In a milestone year, gene therapy is finding a place in medicine
After decades of hope and high promise, this was the year scientists really showed they could doctor DNA to successfully treat diseases. Gene therapies to treat cancer and even pull off the biblical-sounding feat of helping the blind to see were approved by U.S. regulators, establishing gene manipulation as a new mode of medicine.
Almost 20 years ago, a teen's death in a gene experiment put a chill on what had been a field full of outsized expectations. Now, a series of jaw-dropping successes have renewed hopes that some one-time fixes of DNA, the chemical code that governs life, might turn out to be cures. "I am totally willing to use the 'C' word," said the National Institutes of Health's director, Dr. Francis Collins.
[...] The advent of gene editing — a more precise and long-lasting way to do gene therapy — may expand the number and types of diseases that can be treated. In November, California scientists tried editing a gene inside someone's body for the first time using a tool called zinc finger nucleases for a man with a metabolic disease. It's like a cut-and-paste operation to place a new gene in a specific spot. Tests of another editing tool called CRISPR to genetically alter human cells in the lab may start next year. "There are a few times in our lives when science astonishes us. This is one of those times," Dr. Matthew Porteus, a Stanford University gene editing expert, told a Senate panel discussing this technology last month.
Previously: Gene Therapy Cure for Sickle-Cell Disease
Gene Therapy to Kill Cancer Moves a Step Closer to Market
U.S. Human Embryo Editing Study Published
FDA Approves a Gene Therapy for the First Time
Gene Editing Without CRISPR -- Private Equity Raises $127 Million
FDA Committee Endorses Gene Therapy for a Form of Childhood Blindness
FDA Approves Gene Therapy for Non-Hodgkin's Lymphoma
Gene Therapy and Skin Grafting for Junctional Epidermolysis Bullosa
Gene Therapy for Spinal Muscular Atrophy Type 1
Biohackers Disregard FDA Warning on DIY Gene Therapy
CRISPR Used to Epigenetically Treat Diseases in Mice
Gene Therapy Showing Promise for Hemophilia B
Gene Therapy for Retinal Dystrophy Approved by the FDA
CRISPR Treatment for Some Inherited Forms of Lou Gehrig's Disease Tested in Mice
Related Stories
Dr. Lowe, from In the Pipeline, writes about an apparent cure for sickle-cell disease and the challenges of expanding expensive cures to developing countries:
News came recently of an apparent cure, via gene therapy, of sickle-cell disease in a young patient (whose condition was refractory to hydroxyurea and the other standards of care). Blood-cell diseases are naturally one of the main proving grounds for things like this, since their stem cell populations are in easily localizable tissues and the techniques for doing a hard reset/retransplantation on them are (in some cases) well worked out.
This is an important result, but all such approaches face a possible disconnect as they move forward. As it stands, such gene therapy is a rather expensive and labor-intensive process. Patients are carefully identified and handled one at a time, and there are a limited number of medical centers in the entire world that can operate at this level. The problem is, none of them are particularly close to the great majority of people who actually have sickle cell disease.
[...] Is there any hope that gene therapy and cell replacement could get to the point that you could carry it out at a useful rate in some of the places where it would be needed the most? That's going to to hard, but this article at Technology Review by Antonio Regalado shows some progress:
In October, (Jennifer) Adair demonstrated a new technology she thinks could democratize access to gene therapy. Tweaking a cell-processing device sold by German instrument maker Miltenyi, she mostly automated the process of preparing blood cells with a gene therapy for HIV that her center is also testing. Cells dripped in one end came out the other 30 hours later with little oversight needed. She even added wheels. Adair calls the mobile lab "gene therapy in a box."
[...] The many companies that are working on such therapies seem to be paying attention to this sort of work, because it's not only a possible path to getting clinical trials run (and eventually patients treated) in the regions where most such patients are to be found. Companies are going to be selling such things first to people in the wealthier developed countries, but that's only the beginning of the story (as it has been with antiretroviral drugs).
http://blogs.sciencemag.org/pipeline/archives/2017/03/08/gene-therapy-needs-machines
https://www.technologyreview.com/s/603762/this-lab-in-a-box-could-make-gene-therapy-affordable/
http://www.nejm.org/doi/full/10.1056/NEJMoa1609677
https://en.wikipedia.org/wiki/Sickle-cell_disease
https://en.wikipedia.org/wiki/Gene_therapy
Arthur T Knackerbracket has found the following story:
A new era of treating disease has moved a step closer to reality in the United States.
A Food and Drug Administration panel gave a thumbs-up Wednesday to a gene therapy that involves genetically engineering a patient's T-cells to fight a particular type of leukemia, The New York Times reports.
If the FDA agrees with the panel's recommendation and moves to approve the treatment for commercial use, it would be the first such gene-altering treatment to make it to market.
[...] Once the stuff of science fiction, altering human genes has been creeping into reality of late. Also on Wednesday, researchers at Harvard announced they'd managed to encode video files into the genetic material of living cells, demonstrating the viability of a "molecular recorder" that could lead to more disease treatments in the future.
-- submitted from IRC
The human embryo editing study first reported by MIT Technology Review last week has been published in Nature. Scientists led by the Oregon Health & Science University's Shoukhrat Mitalipov edited human embryos to remove the MYBPC3 mutation associated with hypertrophic cardiomyopathy:
The experiment corrected the defect in nearly two-thirds of several dozen embryos, without causing potentially dangerous mutations elsewhere in the DNA.
None of the embryos were used to try to create a baby. But if future experiments confirm the techniques are safe and effective, the scientists say the same approach could be used to prevent a long list of inheritable diseases. "Potentially, we're talking about thousands of genes and thousands of patients," says Paula Amato, an associate professor of obstetrics and gynecology at Oregon Health & Science University in Portland. She was a member of the scientific team from the U.S., China and South Korea.
[...] Amato and others stress that their work is aimed at preventing terrible diseases, not creating genetically enhanced people. And they note that much more research is needed to confirm the technique is safe and effective before anyone tries to make a baby this way. But scientists hoping to continue the work in the U.S. face many regulatory obstacles. The National Institutes of Health will not fund any research involving human embryos (the new work was funded by Oregon Health & Science University). And the Food and Drug Administration is prohibited by Congress from considering any experiments that involve genetically modified human embryos.
Nevertheless, the researchers say they're hopeful about continuing the work, perhaps in Britain. The United Kingdom has permitted genetic experiments involving human embryos forbidden in the United States. "If other countries would be interested, we would be happy to work with their regulatory bodies," says Shoukhrat Mitalipov, director of the Oregon Health & Science University's Center for Embryonic Cell and Gene Therapy.
Also at NYT, MIT, BBC, Science Magazine, and Scientific American.
Correction of a pathogenic gene mutation in human embryos (open, DOI: 10.1038/nature23305) (DX)
Previously: First Known Attempt at Genetically Modifying Human Embryos in the U.S. is an Apparent Success
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm
The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases.
The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).
"We're entering a new frontier in medical innovation with the ability to reprogram a patient's own cells to attack a deadly cancer," said FDA Commissioner Scott Gottlieb, M.D. "New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we're committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving."
Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.
Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient's own T-cells, a type of white blood cell known as a lymphocyte. The patient's T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.
Also at NPR, CNN, BBC, and FierceBiotech.
Novartis press release.
Tech Review warns of a possible investment scam?
Having something better than CRISPR would be high-impact. But Homology's scientific results aren't yet widely accepted. In fact, several scientists told MIT Technology Review that they believe the claims are probably wrong.
"What's surprising is this company raised so much money on something thought to be untrue in the scientific community," says David Russell, a researcher at the University of Washington, in Seattle. "I think there is just a gene-editing frenzy."
Something about specially designed viruses that don't have to "slash open" human genes to change them. Sounds like something the herd (Wall St speculators) would be happy to get behind.
The paper has not yet been published, but here are some additional links to further information:
From Dr. Lowe's "In the Pipeline" blog - http://blogs.sciencemag.org/pipeline/archives/2017/08/31/good-craziness-and-bad-craziness
Conference abstract on the research - http://www.abstractsonline.com/pp8/#!/4399/presentation/1352
AAV vectors -- use in gene therapy - https://en.wikipedia.org/wiki/Adeno-associated_virus#Use_in_gene_therapy
The U.S. Food and Drug Administration recently approved a gene therapy for the first time, to treat a form of leukemia. Now an FDA panel has endorsed a gene therapy for an inherited form of blindness. The FDA usually follows the recommendations of its advisory committees:
Gene therapy, which has had a roller-coaster history of high hopes and devastating disappointments, took an important step forward Thursday. A Food and Drug Administration advisory committee endorsed the first gene therapy for an inherited disorder — a rare condition that causes a progressive form of blindness that usually starts in childhood. The recommendation came in a unanimous 16-0 vote after a daylong hearing that included emotional testimonials by doctors, parents of children blinded by the disease and from children and young adults helped by the treatment.
"Before surgery, my vision was dark. It was like sunglasses over my eyes while looking through a little tunnel," 18-year-old Misty Lovelace of Kentucky, told the committee. "I can honestly say my biggest dream came true when I got my sight. I would never give it up for anything. It was truly a miracle." Several young people described being able to ride bicycles, play baseball, see their parents' faces, read, write and venture out of their homes alone at night for the first time. "I've been able to see things that I've never seen before, like stars, fireworks, and even the moon," Christian Guardino, 17, of Long Island, N.Y., told the committee. "I will forever be grateful for receiving gene therapy."
The FDA isn't obligated to follow the recommendations of its advisory committees, but the agency usually does. If the treatment is approved, one concern is cost. Some analysts have speculated it could cost hundreds of thousands of dollars to treat each eye, meaning the cost for each patient could approach $1 million. Spark Therapeutics of Philadelphia, which developed the treatment, hasn't said how much the company would charge. But the company has said it would help patients get access to the treatment.
Despite the likely steep price tag, the panel's endorsement was welcomed by scientists working in the field. "It's one of the most exciting things for our field in recent memory," says Paul Yang, an assistant professor of ophthalmology at the Oregon Health and Science University who wasn't involved in developing or testing the treatment. "This would be the first approved treatment of any sort for this condition and the first approved gene therapy treatment for the eye, in general," Yang says. "So, on multiple fronts, it's a first and ushers in a new era of gene therapy."
Also at MIT.
Previously: Gene Therapy Cure for Sickle-Cell Disease
Gene Therapy to Kill Cancer Moves a Step Closer to Market
The U.S. Food and Drug Administration (FDA) has approved a gene therapy for non-Hodgkin's lymphoma (blood cancer):
The Food and Drug Administration on Wednesday approved the second in a radically new class of treatments that genetically reboot a patient's own immune cells to kill cancer.
The new therapy, Yescarta, made by Kite Pharma, was approved for adults with aggressive forms of a blood cancer, non-Hodgkin's lymphoma, who have undergone two regimens of chemotherapy that failed.
The treatment, considered a form of gene therapy, transforms the patient's cells into what researchers call a "living drug" that attacks cancer cells. It is part of the rapidly growing field of immunotherapy, which uses drugs or genetic tinkering to turbocharge the immune system to fight disease. In some cases the treatments have led to long remissions.
"The results are pretty remarkable," said Dr. Frederick L. Locke, a specialist in blood cancers at the Moffitt Cancer Center in Tampa, and a leader of a study of the new treatment. "We're excited. We think there are many patients who may need this therapy."
He added, "These patients don't have other options."
About 3,500 people a year in the United States may be candidates for Yescarta. It is meant to be given once, infused into a vein, and must be manufactured individually for each patient. The cost will be $373,000.
Also at The Associated Press, CNN, and STAT News.
Previously: FDA Approves a Gene Therapy for the First Time
FDA Committee Endorses Gene Therapy for a Form of Childhood Blindness
'Butterfly child' given life-saving skin
A child has been given a new genetically modified skin that covers 80% of his body, in a series of lifesaving operations. Hassan, who lives in Germany, has a genetic disease - junctional epidermolysis bullosa - that leaves his skin as fragile as a butterfly's wings. A piece of his skin was taken, its DNA was repaired in the laboratory and the modified skin grafted back on. After nearly two years, the new skin appears completely normal.
[...] Normally, the different layers of the skin are held together by "anchoring proteins". But the junctional epidermolysis bullosa means Hassan's DNA lacks the instructions for sticking his epidermis (the surface layer) to the dermis (the next one down). There is no cure, and about four in 10 patients do not even reach adolescence.
[...] [A] team of biologists specialising in gene therapy were brought in from the University of Modena and Reggio Emilia, in Italy - and the parents gave approval for them to try an experimental therapy.
In September 2015, a 4 sq cm (0.6 sq inches) patch of skin was taken from an area where the epidermis was still intact. The biopsy was then infected with a customised virus. Viruses are good at getting inside cells, and this one contained the missing instructions for binding the layers of skin together.
The now genetically modified skin cells were grown to make skin grafts totalling 0.85 sq m (9 sq ft). It took three operations over that winter to cover 80% of the child's body in the new skin. Hassan's father said his son had spent months covered in so many bandages he had looked like a mummy. But 21 months later, the skin is functioning normally with no sign of blistering. You can even pinch the once incredibly fragile skin, with no sign of damage.
[...] An analysis of the structure of Hassan's skin, detailed in the journal Nature [DOI: 10.1038/nature24487] [DX], has discovered a group of long-lived stem cells are that constantly renewing his genetically modified skin.
Also at NYT and The Washington Post (archive).
Gene therapy's new hope: A neuron-targeting virus is saving infant lives
Evelyn's older sister Josephine had spinal muscular atrophy type 1 (SMA1), a genetic disease that gradually paralyzes babies. She died at 15 months. Evelyn was an unexpected pregnancy, but her parents decided to have the baby despite one-in-four odds of a second tragedy.
Soon after Evelyn was born in December 2014, they were devastated to learn from genetic testing that she, too, had SMA1. "We knew what we were dealing with: We'll love her for as long as we can," says her father, Milan Villarreal. But that same night, frantically searching the internet, they learned about a clinical trial in Ohio and sent an email. At 8 weeks old, Evelyn received a gene therapy treatment that gave her body a crucial missing protein.
And now here she is, not so different from any healthy toddler. Although she has weak thighs and can't run normally or jump, she can walk quickly, dance, trace letters, toss foam blocks, carry a small chair, and climb onto her mother Elena's lap. After the heartbreak of losing their first baby, the Villarreals have watched in amazement as Evelyn has crawled, walked, and talked. "It was just a miracle. Every milestone was like a celebration. We opened a bottle of wine for every little thing she did," Milan says.
The results of the trial Evelyn participated in have blown away gene therapy researchers, too, marking one of the once-troubled field's most dramatic successes yet. All 15 babies treated for SMA1, expected to die by age 2, are alive at 20 months or older, and most can sit up, according to a report this week in The New England Journal of Medicine (NEJM). Like Evelyn, one boy is walking. Although a drug recently approved for SMA1 has achieved similar effects, it must be injected into the spine every 4 months. The gene therapy is intended as a one-time treatment, and it is simply infused into a vein. "I've never seen an effect [of gene therapy] that good in a lethal disease," says neurologist Jerry Mendell of Nationwide Children's Hospital in Columbus, who led the recent trial.
Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy (DOI: 10.1056/NEJMoa1706198) (DX)
Related: Antisense rescues babies from killer disease (DOI: 10.1126/science.354.6318.1359) (DX)
"Cease & Desist" has not worked:
Despite a warning from the federal government about do-it-yourself gene therapy, two companies say they'll continue offering DNA-altering materials to the public.
The companies, The Odin and Ascendance Biomedical, both recently posted videos online of people self-administering DNA molecules their labs had produced.
Following wide distribution of the videos, the U.S. Food and Drug Administration last week issued a harshly worded statement cautioning consumers against DIY gene-therapy kits and calling their sale illegal. "The sale of these products is against the law. FDA is concerned about the safety risks involved," the agency said.
Does the Executive Branch want the market to decide, or not?
Instead of using CRISPR/Cas9 for gene editing, Salk Institute researchers have used gene-activating CRISPR/Cas9 to regulate gene activity in mice:
A new twist on gene editing makes the CRISPR/Cas9 molecular scissors act as a highlighter for the genetic instruction book. Such highlighting helps turn on specific genes. Using the new tool, researchers treated mouse versions of type 1 diabetes, kidney injury and Duchenne muscular dystrophy [open, DOI: 10.1016/j.cell.2017.10.025] [DX], the team reports December 7 in Cell. The new method may make some types of gene therapy easier and could be a boon for researchers hoping to control gene activity in animals, scientists say.
CRISPR/Cas9 is a two-part molecular scissors. A short, guide RNA leads the DNA-cutting enzyme Cas9 to specific places in the genetic instructions that scientists want to slice. Snipping DNA is the first step to making or fixing mutations. But researchers quickly realized the editing system could be even more versatile.
In the roughly five years since CRISPR/Cas9 was first wielded, researchers have modified the tool to make a variety of changes to DNA (SN: 9/3/16, p. 22). Many of those modifications involve breaking the Cas9 scissors so they cannot cut DNA anymore. Strapping other molecules to this "dead Cas9" allows scientists to alter genes or change the genes' activities.
Gene-activating CRISPR/Cas9, known as CRISPRa, could be used to turn on dormant genes for treating a variety of diseases. For instance, doctors might be able to turn on alternate copies of genes to compensate for missing proteins or to reinvigorate genes that grow sluggish with age. So far, researchers have mostly turned on genes with CRISPRa in cells growing in lab dishes, says Charles Gersbach, a biomedical engineer at Duke University not involved in the new study.
Also at GenomeWeb and New Atlas.
A gene therapy trial has shown success in reducing bleeding episodes caused by the inherited blood disorder hemophilia B. Ten participants received a virus that stimulated the production of the blood-clotting protein factor IX. Nine have had no bleeding episodes, while eight no longer need the gene therapy injections every few days:
Previous gene therapy trials for hemophilia B didn't go well, either because patients' immune systems destroyed the modified cells or the cells didn't make enough factor IX. In the new trial, sponsored by Spark Therapeutics and Pfizer, researchers gave the patients' liver cells the gene for an unusually potent version of the factor IX protein. That allowed the team to lower the vector dose, minimizing immune responses. Two patients had elevated liver enzymes in reaction to the vector, but those levels came down after they received steroids. Only 20% of hemophilia patients have the B form, but efforts are also underway to use gene therapy to treat the most common type, hemophilia A.
Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant (DOI: 10.1056/NEJMoa1708538) (DX)
The Food and Drug Administration (FDA) has approved a gene therapy to treat RPE65-mutation associated retinal dystrophy. But it will be expensive:
A first-of-its-kind gene therapy received approval from the Food and Drug Administration on Tuesday to treat a rare, inherited form of childhood blindness.
The FDA marketing clearance of Spark Therapeutics's Luxturna is historic for scientific and financial reasons. Luxturna is the first gene therapy approved in the U.S. that targets a disease caused by mutations in a specific gene.
A Spark spokesman said the company will not disclose the Luxturna price tag until early January. Wall Street analysts expect the gene therapy to command a $1 million price tag—another first, but not necessarily a welcome one. At a time when drug prices are coming under intense scrutiny, Spark will need to convince insurers, politicians, and pharma critics that the benefit to patients offered by Luxturna justifies its high cost.
Also at NPR.
Previously: FDA Approves a Gene Therapy for the First Time
FDA Committee Endorses Gene Therapy for a Form of Childhood Blindness
First step toward CRISPR cure of Lou Gehrig's disease
University of California, Berkeley scientists have for the first time used CRISPR-Cas9 gene editing to disable a defective gene that causes amyotrophic lateral sclerosis, or Lou Gehrig's disease, in mice, extending their lifespan by 25 percent.
[...] The mice were genetically engineered to express a mutated human gene that in humans causes about 20 percent of all inherited forms of the disease and about 2 percent of all cases of ALS worldwide. Though the genetic cause is not known for all cases of ALS, all are accompanied by the premature death of motor neurons in the brain stem and spinal cord. The neurons allow the brain to control muscles, so loss of this connection means loss of muscle control.
[...] The UC Berkeley research team used a virus that Schaffer's team engineered to seek out only motor neurons in the spinal cord and deliver a gene encoding the Cas9 protein into the nucleus. There, the gene was translated into the Cas9 protein, a molecular scissors that cut and disabled the mutant gene responsible for ALS.
In this case, Cas9 was programmed to knock out the mutated gene SOD1 (superoxide dismutase 1). The onset or start of the disease was delayed by almost five weeks, and mice treated by the gene therapy lived about a month longer than the typical four-month lifespan of mice with ALS. Healthy mice can live a couple of years.
Lou Gehrig's disease = amyotrophic lateral sclerosis (ALS).
In vivo genome editing improves motor function and extends survival in a mouse model of ALS (open, DOI: 10.1126/sciadv.aar3952) (DX)
Previously: New Therapy Halts Progression of Lou Gehrig's Disease in Mice
Francis Collins to step down as NIH director
National Institutes of Health Director Francis Collins plans to announce his resignation on Tuesday after nearly three decades at the agency, including 12 years at the helm, three sources tell POLITICO.
The 71-year-old physician-geneticist led the agency under three consecutive presidents — making him the first presidentially appointed NIH director to serve in more than one administration and the longest-serving NIH director.
His departure had been in the works for some time, one person familiar said. Officials from NIH, the Department of Health and Human Services and the White House did not immediately respond to requests for comment.
Previously: NIH Won't Fund Human Germline Modification
Francis Collins Retains Position as Director of the National Institutes of Health
The Era of Biomedical Research on Chimpanzees in the United States is Effectively Over
2017: Gene Therapy's Milestone Year
(Score: 1, Insightful) by Anonymous Coward on Monday January 01 2018, @05:21PM (2 children)
This makes it look like the optimism is based off a bunch of press releases and that the end goal is "approval" rather than actual success. This does not mean I am saying it doesn't work, it is more a comment on the hyped up reporting on this topic.
(Score: 2) by takyon on Monday January 01 2018, @05:35PM (1 child)
Nothing going on here lol.
[SIG] 10/28/2017: Soylent Upgrade v14 [soylentnews.org]
(Score: 1, Disagree) by Anonymous Coward on Monday January 01 2018, @06:35PM
Let me put it this way: publishing a promising "gene editing/therapy" paper is currently easier than creating a blockchain.
(Score: 1, Touché) by Anonymous Coward on Tuesday January 02 2018, @04:39AM
> "I am totally willing to use the 'C' word," said the National Institutes of Health's director, Dr. Francis Collins.
You've explicitly shown you're not willing to use it.