CRISPR milestone pushes gene editing toward its promise


Axios 01 July, 2021 - 05:17pm 96 views

The gene editing system CRISPR-Cas9 can be injected into the blood and directed to the liver to treat patients with a rare condition, according to a recent study.

Why it matters: The ability to edit genes directly in a patient's body expands the list of possible diseases and conditions researchers can try to target with CRISPR-based therapies.

Driving the news: Preliminary but promising results from a small trial in six people indicate a one-time CRISPR-Cas9 treatment led to a decrease in the misfolded protein that causes the condition transthyretin amyloidosis (ATTR).

The trial results don't yet indicate whether symptoms of the disease are alleviated.

The big picture: CRISPR therapies are being developed and studied for a range of diseases and conditions.

But delivering the gene editing system to some cells without it being degraded remains a challenge for the field.

What to watch: Leonard says in addition to continuing to study the AATR therapy in pursuit of FDA approval, Intellia is looking at whether the mRNA approach could be applied to treat sickle cell anemia and eliminate the need for bone marrow transplants.

Go deeper: CRISPR co-discoverer on the gene editor's pandemic push (Axios)

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Read full article at Axios

Gene editor injected into the body treats disease

Science 02 July, 2021 - 08:46am

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The gene editor CRISPR excels at fixing disease mutations in lab-grown cells. But using CRISPR to treat most people with genetic disorders requires clearing an enormous hurdle: getting the molecular scissors into the body and having it slice DNA in the tissues where it's needed. Now, in a medical first, researchers have injected a CRISPR drug into the blood of people born with a disease that causes fatal nerve and heart disease and shown that in three of them it nearly shut off production of a toxic protein by their livers. Although it's too soon to know whether the CRISPR treatment will ease the symptoms of the disease, known as transthyretin amyloidosis, the preliminary data reported last week are generating excitement about what could be a one-time, lifelong treatment. The work also marks a milestone in the race to develop treatments based on messenger RNA, the protein-building instructions naturally made by cells.

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By Jocelyn Kaiser

In a first, CRISPR components infused into patients' blood shut down mutant gene in liver.

By Jocelyn Kaiser

In a first, CRISPR components infused into patients' blood shut down mutant gene in liver.

Astronauts successfully edit genes in space for first time in experimental procedure

MSN UK 02 July, 2021 - 08:46am

Astronauts have successfully performed an experimental gene editing procedure in space for the first time.

The process, which aims to study DNA repair in yeast cells that can be conducted entirely in space, is vital for astronaut safety. Damage to DNA can occur as a result of environmental factors, such as exposure to ultraviolet light.

Outside of Earth’s protective atmosphere, that risk is even greater due to the ionising radiation (heat or light that removes electrons from atoms) that permeates space.

The new technique, applied on board the International Space Station, uses CRISPR/Cas9 genome editing technology to create precise damage to DNA. Scientists can then study the repair mechanisms in better detail than would be possible using radiation, which is harder to use in targeted ways. The technique focuses on double-strand breaks, which are one of the most harmful types of DNA damage as they can cause cell death.

The yeast cell experiment was the first time an organism had its genome edited, the DNA repaired, and then sequenced, all in a spaceflight environment. Future research could build on these methods to better mimic complex DNA damage – leading to new ways to protect spacefarers – as well as investigations into other long-term space exposure and exploration.

"It’s not just that the team successfully deployed novel technologies like CRISPR genome editing, PCR, and nanopore sequencing in an extreme environment, but also that we were able to integrate them into a functionally complete biotechnology workflow applicable to the study of DNA repair and other fundamental cellular processes in microgravity," said Sebastian Kraves, senior author of the study which was published in Plos One.

"These developments fill this team with hope in humanity’s renewed quest to explore and inhabit the vast expanse of space."

Developments to help astronauts survive better in space are being made in a number of areas. A suncream made of skin pigment is being developed to shield them from lethal x-ray radiation, using a material that has never been found to exist in nature.

It was also recently discovered that sperm can survive in space for 200 years without damage to its DNA, which will help scientists plan for mammals – including humans – reproducing outside of our own planet.

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NASA Astronauts Used CRISPR Gene Editing Technology For the First Time in Space

News18 01 July, 2021 - 11:33pm

However, previous research has found that how cells pick a particular repair strategy can be influenced by the microgravity conditions in space. Scientists are concerned that DNA repairs influenced by microgravity conditions may not be adequate, and can lead to harmful consequences.

To study the DNA repair process in space, scientists have developed a new technique that uses CRISPR/Cas9 — a gene-editing technology — to recreate precise damages so that cells can be observed repairing them. The team of researchers led by Sarah Stahl-Rommel has successfully demonstrated the technique and its viability aboard the International Space Station. Rommel works as a microbiologist at NASA’s Johnson Space Center. The guided experiments were conducted in space by NASA astronauts Christina Koch, Tyler Nicklaus Hague, and David Saint-Jacques.

The researchers performed the experiments using the new method on yeast cells. This was the first time gene-editing was happening in space.

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According to Sebastian Kraves, who is the senior author of the research, the research integrates gene-editing techniques in the extreme environment to “functionally complete biotechnology flow” that can be applied for studying other fundamental cell processes as well. “These developments fill this team with hope in humanity’s renewed quest to explore and inhabit the vast expanse of space," said Kraves in a statement by PLOS. The study was published in PLOS ONE on June 30.

Read all the Latest News, Breaking News and Coronavirus News here

Astronauts successfully demonstrate Genetic editing in space for first time

Republic World 01 July, 2021 - 07:19pm

In a spaceflight setting, the yeast cell experiment was the first time an organism's genome was altered, DNA was repaired, and then sequenced. Future studies could improve on these methods to better imitate complex DNA damage, potentially leading to new ways to protect astronauts as well as inquiries into other long-term space exposure and exploration said reports.

Sebastian Kraves, a senior author of the study which was published in Plos One, said that not only was the team able to successfully deploy novel technologies like CRISPR genome editing, PCR, and nanopore sequencing in an extreme environment, but they were also able to integrate them into a functionally complete biotechnology workflow that could be used to study DNA repair and other fundamental cellular processes in microgravity.

A variety of advancements are being made to assist astronauts in surviving in space. To protect people from fatal x-ray radiation, a suncream made of skin pigment is being developed, using a substance that has never been discovered in nature.  Reportedly, scientists have just discovered that sperm may survive in space for 200 years without causing DNA damage, which will aid scientists in planning for mammals – including humans – to reproduce outside of our own planet.

Breakthrough CRISPR Gene Therapy Could Be a 'One and Done' Injection

Singularity Hub 01 July, 2021 - 02:06pm

CRISPR gene editing has had a big decade. The technology, which earned two of its discovers a Nobel Prize in 2020, can target and edit genes more easily than its predecessors. Still, as tantalizing (and controversial) as the technology’s been over the years, it’s mostly been developed in the lab.

That’s changing now as a growing number of clinical trials are beginning to test gene therapies in humans.

Early CRISPR trials have focused on hereditary blindness and diseases of the blood, including cancer, sickle cell anemia, and beta thalassemia.

Although cutting-edge, the therapies can be costly and intense. In one trial for sickle cell anemia, doctors remove cells from the body, edit them in a dish, and then infuse them back into the patient. In another trial, practitioners inject the gene editing system directly into target tissues in the eye.

Such approaches won’t work as readily for other diseases. So researchers and doctors are looking for a general delivery method, like any other medication. Now, a clinical trial from University College London (UCL) has taken a step in that direction.

Participants in the trial suffer from a condition called hereditary transthyretin amyloidosis, in which a mutated gene produces a malformed protein (transthyretin) that builds up in and damages the heart and nerves. The disease is eventually fatal.

Patients received a single infusion of a CRISPR-based therapy into their bloodstream. Blood carried the therapy to the liver, where it switched off the mutated gene and curtailed production of the errant protein. Though the Phase 1 trial was small, the approach had strong results relative to existing options. And it hints at the possibility other genetic diseases may be treated in a similar fashion in the future.

The University of California, Berkeley’s Jennifer Doudna, who shared the Nobel Prize for CRISPR, cofounded Intellia, the company that, alongside fellow biotech company Regeneron, developed the treatment (NTLA-2001) used in the UCL trial.

“This is a major milestone for patients,” Doudna said. “While these are early data, they show us that we can overcome one of the biggest challenges with applying CRISPR clinically so far, which is being able to deliver it systemically and get it to the right place.”

The therapy is made up of three parts. A tiny bubble of fat, called a lipid nanoparticle, carries a payload of CRISPR machinery: a strand of guide RNA and a sequence of mRNA coding for the Cas9 protein.

Billions of these CRISPR-carrying nanoparticles are infused into the bloodstream, making their way to the liver, the source of the dysfunctional protein. The mRNA instructs the cells to produce the Cas9 protein (CRISPR’s genetic ‘scissors’) which then links up with the guide RNA, seeks out the target gene, and snips it.

The cell repairs the DNA at the site of the break, but imperfectly, switching the gene off and shutting down production of the problematic protein.

Interim trial results, reported in the New England Journal of Medicine last weekend, were very encouraging. The trial’s six patients, who received either a low or high dose, reported no serious side effects. Meanwhile, production of the target protein declined by up to 96 percent (and an average of 87 percent) in those given the high dose.

The disease, which affects some 50,000 people worldwide, was untreatable until recently.

Existing drugs, approved by the FDA in 2018, silence the mRNA that produces the malformed thyretin protein, instead of altering its gene. They reduce protein production some 80 percent and keep people alive longer, but don’t work for everyone and require ongoing treatment.

The CRISPR approach, if successful, would be a one-time treatment. That is, by targeting the genes themselves, the protein is permanently silenced.

Patrick Doherty, a trial participant, told NPR he jumped at the opportunity.

Doherty, an avid trekker and hiker, was diagnosed with transthyretin amyloidosis—which had killed his father—after noticing symptoms, like tingling fingers and toes and breathlessness on walks.

“It’s [a] terrible prognosis,” he said. “This is a condition that deteriorates very rapidly. It’s just dreadful.”

Doherty started feeling better a few weeks after the treatment and said improvements have continued.

“A one-hit wonder,” he called it. “A two-hour process, and that’s it for the rest of your life.”

Although the results are promising, there’s reason to temper expectations.

The trial, as noted was small, and focused on safety. Future work will further test safety and efficacy in larger groups, which—as is apparent from recent experience with covid—can reveal rare side effects or prove disappointing despite early success.

Researchers will likely also look out for off-target “snips” in the liver or other cells. A benefit of this approach, however, is the cells break down the mRNA after they’ve made the Cas9 protein. In other words, the gene-editing system doesn’t persist long.

Finally, the treatment may come with a hefty price tag, perhaps running into the hundreds of thousands of dollars according to Bloomerg’s Sam Fazeli.

“Not one person in my field is doing a victory lap, even around their laboratory bench,” Fyodor Urnov, a University of California, Berkeley gene editing expert, told US Today. “We’re all slightly blue because we’re all holding our breath.”

If the trial does prove successful, however, researchers will want to know if they can reach any organ or target tissue with a general infusion. And can genes also be edited in vivo? Instead of merely knocking out a faulty gene, can we safely correct it?

In the future, when the kinks have been worked out and the science more thoroughly proven, Urnov said, gene editing could help millions of people around the world with genetic conditions. And this trial, it seems, is a notable step in that direction.

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Jennifer Doudna Reacts to Intellia CRISPR Breakthrough, Outlines Challenges | BioSpace

BioSpace 01 July, 2021 - 12:00am

Jennifer Doudna is best known for discovering CRISPR/Cas9 gene editing with Emmanuelle Charpentier, and both winning the Nobel Prize in Chemistry in 2020. Doudna also co-founded several companies, including Cambridge, Mass.-based Intellia Therapeutics, which recently announced a major breakthrough in the use of CRISPR/Cas9 gene editing. Doudna recently discussed CRISPR and Intellia with CNBC.

Intellia’s announcement was, along with Regeneron Pharmaceuticals, that they had interim clinical data from their ongoing Phase I trial of their in vivo genome editing candidate, NTLA-2001. NTLA-2001 is being developed as a single-dose treatment for transthyretin (ATTR) amyloidosis. The therapy is based on CRISPR/Cas9, but even more importantly, is the first CRISPR therapy to be administered systemically. 

It has two parts, a guide RNA specific to the disease-causing gene and messenger RNA that encodes the Cas9 enzyme. They are delivered in lipid nanoparticles, which allows the therapy to be administered in the bloodstream. To this point, the use of CRISPR has been only in ex vivo therapy, where cells are taken from the body and engineered using CRISPR in the laboratory before being injected back into the patient.

Of CRISPR gene editing, Doudna said that with CRISPR’s discovery to treatment occurring in less than 10 years, it is “One of the fastest rollouts I think of technology from the fundamental, initial science to an actual application. It’s largely because the technology comes at a moment when there’s enormous demand for genome editing, as well as a lot of knowledge about genomes.”

Doudna discussed several challenges facing CRISPR. As the Intellia announcement emphasized, there are obstacles in getting edited molecules to where they need to be. “This is especially an issue in clinical medicine where being able to edit brain cells, heart cells or muscle cells has incredible potential but right now we don’t really have the tools to introduce the editors into those cells,” Doudna said. “We have the editors; we just don’t know how to get them where they need to go.”

There are also, of course, ethical issues. Most notably, in November 2018, He Jiankui, a Chinese researcher, went public claiming he used CRISPR/Cas9 to change the DNA of embryos for seven couples. A set of twins was born from one of them. 

Jiankui used CRISPR to disable the CCR5 gene, which creates a protein that allows HIV to enter a cell. All of the men of the seven couples had HIV and the women did not. The reported goal of the controversial procedure was to prevent transmission of HIV, even though all seven of the men’s HIV was strongly suppressed by standard HIV drugs. 

The announcement was met by global condemnation, a global moratorium and guidelines on gene editing of germ cells, and He Jiankui receiving a three-year prison sentence in China. At issue was, because he edited the embryos’ germ lines, the changes could be inherited, should any of them go on to have children.

There is an expense issue as well. Doudna pointed out that treating sickle cell disease with CRISPR runs about $2 million per patient. “That is clearly not a price point that will make this available to most people that can benefit from it.”

Early work using CRISPR to modify diseases has mostly been in sickle cell disease. It has been a good target for the technology because, Doudna says, blood stem cells can be “harvested, edited and then reintroduced to patients.”

Eye diseases have also been low-hanging fruit for CRISPR and other gene therapies because it is relatively easy to introduce the therapies directly into the eye. So far, she notes, there has been a success in delivering CRISPR tech to the liver because “a liver is an organ that naturally takes up molecules in the body,” Doudna said.

More troublesome are other organs, such as the brain, heart and muscles. Doudna points out that “there are some technologies already that enable some of this, for example using various kinds of viruses or virus-like particles, and I’m excited about the innovation that will come in the next few years in this regard.”

Doudna also said that human medicine is not the only area where CRISPR is likely to have a major impact. It’s being used in agriculture, for example. Instead of spending months or years on breeding, or current techniques for genetically modifying crops, she said that CRISPR can be used to modify plant genes “without touching anything else. This is opening the door to lots of things now that can be done to both address challenges of climate change, dealing with drought conditions, introducing traits in the plants that give them protection against pests.”

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