study leader, Dr. Joseph Muenzer of the University of North Carolina, Chapel Hill. The main goal of early treatment studies is to test safety, though researchers also look for hints that the therapy is working. Muenzer gave the results at a conference in Greece and consults for the treatment’s maker, California-based Sangamo Therapeutics.
The company’s president, Dr. Sandy Macrae, said tests in about five months will reveal more, but the change in the middle-dose group so far “looks really good.”
“The most rational explanation for this is that what we hoped was going to happen has happened,” he said.
Several independent experts agreed.
“The results are exciting” and suggest that the gene editing is working to some degree, without safety concerns so far, said Dr. Howard Kaufman, a Boston scientist and member of a National Institutes of Health panel that reviewed the study before it began.
Dr. Matthew Porteus, a genetics expert at Stanford University who consults for two other companies developing gene therapies, said more time is needed to see how the patients’ immune system continues to react to the treatment and whether the effects last, but added, “I would be excited about continuing to push along” based on these results.
HOW IT WORKS
Gene editing is intended as a more precise way to do gene therapy, to knock out a bad gene or supply a good one that’s missing. Doctors hope it will give a way to address a host of diseases that can’t be treated well now.
In November, a Phoenix-area man with Hunter syndrome, Brian Madeux, became the first person to test this inside the body. He lacks a gene that makes an enzyme that breaks down certain large sugar compounds called GAGs. These build up in cells and cause havoc throughout the body.
Through an IV, Madeux received many copies of a corrective gene and a gene-editing tool called zinc finger nucleases to help put it in a precise spot in his DNA. He was one of the two patients given a very low dose of the treatment, because this first-in-human testing called for extreme caution.
In Madeux and the other low-dose patient, levels of the tell-tale sugar compounds in urine rose 9 percent on average after four months. Muenzer said it’s hard to know whether this is a significant change; little is known about the biology of these compounds, including whether they fluctuate during the day or before or after meals.
A liver biopsy on one patient given a low dose of the therapy found no evidence that the gene editing had occurred, but Sangamo scientists said this dose is far below the level at which such signs had been detected in research on primates.
Two other patients were given a middle dose that was twice what the first two patients received. Their GAG levels declined by 51 percent after four months, on average. Two of the main types of these sugars that accumulate in tissues declined 32 percent and 61 percent, respectively.
It is not yet known if declines like these can improve patients’ health or slow the progression of the disease.
“This is not proof that this is a successful therapy yet, that these patients had enough gene editing to now supply them with the enzyme they need for the rest of their life,” Muenzer said.
But he said an important goal was met: the treatment seems safe. There were two serious side effects — one patient was hospitalized for bronchitis and another for an irregular heartbeat — but those were deemed due to their disease and pre-existing conditions, not the gene treatment.
Blood tests did not detect the missing enzyme. Company scientists said this could be because any that was being made was rapidly used by cells rather than getting into the bloodstream — an explanation some outside experts agreed with. What counts, they said, was seeing the result of enzyme activity, the drop in sugars.
Two more patients have been given the highest dose being tested — 10 times the starting dose — for a total of six patients in the study. The next step is to start taking patients off the weekly enzyme treatments they’ve been receiving to see if the gene therapy has changed their bodies so they make enough of the enzyme themselves.
More results are expected at a medical meeting in February.
“We need to see sustained levels for this to be practical. If this only works for six months, that’s not very beneficial,” Muenzer said. “Time’s going to tell.”
In an interview at his home in Arizona last month, Madeux, 45, told The Associated Press he volunteered for the study in hope of being able to stop the weekly, three-hour enzyme infusions, but also to help find a treatment for future generations with the disease.
“I’m old and having Hunter’s has done a lot of damage to my body,” Madeux said. “I’m actually pretty lucky I’ve lived this long.”
Marilynn Marchione can be followed at http://twitter.com/MMarchioneAP .
This Associated Press series was produced in partnership with the Howard Hughes Medical Institute’s Department of Science Education. The AP is solely responsible for all content.
Lesson from Brazil: Museums are not forever
September 5, 2018
Brazil’s gutted National Museum now resembles an archaeological ruin itself.
Lecturer on Anthropology, University of Colorado Denver
Chip Colwell has received funding from the National Endowment for the Humanities, and is participating on projects funded by the Institute of Museum and Library Services. He is also a senior curator of anthropology at the Denver Museum of Nature & Science.
We now know what history going up in flames looks like.
On Sept. 2, the National Museum of Brazil lit up Rio de Janeiro’s night sky. Perhaps started by an errant paper hot air balloon landing on the roof or a short circuit in a laboratory, the fire gutted the historic 200-year-old building. Likely gone are a collection of resplendent indigenous ceremonial robes, the first dinosaur found in South America, Portuguese royal furniture, ancient Egyptian mummies, a vast library and so much more. In six hours, an estimated 18 million artifacts were turned to smoke and ash.
The images of the hollowed-out museum are a living nightmare for a curator like me. I know that most museum collections are truly irreplaceable. But, for me, the fire is also a vital reminder that the greatest dangers to humanity’s collective heritage are not natural disasters but human ones.
There’s an important lesson for all of us in the fire’s embers.
The perils museums face
A museum presents itself as permanent and timeless. It’s why so many sport Greek columns, sterile white walls and clean objects under clear glass. The message is that the museum and its treasures should exist beyond the fleeting moment of our visit – connecting past, present and future. Whether displaying dinosaurs or dodos, art or archaeology, the museum is our bank vault for the world’s natural wonders and human achievements. The museum aspires to be a fortress against time.
The reality is that time is inexorable and relentless. Museums are locked in a constant struggle against decay and an almost absurdly wide-ranging array of natural and human threats. There’s even a formal list of the evil-sounding “agents of deterioration” that museums use to evaluate risks to their collections, ranging from bugs to temperature to water to fire.
These risks are constantly evolving. War might turn a museum overnight into a looter’s paradise, as in the case of the National Museum of Iraq. Market forces or colonial revenge may spur thieves to steal artifacts, as recently seen with a pandemic of thefts of Chinese art. Some are even adding climate change to the menaces facing collections, such as the Bass Museum along Miami Beach, as it prepares for rising sea levels.
For museum curators, a terrifying range of hazards could devastate the treasures we are appointed to safeguard. Tragically, fire has long been at the top of the list. As early as 1865, the Smithsonian in Washington, D.C. – “America’s attic,” as it is famously known – caught aflame, resulting in what was then called a “national calamity.” In more recent years, infernos destroyed Madagascar’s royal palace museum, Delhi’s natural history museum and a history museum in Washington state, which housed rare artifacts from the late musician Kurt Cobain.
Despite the known risk of fire, reports suggest that Brazil’s National Museum was woefully unprepared. It apparently lacked a fire suppression system. Nearby fire hydrants went dry.
The spark that started the fire was perhaps an unforeseen event, but the conflagration that followed was not.
Collections don’t care for themselves
Most hazards that endanger museums can be mitigated. Conservation programs can hunt artifact-eating bugs, storage rooms can control temperature and humidity, security systems can prevent burglary and more. But implementing such protections requires serious resources.
By all accounts, this is where Brazil’s caretakers failed. As a national museum, Brazil’s elected officials were responsible for directing the appropriate funds to the museum. Instead, they underfunded the museum and allowed it to fall into disrepair. With the proper buildings and equipment, Brazil’s museum fire would likely not have been so disastrous.
Such indifference is not limited to Brazil. For example, a 2016 report found that Canada’s six national museums are underfunded by about US$60 million each year. In the United States, President Trump’s 2019 fiscal year budget sought to entirely eliminate three vital federal agencies – the National Endowment for the Humanities, National Endowment for the Arts and Institute of Museum and Library Services – that preserve much of the country’s cultural heritage in museums. Congress, however, passed a spending bill in 2018 that modestly increased funding for all three agencies.
From Brazil, those holding the purse strings on citizens’ behalf must learn that museums are not forever. Collections are never permanently safe. They require focused investments and proactive stewardship to ensure their survival long into the future. Otherwise, it’s only a matter of time before the next fire.
This article has been updated to clarify 2018 U.S. budget allocation for museum-related agencies.
New technique heals wounds with reprogrammed skin cells
September 5, 2018
Juan Carlos Izpisua Belmonte
Professor, Gene Expression Laboratory, Salk Institute for Biological Studies and Adjunct Professor, Cell and Developmental Biology, University of California San Diego
Juan Carlos Izpisua Belmonte does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.
University of California provides funding as a founding partner of The Conversation US.
People with severe burns, bedsores or chronic diseases such as diabetes are at risk for developing wounds known as cutaneous ulcers, which can extend through multiple layers of the skin.
Apart from being extremely painful, these wounds can lead to serious, sometimes deadly, infections or amputations. Typically, these ulcers are treated by surgically transplanting existing skin to cover the wound. However, when the ulcer is especially large, it can be challenging to graft enough skin. In such cases, researchers may isolate skin stem cells from a patient, grow them in the laboratory and transplant them back into the patient. But the procedure is time-consuming, risky for the patient and not necessarily effective.
The dramatically rising rates of diabetes alone underscore an urgent need to develop new, effective methods for the treatment of cutaneous ulcers.
My laboratory at the Salk Institute focuses on developing stem-cell-based approaches to “reprogram” cells from one type into another for the purpose of regenerative medicine.
In a report in the journal Nature, we describe a new technique to directly convert the cells naturally present in an open wound into new skin cells by reprogramming the wounded cells to a stem-cell-like state, in which cells revert to an earlier, more flexible state from which they can develop into different cell types.
A postdoctoral research associate in my lab, Masakazu Kurita, who has a background in plastic surgery, knew that a critical step in wound healing was the migration of stem-cell-like cells called basal keratinocytes – from nearby, undamaged skin – into wounds.
Basal keratinocytes are precursors to many different types of skin cells. But large, severe wounds such as cutaneous ulcers no longer have any basal keratinocytes. Moreover, as these wounds heal, the cells multiplying in the area – known as mesenchymal cells – are involved primarily in closing the wound and inflammation, but they cannot rebuild healthy skin.
We wanted to convert these mesenchymal cells into basal keratinocytes, without ever taking them out of the body.
To do so, we compared the levels of different proteins inside the two cell types – mesenchymal cells and keratinocytes – to figure out what distinguished them and find out what we would need to change in order to reprogram one cell type into the other.
We identified 55 proteins, which we call “reprogramming factors,” that are potentially involved in determining and maintaining the cellular identity of basal keratinocytes. We conducted further experiments on each potential reprogramming factor and narrowed the list down to four factors that would transform mesenchymal cells into basal keratinocytes in vitro in petri dishes. These keratinocytes then formed all the cells present in healthy new skin.
We then tested the power of these four factors to treat skin ulcers on mice. Just 18 days after we applied a topical solution containing these four factors directly onto the ulcers, we saw healing happen. These four factors reprogrammed the mesenchymal cells in the wound into keratinocytes which then grew into the many cells types that make up healthy skin, closing and healing the sore. These cells continued to grow and join the surrounding skin, even in large ulcers. When we examined the mice three months and six months later, we saw that the newly generated cells functioned like healthy skin. Rodent skin heals differently from human skin, so there was no visible scar tissue, though it should have been there.
Further work is necessary to ensure the safety of this approach, especially over a much longer term, but as an initial test of the concept, the results are very promising.
We are optimistic that our approach represents an initial proof of principle for in vivo regeneration of an entire three-dimensional tissue, like the skin, not just individual cell types. In addition to wound healing, our approach could be useful for repairing skin damage, countering the effects of aging and helping us to better understand skin cancer.