Washington Post features HDF President Nancy Wexler and CEO Meghan Donaldson

Pope Francis caresses a sick woman during an audience with Huntington's disease sufferers and their families on May 18, 2017. (Andrew Medichini/AP)

“I'm ecstatic,” said Nancy Wexler, who in 1993 identified the mutation. “Huntington's is horrible, one of the worst diseases known to mankind, and certain death. . . . We know it’s a bad gene, making a bad protein, that makes people sick, that kills your brain cells. Anything that could impact that, we knew that that could be a cure.”

Read the full story here.

Biggest news in Huntington's disease research since the identification of the HD gene!

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The Hereditary Disease Foundation congratulates Dr. Sarah Tabrizi, director of the University College London's Huntington Centre and the global lead investigator on the study, and her team on their breakthrough discovery. Congratulations also to C. Frank Bennett, senior vice president of research at Ionis Pharmaceuticals and longtime Scientific Advisory Board of the Hereditary Disease Foundation.

To read about this clinical trial, visit http://www.bbc.com/news/health-42308341.

Dr. Nancy Wexler, President of Hereditary Disease Foundation, said, "I'm ecstatic to see these promising positive results! If this therapy works to prevent or reverse HD, for the first time we will have something to immediately give people when they have a genetic test and discover that they are destined to die in the most catastrophic way."

This extraordinary and exciting breakthrough brings hope to the thousands of Huntington's disease patients and families worl dwide. This study will have an amazing impact on the HD community!

On November 6, the Hereditary Disease Foundation held a Symposium and Gala to launch our 50th Anniversary celebration. Sarah Tabrizi presented at the Symposium the latest from the "first in human" drug trial which "silences" - or turns down - the HD gene. Sarah also is the recipient of the Hereditary Disease Foundation's 2017 Leslie Gehry Brenner Prize for Innovation in Science for her research to discover treatments to prevent or reverse HD. We couldn't be prouder!

Sarah Tabrizi and Frank Bennett have been a part of the Hereditary Disease Foundation research family for many years. We are thrilled to see this research advance to such a remarkable point! A cure for the Huntington's disease is indeed within our reach.

Sarah Tabrizi's presentation about the Ionis clinical trial, November 6, 2017

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Sarah Tabrizi presented the latest from the “first in human” drug trial which “silences” – or turns down – the HD gene at the Hereditary Disease Foundation's 50th Anniversary Symposium and Gala on November 6, 2017.

Watch her presentation here.

Sarah also received the 2018 Leslie Gehry Brenner Prize for Innovation in Science that evening.

GIVE THE GIFT OF CURES!

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With your support, the Hereditary Disease Foundation is able to fund innovative research towards curing Huntington's disease and impacting other brain disorders. The Foundation focuses on curing Huntington's disease, not only because of its devastating consequences to individuals and families with the disease, but because it is a model for curing other brain disorders like Parkinson's, Alzheimer's and Lou Gehrig's (ALS) diseases. 

Make a gift to the HDF in honor of a family member, a friend, a special event or just because! Learn about the different ways you can give to us.

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Happy holiday season!

Sarah Tabrizi receives 2017 Leslie Gehry Brenner prize for Innovation in Science

Professor Sarah Tabrizi wins international award for hereditary disease research

9 November 2017

Professor Sarah Tabrizi, director of the UCL Huntington’s Disease Centre at the UCL Institute of Neurology, has received the 2017 International Leslie Gehry Brenner prize for Innovation in Science.

Awarded by the Hereditary Disease Foundation on November 6 in New York, the $100,000 prize is in recognition of “her outstanding contributions to innovative clinical trials and to clinical care for people with Huntington's disease and their families.”

The award committee commended Professor Tabrizi for her work advancing the mechanistic understanding of Huntington’s disease pathobiology and developing novel therapies for Huntington’s disease (HD).

The prize was donated by architect Frank Gehry and his family, in memory of his daughter Leslie who died of cancer in 2008.

Professor Tabrizi co-founded the UCL Huntington’s Disease Centre in 2016 with Professor Gillian Bates, who won the Leslie Gehry Brenner Award in 2012 for developing the first mouse model of HD.

Professor Tabrizi’s research programme seeks to discover effective disease-modifying treatments that prevent or reverse the neurodegenerative process in HD. She leads a research group that follows two distinct but complementary approaches: basic science focusing on cellular mechanisms of neurodegeneration, and a programme to translate those findings into treatments and cures. She and her collaborators have developed means of identifying and measuring the HD gene and its protein in human blood and cerebrospinal fluid (CSF).

She leads a team at the UCL Huntington’s Disease Centre that is currently conducting a trial of a novel ‘gene silencing’ treatment for HD, sponsored by Ionis Pharmaceuticals. It’s the world’s first trial in patients to slow, stop, prevent or reverse HD, using a method that targets the root cause of the disease, a gene producing a protein called huntingtin.

She has published over 250 peer-reviewed publications to date, she was elected a fellow of the UK Academy of Medical Sciences in 2014, and in 2010 helped set up the UK All-Party Parliamentary Group for HD.

“I am honoured to receive this award and I am deeply grateful to the Hereditary Disease Foundation and to the Gehry family for their support of research that seeks to improve the lives of people with hereditary diseases such as Huntington’s disease. The award is a testament to the tireless efforts of the UCL HD Centre team and our collaborators as we seek to lead world-class research from bench to bedside. Every year we are getting closer to identifying treatments that could slow down the disease process, and ways to prevent or delay disease onset in HD gene carriers” Professor Sarah Tabrizi

“Congratulations to Sarah on this major achievement. We are proud to host the UCL HD Centre at the UCL Institute of Neurology, Queen Square. It is the largest and most productive clinically-focused HD research group in the UK, and is at the forefront of neurodegenerative disease research and has real potential to transform people’s lives.” Professor Michael Hanna, Director of the UCL Institute of Neurology

“We are thrilled to present the Leslie Gehry Brenner Prize to Sarah Tabrizi. Professor Tabrizi has channelled her passion for scientific research into discovering ways to prevent or reverse Huntington's Disease. We thank her and her superb global team for their extraordinary work.” Professor Nancy Wexler, President of the Hereditary Disease Foundation

PRESS ADVISORY: Hereditary Disease Foundation Announces 2017 Leslie Gehry Brenner Prize for Innovation in Science at Symposium and Gala Dinner in New York - A Celebration of 50 Years of Discovery

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The Hereditary Disease Foundation will announce the recipient of the 2017 Leslie Gehry Brenner Prize for Innovation in Science at its 50th Anniversary Symposium and Gala on Monday, November 6, 2017, at the Metropolitan Club in New York City.  Symposium at 6pm, Reception at 7pm, Dinner/Awards Ceremony at 8 p.m.

WHO:  Keynote Address

Francis S. Collins, MD, PhD, Director of the National Institutes of Health

Speakers

Jang-Ho J. Cha, MD, PhD, Novartis Institutes for BioMedical Research

Sarah J. Tabrizi, FRCP, PhD, FMedSci, University College London Institute of Neurology

WHAT:  A Celebration of 50 Years of Discovery Symposium and Awards Dinner

WHEN:  Monday, November 6, 2017

WHERE:  The Metropolitan Club, One East 60th St., New York City

The Hereditary Disease Foundation facilitates collaborative and innovative scientific research to further the understanding of Huntington’s disease, a genetic disorder that strikes in early- to mid-adulthood, destroying brain cells, and bringing on severe and progressive declines in personality, cognitive ability, and mobility. As a disease caused by a mistake on a single gene, Huntington’s disease is an ideal model for other brain disorders. Research organized by the Foundation led to the discovery of the genetic marker for Huntington’s disease in 1983. The Foundation organized and funded a decade-long international collaboration of over 100 scientists who discovered the gene that causes Huntington’s in 1993. This work played an important role in the development of the Human Genome Project. For information visit http://www.hdfoundation.org.

PRESS CREDENTIALS REQUIRED

Contact: Myrna Manners, Manners Dotson Group

718.986.7255, mmanners@mannersdotson.com

Michael David Rawlins invested with the accolade of a Knight Grand Cross of the Most Excellent Order of the British Empire

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By Nancy Sabin Wexler, October 14, 2017

On Friday, October 13, 2017, my very good friend Michael David Rawlins was invested at Buckingham Palace by Her Majesty the Queen, with the accolade of a Knight Grand Cross of the Most Excellent Order of the British Empire. He is only the fourth physician in 100 years to be granted this very prestigious award. Most awardees are either senior military figures or men and women who have rendered very substantial public service.

The formal citation for Sir Michael, as read out at the ceremony in Buckingham Palace stated that his award has been given “For services to the Safety of Medicines, to Healthcare and to Innovation.” The longer citation, published by the Cabinet Office, reads: “Sir Michael Rawlins, currently chair of the Medicines and Healthcare products Regulatory Agency and UK Biobank was also the founding chair of the National Institute of Clinical Excellence. Under his leadership NICE became an internationally recognised organisation, pioneering processes which have been copied world over. It has facilitated faster NHS uptakes of new technologies and procedures, offering opportunities to patients in a way not experienced before. He has previously served as chair of the Advisory Council on the Misuse of Drugs and President of the Royal Society of Medicine.”

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Sir Michael has been a good friend to the Hereditary Disease Foundation for many years. He has travelled to Venezuela on many occasions. On his first visit, he came to investigate prospects for doing clinical trials in the Lake Maracaibo region, but later arranged visits through the good offices of the UK Ambassador in Caracas. Sir Michael also visited the Casa Hogar, in Maracaibo, and helped promote its work to a global audience.

In the UK, he is also instrumental – with Charles Sabine – in establishing an All Party Parliamentary Group (APPG) for Huntington’s Disease in the UK parliament. The APPG provides an opportunity for parliamentarians from across the political divide, and with members from both the House of Commons and the House of Lords, to draw attention to the critical needs of Huntington’s families. It was originally chaired by a very distinguished neurologist, Lord (John) Walton of Detchant. The former Health Secretary, the Right Honorable Frank Dobson, later took on the chairmanship of the APPG.

Charles Sabine, a former NBC journalist and a member of an HD family, has recently been instrumental in forming an organization known as “HDdennomore” (pronounced “Hidden No More). Charles and Elena Cattaneo (the Director of the University of Milan’s Centre for Stem Cell Research and also a Senator for Life in the Italian Parliament) were responsible for organizing the Papal Audience for HD families on May 18, 2017. This was attended by representative families from nearly 30 different countries, including many from South America. Of these, 20 families came from Venezuela. The Pope, in his address, encouraged the Church to embrace those with HD and their families and afterwards hugged them all. He also encouraged HD scientists to increase their efforts in finding treatments and cures. The Papal audience in May also reminded us that the burden of the political crisis in Venezuela is being heavily born by the HD families who have very limited access to food, water and medicines.

I look forward to encouraging this momentum. It has been created by the energy of so many talented and innovative people who together will change the world for the better.

 

Big news in clinical trials for HD! Wave Life Sciences Initiates Two Phase 1b/2a Clinical Trials: PRECISION-HD1 and PRECISION-HD2 in Patients with Huntington’s Disease

Trials Evaluate the First Allele-Specific Investigational Drugs for Huntington’s Disease, WVE-120101 and WVE-120102

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Jul. 17, 2017-- Wave Life Sciences Ltd. (NASDAQ:WVE), a biotechnology company focused on delivering transformational therapies for patients with serious, genetically-defined diseases, today announced the initiation of the Company’s PRECISION-HD program, which includes PRECISION-HD1 and PRECISION-HD2, the Company’s two Phase 1b/2a clinical trials evaluating WVE-120101 and WVE-120102, respectively, for patients with Huntington’s disease (HD).

“Wave’s PRECISION-HD program is the first to target the underlying cause of Huntington’s disease with an allele-specific approach,” said Michael Panzara, MD, MPH, Neurology Franchise Lead of Wave Life Sciences. “Obtaining approvals to initiate these global studies as part of our first clinical program marks an important milestone for Wave. More importantly, these investigational compounds have the potential to address a critical unmet need for the HD patient community where no disease-modifying treatments are currently approved.”

PRECISION-HD1 and PRECISION-HD2 are Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled studies that will primarily evaluate the safety and tolerability of single and multiple doses of WVE-120101 and WVE-120102, respectively, administered intrathecally in HD patients. Additional exploratory objectives include assessing the impact that each compound has on the toxic mutant protein known to cause loss of brain cells in HD, as well as evaluating potential clinical effects and impact on brain atrophy as measured by magnetic resonance imaging (MRI). Both PRECISION-HD trials will follow the same protocol, and each will target a single nucleotide polymorphism, or “SNP,” that marks a separate and distinct location on the mutant huntingtin (HTT) gene transcript. Wave intends to enroll approximately 50 patients globally in each of the two studies through multiple sites, in Canada initially, with Europe and the United States to follow.

The PRECISION-HD trials for WVE-120101 and WVE-120102 will include adult patients with early manifest HD who carry a SNP at the rs362307 (“SNP1”) or the rs362331 (“SNP2”) location, respectively. Potential HD patients for the PRECISION-HD program will be pre-screened for the presence of SNP1 or SNP2, and directed to the appropriate study upon qualifying for entry. Approximately two-thirds of all HD patients are expected to carry either SNP1, SNP2, or both, in association with the HD gene.

SNPs are a common type of genetic variation that normally occur in all humans, but may also act as biological markers to aid in locating genes associated with a particular disease. Previous HD research has identified multiple SNPs that are associated with the disease-causing expanded cytosine-adenine-guanine (CAG) repeat, which is an abnormality present in all HD patients that results in the production of mutant huntingtin protein, and causes HD. Therefore, Wave is utilizing common SNPs to precisely target the underlying cause of the disease.

“Reducing the disease-causing mutant huntingtin while preserving the healthy protein would be an important breakthrough for the HD community," said Dr. Edward Wild, Principal Researcher at University College London Huntington's Disease Centre, Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, London, and member of the PRECISION-HD Clinical Advisory Committee. "The pre-clinical data for Wave’s targeted compounds are encouraging and I am thrilled that we are beginning to explore the potential of these compounds in HD patients in this exciting programme.”

About Huntington’s Disease (HD)

HD is a debilitating and ultimately fatal autosomal dominant disorder, characterized by cognitive decline, psychiatric illness and chorea. HD causes nerve cells in the brain to deteriorate over time, affecting thinking ability, emotions and movement. HD is caused by an expanded cytosine-adenine-guanine (CAG) triplet repeat in the huntingtin (HTT) gene that results in production of mutant HTT (mHTT) protein. Accumulation of mHTT causes progressive loss of neurons in the brain. Wild-type, or healthy, HTT protein is critical for neuronal function, and suppression may have detrimental long-term consequences. Approximately 30,000 people in the United States have symptomatic HD and more than 200,000 others are at risk for inheriting the disease. There are currently no approved disease-modifying therapies available.

About WVE-120101 and WVE-120102

WVE-120101 and WVE-120102 are investigational stereopure antisense oligonucleotides designed to selectively target the mHTT mRNA transcript of SNP rs362307 (SNP1) and SNP rs362331 (SNP2), respectively. These are the two most common SNPs associated with the mutant allele, which is believed to encompass approximately two-thirds of the HD patient population. In vitro studies in patient-derived cell lines have shown that WVE-120101 and WVE-120102 selectively reduce levels of mHTT mRNA and protein, while leaving wtHTT mRNA and protein largely intact.

About Wave Life Sciences

Wave Life Sciences is a biotechnology company focused on delivering transformational therapies for patients with serious, genetically-defined diseases. Our chemistry platform enables the creation of highly specific, well characterized oligonucleotides designed to deliver superior efficacy and safety across multiple therapeutic modalities. Our pipeline is initially focused on neurological disorders and extends across several other therapeutic areas.

Forward Looking Information

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding the initiation of clinical trials for WVE-120101 and WVE-120102, including Wave’s ability to screen and enroll patients; Wave’s ability to implement its global clinical development plans for WVE-120101 and WVE-120102 for the treatment of Huntington’s disease; the potential benefits of Wave’s allele-specific approach; and Wave’s strategy and business plans. The words "may," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "estimate," "predict," "project," "potential," "continue," "target" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on Wave management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, uncertainties inherent in research and drug development, future clinical data and analysis, the decisions of global regulatory authorities as to whether and when to approve any application that may be filed for any of our candidates as well as their decisions regarding labelling and other matters that could affect the availability or commercial potential of such product candidates, the absence of guarantee that the product candidates if approved will be commercially successful, the future approval and commercial success of therapeutic alternatives, our ability to benefit from external growth opportunities and/or obtain regulatory clearances, risks associated with intellectual property, volatile economic conditions, healthcare reform, as well as those discussed or identified in Wave’s public filings with the SEC. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in Wave’s Annual Report on Form 10-K for the year ended December 31, 2016, as filed with the Securities and Exchange Commission (SEC) on March 16, 2017, and in other filings that Wave makes with the SEC from time to time. Any forward-looking statements contained in this press release represent Wave’s views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Wave explicitly disclaims any obligation to update any forward-looking statements.

 

View source version on businesswire.com: http://www.businesswire.com/news/home/20170717005291/en/

Source: Wave Life Sciences Ltd.

Media and Investors
WAVE Life Sciences
Jillian Connell, 617-949-2981
jconnell@wavelifesci.com

 

AMAZING, ORIGINAL AND PATHBREAKING RESEARCH OPENS DOORS PREVIOUSLY SHUT!!

By Nancy S. Wexler, Ph.D.

We owe a wonderful thank you and congratulations to the late Paul H. Patterson of Caltech. Paul trained in the golden age of Neuroscience at Harvard University. In 1991 he joined the faculty at Caltech and the Scientific Advisory Board (SAB) of the Hereditary Disease Foundation. He was a wonderful, creative and thoughtful member of our SAB for 23 years. Tragically, Paul died in 2014 of a glioblastoma at the age of 70.

Paul was an expert of making and understanding antibodies, including monoclonal antibodies. He understood the delicate interplay between the immune system and our neurobiology. The HD protein is one of the most gigantic in our bodies.

Paul ingeniously made a number of antibodies recognizing different parts of this huge protein.

Paul and my Dad, Milton Wexler, were very good friends. They appreciated each other’s independent, iconoclastic approach to life. The antibodies Paul created are named for my DAD, MW1-MW 8. Paul shared these antibodies with scientists throughout the world to make progress.

The Hereditary Disease Foundation remains proud to have funded Paul’s seminal path-breaking work.

Huntington’s disease (HD) poses unique challenges for cure hunters. The abnormal protein clumps up inside the cell and causes problems. Any therapy must actually get inside the cell to work. Alzheimer’s and Parkinson’s clump outside the cell so they are easier to target.

Paul developed an “intrabody,” an antibody fragment that works against a target within the cell. In the September 3, 2008 issue of the Journal of Neuroscience, Paul and his group published the discovery of a very successful intrabody called “Happ1” which targets only the abnormal form of the HD and leaves the normal one intact and functioning – a small miracle!

And this intrabody was used to treat Huntington's disease in a variety of HD mouse models. It actually treated the symptoms of HD, and even reversed the mouse’s symptoms. This was the miracle we were waiting for!!!!

Paul understood the gravity of the next phase of being a cure hunter! DELIVERY, DELIVERY, DELIVERY!!!!!!!!!!!!!!!!!!!!!!!

Especially of a brain disease, how do you target delivery of your therapy to the brain? 

All gene therapy trials face this obstacle. The current Ionis trial of HTTRx delivers their therapy through the spinal cord into the cerebrospinal fluid (CSF) CSF. This is a fine and appropriate way of delivering it.

But Paul Patterson always thinks big and out of the box. Our brain has a protective “coating” around it called “the blood- brain barrier.” It prevents lots of trash from getting in. But also prevents lots of therapies from getting in, including gene therapies which could actually cure HD. If gene therapies cured the disease, the earlier the treatment was given the better.

Paul and his postdoctoral student Benjamin E. Deverman began developing a virus that will cross the blood brain barrier. This is an extremely clever virus. The Hereditary Disease Foundation began supporting Ben as a postdoctoral fellow beginning in 2014.

Paul and Ben developed a whole series of viruses that are color coded with different fluorescent protein tags. They can light up different neurons in the central nervous system and the periphery.

Tragically, Paul died in 2014, shortly after Ben joined his lab. Ben understood that Paul named his antibodies “MW” after my Dad. He decided to honor and recognizes Paul’s amazing and important mentorship by naming each antibody after him: “AAV-PHPs.”

These incredible antibodies can be loaded with a gene therapy for HD. They can be delivered as a shot in the arm. They travel through the bloodstream and across the blood brain barrier into all parts of the brain. This medicine will treat all the neurons in the brain!!!!!!!!

Ben just published his phenomenal work in the June 26, 2017 issue of Nature Neuroscience. Bravo Ben, bravo posthumously to Paul H. Patterson!!!!!!!!!!!!!

The world is a safer and healthier place thanks to all your efforts!!!!!!!! We all can’t wait until the next gene therapy trial is launched with this amazing safe and direct to all parts of the brain cure for HD takes it next step!

Thanks to Paul and Ben for preserving against all odds and succeeding!

Scientists deploy GM sheep in fight to treat Huntington’s disease

Jenny Morton, a professor of neurobiology at Cambridge University, with transgenic sheep imported from New Zealand to assist with research into Huntington’s disease. Photograph: Antonio Olmos for the Observer

Jenny Morton, a professor of neurobiology at Cambridge University, with transgenic sheep imported from New Zealand to assist with research into Huntington’s disease. Photograph: Antonio Olmos for the Observer

"It is hoped to gain a more detailed picture from these tests of how cognitive decline progresses and so pave the way for drugs to slow its impact," says longtime Huntington's disease researcher Jenny Morton.

Read Guardian article.

Read the full scientific report about the sheep helping with HD research.

 

Huntington’s Disease: Gene Editing Shows Promise in Mouse Studies (by Francis Collins)

Francis Collins (red arrow above) was one of the original HD Gene Hunters

Francis Collins (red arrow above) was one of the original HD Gene Hunters

Posted on June 27, 2017 by Dr. Francis Collins on NIH Director’s Blog

My father was a folk song collector, and I grew up listening to the music of Woody Guthrie. On July 14th, folk music enthusiasts will be celebrating the 105th anniversary of Guthrie’s birth in his hometown of Okemah, OK. Besides being renowned for writing “This Land is Your Land” and other folk classics, Guthrie has another more tragic claim to fame: he provided the world with a glimpse at the devastation caused by a rare, inherited neurological disorder called Huntington’s disease.

When Guthrie died from complications of Huntington’s a half-century ago , the disease was untreatable. Sadly, it still is. But years of basic science advances, combined with the promise of innovative gene editing systems such as CRISPR/Cas9, are providing renewed hope that we will someday be able to treat or even cure Huntington’s disease, along with many other inherited disorders.

My own lab was part of a collaboration of seven groups that identified the Huntington’s disease gene back in 1993. Huntington’s disease occurs when a person inherits from one parent a mutant copy of the huntingtin (HTT) gene that contains extra repetitions, or a “stutter,” of three letters (CAG) in DNA’s four-letter code. This stutter leads to production of a misfolded protein that is toxic to the brain’s neurons, triggering a degenerative process that, over time, leads to mood swings, slurred speech, uncontrolled movements, and, eventually, death. In a new study involving a mouse model of Huntington’s disease, researchers were able to stop the production of the abnormal protein by using CRISPR tools to cut the stutter out of the mutant gene.

The progress, reported in the Journal of Clinical Investigation [1], comes from the NIH-supported team of Su Yang, Renbao Chang, Xiao-Jiang Li, and colleagues at Emory University School of Medicine, Atlanta. The group’s previous work showed that halting the production of mutated (or even healthy!) HTT protein in mature neurons doesn’t hurt the cells or cause obvious neurological problems in mice [2]. So, the researchers now wanted to see if halting HTT production in millions of neurons in the striatum, which is a part of the inner brain that controls motor skills, could reverse early signs of disease that typically appear in affected mice before the age of 9 months.

To get their answers, the researchers injected millions of inactivated viral particles directly into the striatum of a few 9-month-old mice, engineered to produce the mutant form of HTT protein. Each particle, like a Trojan horse, delivered to the neurons one of the two pieces of the CRISPR/Cas9 editing system: either a short guide RNA sequence to mark for removal the HTTgene’s CAG repeats or a scissor-like Cas9 enzyme to snip out the repeats. In this strategy, both the health and abnormal copies of the HTT gene were “knocked out,” resulting in the production of no HTT protein.

Remarkably, three weeks later, the researchers found that the CRISPR/Cas9 gene editing had reversed the disease process in their mouse model. Neurons in the striatum had stopped making the HTT protein. What’s more, the toxic, abnormal HTT protein that had already clumped together in and around the neurons—and which likely would have would have killed them—had begun to clear to varying degrees in the mice. The same went for other protein abnormalities associated with the progression of Huntington’s disease.

There was even better news to come. The Emory team repeated the CRISPR/Cas9 injections into the striatum of a dozen 9-month-old mice and got a similar protein-clearing outcome. Then, over the next three months, the researchers found that the animals’ balance, muscle coordination, and mobility had improved compared to mice given sham shots of CRISPR/Cas9. Interestingly, the degree of improvement in their motor skills corresponded with the amount of toxic protein that had been cleared from the striatum.

As exciting as gene editing is as a potential treatment for Huntington’s disease, the research is still very much in its early stages. For example, while the Emory researchers were able to establish that adult mice could live well without a functioning copy of HTT, they remain uncertain whether that’s also the case in humans.

Another potential safety concern with CRISPR/Cas9 is off-target editing. Last May, in a very controversial article, it was reported that CRISPR/Cas9 can sometimes go astray and snip away at healthy genes in animal studies, leaving behind hundreds of unintended mutations in its wake [3]. However, the Emory team reported that off-target editing did not appear to be a major problem in its latest study. Sequencing of genomic DNA taken from the striatum of the mice showed that CRISPR/Cas9 editing occurred “predominantly” around their target sequences without significant genomic editing in the most likely off-target locations. While this is only one study, it’s reassuring news as more animal studies testing the potential curative power of CRISPR/Cas9 editing move forward.

This utilization of CRISPR/Cas9 to pursue a cure for Huntington’s disease is one more example of how this powerful new technology might be applied to the thousands of diseases due to a specific mutation in DNA; efforts are already underway for other conditions like sickle cell disease and muscular dystrophy. Given the promise, the NIH Common Fund is actively exploring ways in which this approach could be accelerated.

References:

[1] CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease. Yang S, Chang R, Yang H, Zhao T, Hong Y, Kong HE, Sun X, Qin Z, Jin P, Li S, Li XJ. J Clin Invest. 2017 Jun 19. [Epub ahead of print]

[2] Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis. Wang G, Liu X, Gaertig MA, Li S, Li XJ. Proc Natl Acad Sci U S A. 2016 Mar 22;113(12):3359-3364.

[3] Unexpected mutations after CRISPR-Cas9 editing in vivo. Schaefer KA, Wu WH, Colgan DF, Tsang SH, Bassuk AG, Mahajan VB. Nat Methods. 2017 May 30;14(6):547-548.

Links:

Huntington’s Disease Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Li Laboratory (Emory University, Atlanta)

NIH Support: National Institute of Neurological Disorders and Stroke