Harvard

A personal reason to develop a better gene therapy

/ Kevin McCormack / 2 Comments

THIS BLOG IS ALSO AVAILABLE AS AN AUDIOCAST ON SPOTIFY

Credit : Allison Dougherty, Broad Communications

For Sharif Tabebordbar, finding a gene therapy for genetic muscle wasting diseases was personal. When he was a teenager, his father was diagnosed with a rare genetic muscle disease that eventually left him unable to walk.

In an interview with the Broad Institute at MIT he said: “I watched my dad get worse and worse each day. It was a huge challenge to do things together as a family – genetic disease is a burden on not only patients but families. I thought: This is very unfair to patients and there’s got to be a way to fix this. That’s been my motivation during the 10 years that I’ve been working in the field of gene therapy.”

That commitment now seems to be paying off. In a study published in the journal Cell, Tabebordar and his team at MIT and Harvard showed how they have developed a new, safer and easier way to deliver genes to help repair wasting muscles.   

In earlier treatments targeting genetic muscle diseases, researchers used a virus to help deliver the gene that would correct the problem. However, to be effective they had to use high doses of the gene-carrying virus to ensure it reached as many muscles throughout the body as possible. But this meant that more of the payload often ended up in the liver and that led to severe side effects in some patients, even a few deaths.

The usual delivery method of these gene-correcting therapies is something called an adeno-associated virus (AAV), so Dr. Tabebordar set out to develop a new kind of AAV, one that would be safer for patients and more effective at tackling the muscle wasting.

They started by taking an adeno-associated virus called AAV9 and then set out about tweaking its capsid – that’s the outer shell that helps protect the virus and allows it to attach to another cell and penetrate it to deliver the corrected gene. They called this new viral vector MyoAAV and in tests it quickly showed it had an enhanced ability to deliver genes into cells.

The team showed that it not only was around 10 times more efficient at reaching muscle than other AAVs, but that it also reduces the amount that reaches the liver. This meant that MyoAAV could achieve impressive results in doses up to 250 times lower than those previously used.

In animal studies MyoAAV showed encouraging results in diseases like Duchenne Muscular Dystrophy and X-linked myotubular myopathy. Dr. Amy Wagers, a co-senior author of the study, says they are hopeful it will be equally effective in people.

“All of these results demonstrate the broad applicability of the MyoAAV vectors for delivery to muscle. These vectors work in different disease models and across different ages, strains and species, which demonstrates the robustness of this family of AAVs. We have an enormous amount of information about this class of vectors from which the field can launch many exciting new studies.”

CRISPR cluster: How the media spotlight is focusing on gene editing tool

/ Kevin McCormack / Leave a comment

Illustration by Ashley Mackenzie: from New York Times Sunday Magazine

Illustration by Ashley Mackenzie: from New York Times Sunday Magazine

Getting in-depth stories about science in general, and regenerative medicine in particular, into the mainstream media is becoming increasingly hard these days. So when you get one major media outlet doing a really long, thoughtful piece about a potential game-changing gene-editing technology it’s good news. But when you get three major media outlets, all reporting on the same technology, all in the space of less than one week, and all devoting lots of words to the pieces, then it’s really a cause for celebration.

That’s what happened in the last few days with features on the gene editing technology CRISPR in the New York Times Sunday Magazine,  the New Yorker Magazine,  and STAT, a new online health and life-sciences publication produced by the Boston Globe.

Making the story personal

Feng Zhang: photo courtesy of the Broad Institute

Feng Zhang: photo courtesy of the Broad Institute

Each takes a similar approach, focusing on the individuals behind the new approach – Feng Zhang at Harvard/MIT and Jennifer Doudna at the University of California, Berkeley. The fact that the two are involved in a fight over patent rights for the process adds an extra element of friction to a story that already has more than its share of drama.

In the New Yorker, Michael Specter neatly summarizes why so many people are excited about this technology:

“With CRISPR, scientists can change, delete, and replace genes in any animal, including us. Working mostly with mice, researchers have already deployed the tool to correct the genetic errors responsible for sickle-cell anemia, muscular dystrophy, and the fundamental defect associated with cystic fibrosis. One group has replaced a mutation that causes cataracts; another has destroyed receptors that H.I.V. uses to infiltrate our immune system.”

Jennifer Doudna: Photo courtesy of iPSCell.com

Jennifer Doudna: Photo courtesy of iPSCell.com

Sharon Begley in STAT, writes that this discovery could bring cures to some of the deadliest health problems we face, from cancer to Alzheimer’s, but that it also comes with big ethical questions hanging over it:

“He (Zhang) has touched off a global furor over the possibility that a genetics tool he developed could usher in a dystopian age of designer babies.”

Jennifer Kahn in the New York Times Sunday Magazine follows up on that thought, writing about Doudna:

“But she also notes that the prospect of editing embryos so that they don’t carry disease-causing genes goes to the heart of CRISPR’s potential. She has received email from young women with the BRCA breast-cancer mutation, asking whether CRISPR could keep them from passing that mutation on to their children — not by selecting embryos in vitro, but by removing the mutation from the child’s genetic code altogether. ‘‘So at some point, you have to ask: What if we could rid a person’s germ line, and all their future generations, of that risk?’’ Doudna observed. ‘‘When does one risk outweigh another?’’

Each article makes for fascinating reading. Collectively they highlight why CRISPR is such a hot topic, on so many different levels, in science right now.

The topic is going to be the focus of a conference, featuring scientists from the US, Europe and China, being held at the National Academy of Sciences in Washington DC the first week of December.

CIRM is also getting involved in the debate and is holding a science-policy workshop on February 4th, 2016 in Los Angeles to consider the future use of genome editing technologies in studies sponsored by CIRM.

At World Stem Cell Summit improvements in the precision with which we can edit our genes grabs spotlight

/ Don Gibbons / 1 Comment

Just a day and a half into this year’s World Stem Cell Summit in San Antonio and there have been numerous highlights. But a pair of sessions on gene editing grabbed the attention of many of the scientists at the meeting. One of the renown leaders in the field, Harvard’s George Church wowed the scientists, but I fear the heavy dose of scientific detail may have overwhelmed many of the patient advocates that make the attendee mix at this meeting special.

George Church speaking recently [Credit: PopTech.org]

George Church speaking recently [Credit: PopTech.org]

In 2013, Church first published results using a new gene-editing tool he helped perfect called CRISPR, and almost immediately it became the most talked-about tool for advancing stem cell research. As powerful as stem cells may be by themselves, in many situations, they become even more powerful—especially if you use them to deliver a gene that corrects an error in a patient’s cells. Before 2013 we had a few ways to edit genes in living cells and all were modestly effective at making the desired change and relatively specific in making only a few unwanted changes, called “off target” edits.

In some uses, particularly when cells are being modified in the lab for specific and small targets, these other editing techniques are probably OK. This is what several CIRM-funded teams (links) are doing with diseases like sickle cell anemia and HIV, where you can target blood-forming stem cells and even giving a small percentage the proper gene edit may be sufficient to cure the disease. But with something like muscular dystrophy where the gene editing would be required throughout the body and have to be done in the patient not in the lab, you need to improve the efficiency and precision.

CRISPR/Cas9 [Credit: University of California, San Francisco]

CRISPR/Cas9 [Credit: University of California, San Francisco]

After that first publication CRISPR was viewed as a home run in efficiency, taking the number of cells with the gene correction from a few percent to 50 percent or more. But it still had off-target effects. Yet only a year after the technology was introduced, a few teams developed so-called “next generation” CRISPR that comes close to perfect precision, causing an unintended edit in just one in a billion cells, by Church’s estimate.

I have never seen the full name of CRISPR spelled out in a scientific presentation, and after a visit to Wikipedia I know why. Here it is: Clustered Regularly Interspersed Short Palindromic Repeats. Basically, Church took advantage of something that occurs naturally in many bacteria. Just as we are susceptible to viruses, bacteria have their version known as phages. When those parasites integrate their DNA into the bacteria’s genes, part of the bacterial DNA forms CRISPRs that can partner with a protein called Cas to cut the phage DNA and keep the phage from hurting the host bacteria.

In a research setting, creating that “nick” in the DNA is the first step in harnessing CRISPR to insert a desired gene. So, that extreme precision in finding spots on our DNA where we want to create an opening for inserting a new gene became this valuable research tool. It can create a nick as precise as a single nucleotide base, the building blocks of our DNA.

Church and two additional speakers gave detailed descriptions about how the technology has improved and how it is being used to model disease today and is expected to be used to treat disease in the near future. An exciting future is in store.

Don Gibbons

Scientists Develop Stem Cell ‘Special Forces’ in order to Target, Destroy Brain Tumors

/ cirmweb / 2 Comments

Curing someone of cancer is, in theory, a piece of cake: all you have to do is kill the cancer cells while leaving the healthy cells intact.

But in practice, this solution is far more difficult. In fact, it remains one of the great unsolved problems in modern oncology: how do you find, target and destroy each individual cancer cell in the body—while minimizing damage to the surrounding cells.

Encapsulated toxin-producing stem cells (in blue) help kill brain tumor cells in the tumor resection cavity (in green). [Credit: Khalid Shah, MS, PhD]

Encapsulated toxin-producing stem cells (in blue) help kill brain tumor cells in the tumor resection cavity (in green). [Credit: Khalid Shah, MS, PhD]

But luckily, Harvard Stem Cell Institute scientists at Massachusetts General Hospital may have finally struck gold: they have designed special, toxin-secreting stem cells that can target and destroy brain tumors. Their findings, which were performed in laboratory mice and which appear in the latest issue of the journal STEM CELLS, offer up an entirely unique method for eradicating deadly cancers.

Harvard Neuroscientist Khalid Shah, who led the study, explained in last Friday’s news release that the idea of engineering stem cells to kill cancer cells is not new—but there was a key difference in scientists’ ability to target individual cells vs. difficult-to-reach tumors, which is often the case with brain cancer:

“Cancer-killing toxins have been used with great success in a variety of blood cancers, but they don’t work as well in solid tumors because the cancers aren’t as accessible and the toxins have a short half-life.”

The solution, Shah and his team argued, was stem cells. Previously, Shah and his team discovered that stem cells could be used to circumvent these problems. The fact that stem cells continuously renew meant that they could also be used to continually deliver toxins to brain tumors.

“But first, we needed to genetically engineer stem cells that could resist being killed themselves by the toxins,” said Shah.

In this study, the research team introduced a small genetic change, or mutation, into the stem cells so that they become impervious to the toxin’s harmful effects. They then introduced a second mutation that allowed the stem cells to maintain and produce and secrete toxins throughout the cells’ lifetime—effectively giving it an unlimited supply of ammunition to use once it encountered the brain tumor.

They then employed a common technique whereby the toxins were tagged so that they only sought out and infected cancer cells—leaving healthy cells unscathed.

“We tested these stem cells in a clinically relevant mouse model of brain cancer,” Shah described. “After doing all of the molecular analysis and imaging to track the inhibition of protein synthesis within brain tumors, we do see the toxins kill the cancer cells and eventually prolonging the survival in animal models.”

While preliminary, these results are encouraging. As the team continues to refine their method of development and delivery, they are optimistic that they can bring their methods to clinical trial within the next five years.