ALS Research Update from New York Genome Center Scientific Director and CEO – Dr. Tom Maniatis

From donations raised through the ALS Ice Bucket Challenge, The ALS Association, in partnership with the Greater New York Chapter, made a $2.5 million commitment to the Center for Genomics of Neurodegenerative Disease (CGND) at the New York Genome Center (NYGC). This commitment, combined with a matching gift from the Tow Foundation, was one of the driving forces supporting the NYGC’s ALS research program in 2014. Three years later, the NYGC’s CGND has made enormous headway in the ALS genetics space and has become one of the major leaders in the field. Their accomplishments are broad in that they have sequenced and analyzed hundreds of ALS DNA samples, while pairing this information with patient clinical history and more. We are pleased to note that Tom Maniatis, PhD, one of the NYGC’s original founders and renowned ALS researcher, was recently appointed Scientific Director and Chief Executive Officer of the NYGC.

For part II of our NYGC progress update, today we sat down with Dr. Maniatis to learn how ALS Association donations impacted the NYGC over the years and his vision for the Center’s future.

Thank you Dr. Maniatis, for taking the time to sit down with us today and congratulations on your new position as Scientific Director and CEO of the NYGC. I know you have a long history with The ALS Association. Can you tell us about that and how you got involved in ALS research?

Over 20 years ago, my sister was diagnosed with ALS. Soon after her diagnosis, I was approached by Robert Abendroth, one of the original founders of The ALS Association, about the possibility of chairing a committee whose objective was to attract scientists doing basic research, like myself, into ALS research. At the time, ALS research was dominated by clinicians, which is important, but there was an element of basic cutting-edge research that was missing from The ALS Association research program. I came onboard and chaired the committee with Robert. Together, we brought in basic research scientists, and ideas emerged, programs were generated, and funds were provided. Things really started moving. However, it became clear that in order for this program to become successful, it required a full-time scientific research administrator. That was when Dr. Lucie Bruijn was recruited to help run The ALS Association research program. I worked closely with her over many years to develop and expand The ALS Association’s research committee and programs. The earliest advance was to focus on ALS genetics, which clearly influenced my decisions about helping to establish the NYGC later.

How did ALS research get established at the NYGC?

When I first came to New York in 2010, I had already worked on trying to understand the interactions between astrocytes (i.e. neuron support cells) and neurons, which was funded by The ALS Association. We were working on mouse stem cell differentiation into motor neurons and then later human stem cells. We also studied how gene mutations affected transcription and gene expression. This is an area where I worked much of my life. At that time, the genomic methods were just being developed. It became clear the infrastructure needed for this type of work did not yet exist in New York, so there was relatively little activity in genomics. I reached out to the scientific leadership in New York and was pleased that everyone had the same concern and a common desire to establish a robust genome center in New York City. Our institutional founding members, comprised of the top academic leaders, came together in 2011. The institutional founding members of the genome center provided startup financial support and an agreement to serve on the NYGC Board of Directors. That is how we got started. It was a consequence, in a very direct way, of my interest in ALS.

How has ALS Association funding support impacted the NYGC?

The ALS Association contribution of $2.5 million and the matching grant from Leonard Tow and the Tow Foundation made it possible for the NYGC to create the infrastructure to establish a unique global ALS Consortium. This landmark initiative is defined by data sharing, having common Internal Review Board procedures, including patient consent forms, and an agreement to collaborate in generating and analyzing ALS genomic data. Lucie recently commented on how unusual it was to see something this vibrant and internationally connected come together so quickly. That was really our goal.

Do you have a message for our donors that made this support to the NYGC possible?

I believe that the approach we are taking is fundamentally important for ALS research, as it provides the infrastructure for ultimately developing effective treatments for ALS. We got this important initiative off the ground, but it, of course, requires continued funding. The more patients we can sequence, the more information we are going to have. The cost for each patient for whole genome sequencing is significant. Supporting the framework and infrastructure that allows us to continue this is very important. We must continue to raise funds to keep this initiative going. There is always a threat of not being able to fund it, and as a result, lose the momentum in this program. So, that is the message – to emphasize the importance of the continuity of financial support for the NYGC’s work in ALS research. The ALS Association’s investment in this research will help fulfill our joint mission to better understand the mechanisms of this devastating disease and discover new therapies and therapeutics to improve the lives of ALS patients.

Sequencers_1
Sequencers at the New York Genome Center

What do you see as the future of the NYGC?

There are three main areas that we are currently focusing on: ALS, cancer genetics, and autism. There is actually some symmetry in these three research programs. The one you know about is in ALS, which is a consortium-based effort to collect genomic data of ALS patients, along with their clinical data. The goal is to harmonize this information in a way that one can explore the nature of the effects of ALS mutations. Dr. Hemali Phatnani leads this program. Her NYGC laboratory and the Center for Genomics of Neurodegenerative Disease, reflect our primary objective – to have consortium based aggregation of clinical and genomic data. We use this data to better understand ALS disease pathways utilizing cutting-edge genomic technology and disease models. That is our major effort at the NYGC.

There is also a symmetric effort going on at the NYGC in cancer genetics. Here we are working with Drs. Harold Varmus, Charles Sawyers, and all of the institutional members of the NYGC, with the goal of establishing a large-scale, shared database of genomic and clinical cancer data. The NYGC excels at generating data and one of our real strengths has been in genome sequencing. I think we are recognized as one of the major players in the whole genome sequencing. Because of our unique expertise, we were awarded a prestigious Center for Common Disease Genomics grant from the National Institutes of Health. Obtaining this award was significant, considering we were only in operation for two years at the time.

This grant supports our research program in autism. Because of the cooperation with the Simons Foundation and two of the top geneticists in autism – Drs. Evan Eichler and Michael Wigler – this is a major program at the NYGC. We are also in discussion with various neurologists in the city about establishing a similar program in other neurodegenerative diseases. Our overall objective is to be an intellectual and data center for these major disease areas and enable the New York scientific community to use genomic approaches to study disease pathways, which we obviously feel is required to develop drugs to treat these diseases.

Thank you for taking the time to sit down with us today to share the NYGC story and your vision for its future. We look forward to hearing the many more great successes targeting ALS coming out of the NYGC!

Read part I of our interview on October 6, 2017 featuring NYGC CGND Director, Dr. Hemali Phatnani.

For more information about the New York Genome Center, click here and here.

Article originally written by the ALSA National Office

A Patient Advocate and Doctor’s Perspective on Clinical Trials: Update on the Retigabine Phase II Trial

Last week, Dr. Brian Wainger of Massachusetts General Hospital and Stephen Winthrop, Chairman of The ALS Association Board of Trustees, gave their unique clinical trial perspectives during the Northeast ALS Consortium (NEALS) webinar titled, “Retigabine Clinical Trial Update & Discussion with ALS Patient Advocate Stephen Winthrop.” For many years, The ALS Association has proudly partnered with NEALS to run ALS centered webinars to disseminate the most up-to-date information to the ALS community. Today’s post discusses the actively enrolling Retigabine clinical trial, which The ALS Association funds, as well as an honest perspective on what it is like to participate in ALS clinical trials.

 

Patient advocate and a championed NEALS Research Ambassador, Stephen Winthrop (pictured LEFT), joined the discussion to give his thoughtful perspective of clinical trial participation. Stephen was diagnosed with ALS almost four years ago and has been involved in over 12 ALS clinical trials – both observational (does not test a drug) and interventional (tests a drug), including the Retigabine study. The decision to participate in a clinical trial is a complicated question with arguments for and against. Stephen provides honest insights on the pluses and minuses of clinical trial involvement, while giving real life examples of some of his experiences.

“The quality and the experience will vary depending on the test and the individuals you are working with. It is a big question of fit,” Stephen explains.

He goes on to state, “The only way we are going to beat this awful disease is by finding a cure and one small way I can do that is by participating in clinical trials. Yes, it involves a needle stick and yes it takes a little time out of your day, but it is worth it. You are helping.”

Dr. Wainger (pictured RIGHT), one of the Principle Investigators of the Retigabine phase II clinical trial, gave a brief trial overview and update. The Retigabine trial is a double-blinded, placebo-controlled study to test the drug as a potential treatment for people living with ALS. The trial is actively recruiting at 12 sites in the U.S. The primary goals are to measure the effects of Retigabine on upper and lower motor neurons (i.e. the cells that die in ALS) physiology in people with ALS and evaluate safety outcomes.

During the first part of the webinar, Dr. Wainger explains the trial clinical rationale and goes over the study in detail including the goals, inclusion/exclusion criteria, the study timeline and what the study requires from its participants. The goal is to enroll at least 30 more ALS patients into the trial as soon as possible.

Watch the webinar here for all the detailed information.

The trial focuses on hyperexcitability of motor neurons. It was previously shown that people living with ALS have motor neurons (both upper and lower) that fire too many signals, meaning they are hyperexcitable. Too much firing leads to motor neuron damage. Retigabine is designed to reduce the over firing of motor neurons.

To physiologically test motor neuron hyperexcitability in trial participants in real time, the investigators use techniques called transcranial magnetic stimulation (TMS) and nerve conduction studies. These specialized tests are a way to measure the connections between motor neurons and muscles. TMS works by stimulating the motor cortex (part of the brain that controls muscle movement) with a magnet and records the response of the muscles in the hand. Nerve conduction studies evaluate the ability of motor neurons to conduct signals to muscles. An important secondary outcome of this study is to determine the potential for the use of these techniques for future ALS trials.

Stephen explains, “What they were trying to do using TMS, which looks like a ping pong paddle held above my head, was to try to make my right thumb to twitch by increasing the magnetic field. No pain was involved to see if my thumb twitched or did not twitch.”

One unique aspect of the Retigabine clinical trial to highlight is that each trial participant will donate a blood sample to be made into induced pluripotent stem cells (iPSCs). These iPSCs are then made into motor neurons in a dish, which reflect the exact genetic makeup of the person they were derived from.

The effects of Retigabine on patient derived motor neurons will also be tracked and compared to the impact of the drug on the patient. This is the first ALS clinical trial to attempt this type of comparison, which has potential as a prognostic and diagnostic tool. Patient derived iPSCs could even possibly predict how a subgroup of ALS patients respond to a drug, which would improve clinical trial design and recruitment.

Stephen adds, “There are so many aspects of this study that is adding to the knowledge base that Brian and his colleagues around the country and around the world are using that plant seeds for clinical successes in the future.”

“One of the things I have said about participating in a clinical trial is that when you are in a room with someone with ALS, do not forget about the human dimension of what you are looking at here. Don’t forget to say to a potential participant, ‘I am sorry that you have been struck by this awful disease,’ and just let that pause. Don’t forget to say, ‘Thank you or thanks for your small part.’”

“In my own experience, those seemingly routine personal touches go a long way, because in the end I do think their decision to participate is fueled in part by just a little whisper of a hope that this will maybe help me. The bigger piece is that you, as a participant, are part of an army of people – I truly believe – will bring an end to this disease.”

We are thankful to Stephen for giving his honest perspectives and we value his dedication to the fight against ALS. With passionate, committed physicians, researchers, clinic staff, allied professionals and especially clinical trial participants – both living with ALS and healthy – all working together in clinical trials, we are many steps closer to a cure.

Watch the full webinar here.

For more information about the Retigabine trial visit the NEALS trial siteand clinicaltrials.gov #NCT02450552.

Revolutionary Study Identifies New Genes Involved in ALS

Barrow Neurological Institute and IBM Watson Health today announced results of a revolutionary study that has identified new genes linked to amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The discovery gives ALS researchers new insights that will pave the way for the development of new drug targets and therapies to combat one of the world’s most devastating and deadly diseases.

The groundbreaking discovery involved IBM Watson, a cutting-edge form of artificial intelligence, to help unravel the mysteries of the brain and provide Barrow scientists with never-before-known data. IBM Watson became known around the nation in 2011 when it competed against human contestants on Jeopardy, and won. Continue reading Revolutionary Study Identifies New Genes Involved in ALS

New Disease Mechanism Revealed for C9orf72 Gene Mutations

research news banner 2015In a new study funded by The ALS Association, Yong-Jie Zhang, Ph.D., Leonard Petrucelli, Ph.D., and their research team from the Mayo Clinic in Jacksonville, Fla. have uncovered a new and potentially important disease mechanism that occurs in the C9orf72 gene, the most common genetic form of ALS. This study was published today in top-tiered scientific journal Nature Neuroscience.

Continue reading New Disease Mechanism Revealed for C9orf72 Gene Mutations

New Discovery of Normal Function of ALS Gene Will Aid Drug Development to Slow or Stop Disease

ALS research news banner 2015Mutations in the C9orf72 gene are known to be the most common genetic cause of ALS. According to new research, C9orf72 is important for immune system function in its normal form, an important discovery made by scientists Jacqueline O’Rourke, Ph.D., and Robert Baloh, M.D., of Cedars-Sinai Medical Center in Los Angeles, that is likely to influence the development of treatments aimed at silencing the C9orf72 mutant gene. The findings were published today in the journal Science.

Continue reading New Discovery of Normal Function of ALS Gene Will Aid Drug Development to Slow or Stop Disease

Spotlight on Dr. Javier Jara, A 2010 Safenowitz Fellow

ALS Researcher Javier Jara, Ph.D.

“Our ability to make progress in ALS depends so much on attracting the best young scientists into the field. The ALS Association’s Milton Safenowitz Post-Doctoral Fellowship program is a critical part of that effort. Almost 90 percent of our Fellows stay in ALS research, making up a significant fraction of the younger generation of ALS researchers.”
– Dr. Lucie Bruijn, Ph.D., M.B.A., Chief Scientist, The ALS Association

The Milton Safenowitz Post-Doctoral Fellowship for ALS Research Award is designed to encourage and facilitate promising young scientists to enter the ALS field. The award program was founded by the Safenowitz family, through the Greater New York Chapter of The ALS Association, and awards are given in memory of Mr. Safenowitz. Fellows work with a senior mentor and receive extensive exposure to the ALS research community through meetings and presentations. More than 90 percent of Milton Safenowitz fellows remain in ALS Research and contribute significantly to the advances made in the field.

Javier Jara, Ph.D., is a Research Assistant Professor in Dr. Hande Ozdinler’s laboratory in the Department of Neurology at the Northwestern University Feinberg School of Medicine in Chicago. He was funded by The ALS Association’s Milton Safenowitz Post-Doctoral Fellowship for ALS Research from 2010-2012 and recently was awarded his own Investigator-Initiated grant by The Association.

The award helped support Dr. Jara research including a project that focuses on how upper motor neurons die in ALS and how to intervene to prevent their death. The results of this project were featured in the January 21, 2016, issue of Gene Therapy. Recently, we sat down with Dr. Jara to learn more about his exciting research project and to get to know the person behind the science.

Continue reading Spotlight on Dr. Javier Jara, A 2010 Safenowitz Fellow

The ALS Association Invests More Than $1.9 Million to Discover Treatments for ALS

research news banner 2015

The ALS Association is pleased to announce five new Translational Research Advancing Therapy for ALS (TREAT ALS™) grant recipients to fund milestone driven amyotrophic lateral sclerosis (ALS) research. The TREAT ALS™ portfolio is a diverse collection of ALS research to find treatments and a cure for ALS. These awards include a TREAT ALS™ Drug Development Contract grant and ALS Association-Initiated grants totaling $1,950,340.

Continue reading The ALS Association Invests More Than $1.9 Million to Discover Treatments for ALS

The ALS Association Funds Five New Grants in the TREAT ALS™ Porfolio

March 2016

TREAT ALS™ Drug Development Contracts

Drug development contracts are milestone-driven awards designed to rapidly bring the most promising potential therapies closer to clinical trials. Many of the contracts are in partnership with industry. Academic-industry partnerships are invaluable to drive treatment approaches for ALS more rapidly to the clinic.

Continue reading The ALS Association Funds Five New Grants in the TREAT ALS™ Porfolio

Long Island PALS Accepted as Research Ambassador at Annual NEALS Conference

2015 CRLI

As a retired optometrist from Long Island, Frank Verdone has a clear understanding of the science behind clinical trials that may help to find a cure for ALS. As a person living with ALS, the 55-year old former long distance runner has enthusiastically volunteered to be trained as a NEALS Research Ambassador to educate others about the latest ALS clinical trials and inspire PALS to participate in them.

When Theresa Imperato, RN, Nurse Coordinator at the ALSA Certified Center at Stony Brook University Hospital, got an announcement that NEALS was seeking Research Ambassadors, she thought of Frank because of his medical background and interest in current research. “He wants to find a cure if not for himself but also for those diagnosed in the near future,” Theresa said. Frank has also participated in ALS studies so he has first-hand experience with clinical research.

As a result, Frank was accepted into the program and attended the 14th Annual NEALS Consortium Conference last November. The ALS Clinical Research Learning Institute, sponsored by the ALS Association’s TREAT ALS initiative, is an intensive two day program dedicated to educating attendees on clinical research and therapy development and empowering them to be advocates for ALS clinical research. ALS Association Chief Scientist Dr. Lucie Bruijn was also in attendance. “We brought this information back to our support groups to explain why clinical trials are so necessary and to try to get patients involved,” said Frank, who was one of 34 Research Ambassadors from all over the country including one couple from Canada and one from Puerto Rico. Of those, 15 were PALS who take on the role permanently.

Frank’s wife, Mary, accompanied him to the NEALS meeting where she learned how much work is being done in the field, how compassionate the researchers are, and that there is hope for an effective treatment in the near future. Frank noted that meeting other patients and caregivers was a comfort to them; to know that they were not alone in the fight for a cure.

Frank is a dedicated advocate for the Greater New York Chapter and a natural fit as Ambassador because he finds inspiration in educating people about ALS. He often visits local school districts to talk about ALS and the story of Lou Gehrig. “These are life lessons for all children at any age,” Frank said. “After our presentation, principals and teachers always comment on how this is the best presentation they have ever heard and students are compelled to run fundraisers for our cause afterwards.”

In addition to advocacy work, Frank keeps very busy. He attends the Chapter’s monthly support group and ALS clinic at Stony Brook University Hospital. “I find the support groups to be a wealth of information,” he said. “And all of the medical providers and staff at the clinic provide us with the best care.” Frank serves on the board of Long Island based Ride For Life. He and his family started Team FrankV in his honor to raise awareness and funds for the Long Island Walk to Defeat ALS.

For more information about becoming an ALS advocate please contact Jeanne Traugot, Director of Development, at (212) 720-3051 or jtraugot@als-ny.org.

New Evidence Supports Nuclear Transport Disruption as a Key ALS Pathway

research news banner 2015

Researchers from the Max Planck Institute of Biochemistry in Martinsried, Germany demonstrated that protein aggregates, like those found in the neurons of most people with ALS, are toxic when they occur in a cell’s cytoplasm, not its nucleus. The study was published in the Jan. 8, 2016 issue of the journal Science titled, “Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA.” These cytoplasmic aggregates interrupted transport of materials to and from the nucleus. The findings add to earlier publications highlighting the potential of disrupted nuclear transport as a disease pathway in ALS and may lead to better targeting of therapy.

In the study, researchers introduced artificial proteins that carried localization sequences, akin to zip codes, that restricted them to either the cell’s nucleus or its surrounding cytoplasm. The proteins were designed to form aggregates, clumps of protein that are thought to interfere with cell function. Protein aggregates are a common feature in numerous neurodegenerative diseases, including ALS, Alzheimer’s disease, Parkinson’s disease, among others. The researchers found that only the cytoplasmic aggregates were toxic.

The team also found that cytoplasmic aggregates disrupted transport of materials across the nuclear membrane. Disrupted nuclear transport has recently emerged as a potentially major disease pathway in ALS, following work by ALS Association-funded researchers.

“The results in this study strengthen the case that interference with nuclear transport is a key element of the disease process in ALS,” said Association Chief Scientist Lucie Bruijn, Ph.D., M.B.A. “Treatments that are aimed at preventing or reducing cytoplasmic aggregation of ALS-related proteins, including TDP-43, will be important to explore for their potential in ALS.”