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.

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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.

Q&A with Dr. Javier Jara – Novel Neuroinflammation Study Published

Dr Javier Jara 2The ALS Association sat down with Dr. Javier Jara, Research Assistant Professor at Northwestern University Feinberg School of Medicine, who just published groundbreaking work focused on brain inflammation caused by ALS. This work was published in the July issue of the Journal of Neuroinflammation. The ALS Association has proudly supported Dr. Jara since 2010 through both our Milton Safenowitz Postdoctoral Fellowship Program and a recent Investigator-Initiated Grant.

Q: Thank you for joining us today! We were happy to hear the great news that your paper was just published. It is always rewarding to hear of our scientists’ successes. Congratulations! First, our readers and I would love to know why you love working in ALS research.

A: ALS is a very complex disease in which several cellular systems are disturbed. This allows me to tackle the disease from different angles, which could be a more efficient strategy to understand disease pathways.

Q: What are the major findings of your paper?

A: This paper sought to understand the role of inflammation, especially in the motor cortex of ALS (i.e. part of the brain responsible for muscle movement). We were able to study cells that are involved in immune response in the spinal cord and brain using green and red fluorescent protein tags. These cells were increased in numbers early in the disease and we were able to observe them in the vicinity of dying upper motor neurons in the motor cortex. Our observations in human ALS motor cortex also correlated with an increase of activated cells that participate in the immune response, which is important. Our studies are novel and bring a new perspective to the role of the immune response in ALS motor cortex pathology.

“This work would not have been possible without the support of The ALS Association through the Milton Safenowitz Postdoctoral Fellowship Program. Obtaining this fellowship changed my career and I am extremely grateful for the donor’s support. I encourage donors to continue their hard work to support patient care and research.” – Dr. Jara

Q: What is the significance of your research?

A: By developing a novel ALS model to investigate inflammation, we were able to set up a strong foundation for future studies to understand the role of cells involved in the immune response. Because these cells are labeled with a fluorescent tag, we can visualize and isolate them from the brain and spinal cord at different stages of disease initiation and progression. We can also use various models that develop ALS due to different underlying causes.

Q: What are your next steps?

A: We are currently investigating the secreted factors and proteins that are increased during disease in these immune cells with the hope to establish novel molecular markers and identify therapeutic pathways.

Javier Jara_option2

Q: When we first funded your research, you were a Postdoctoral Fellow. Since then you have been promoted to Research Assistant Professor, which is excellent! What are your future career goals?

A: I would like to set up my own line of research in the near future and for this purpose I would like to obtain an independent faculty position. In 2015, I was funded by The ALS Association to set up an independent line of investigation from Dr. Ozdinler’s lab to understand the relationship between brain injury and ALS. With The Association grant and Dr. Ozdinler’s support, I was able to investigate what happens to upper motor neurons after a single mild cortical injury insult. These studies have been fruitful and I am currently writing a manuscript.

Q: What do you enjoy doing outside the lab?

A: I am a runner and I enjoy running marathons. I have done five marathons so far, and I am always looking forward every year to start a new running season!

That is impressive! Thank you for joining us today. We are looking forward to hearing more great things out of your lab and to read your next manuscript!

Read more about Dr. Jara here and here.

Paper citation:

Evidence for an early innate immune response in the motor cortex of ALS.

Jara JH, Genç B, Stanford MJ, Pytel P, Roos RP, Weintraub S, Mesulam MM, Bigio EH, Miller RJ, Özdinler PH.

J Neuroinflammation. 2017 Jun 26;14(1):129. doi: 10.1186/s12974-017-0896-4.

PMID:28651542

Read free article here.

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

Senate Passes 21st Century Cures Act, December 7th

Senate Passes 21st Century Cures Act

Yesterday, the Senate passed the 21st Century Cures Act, sending the groundbreaking legislation to President Obama’s desk for a signature. The new law will provide billions of dollars to help accelerate the discovery, development, and delivery of promising new treatments by funding research and streamlining the drug review process. Importantly, the bill also will help preserve access to complex rehab technologies (CRT) power wheelchair accessories.

The 21st Century Cures Act is groundbreaking legislation that has taken over two years of negotiations. Thank you to all of the ALS Advocates who wrote letters, made phone calls and spoke to legislators about the legislation. Because of your hard work, ALS Association priorities were included in the final legislation. Continue reading Senate Passes 21st Century Cures Act, December 7th

The ALS Association and Prize4Life Announce Five Finalists for $400K Assistive Technology Challenge

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November 22, 2016
The ALS Association and Prize4Life announced today the five finalists for the ALS Assistive Technology Challenge, a $400,000 award for the development of flexible, accessible technology to help people with ALS communicate with ease. The winner of the challenge will be selected in Dublin, Ireland, on Monday, Dec. 5 at the International Symposium of ALS/MND.

“Each one of the five finalist groups took a unique approach for tackling the challenges facing people living with ALS. We are very excited about these innovative and groundbreaking technologies and are confident that any one of them has the potential to make a significant impact on the quality of live of people living with ALS and their families and caregivers,” said Maya Bronfeld, Ph.D., Prize4Life Scientific Officer. Continue reading The ALS Association and Prize4Life Announce Five Finalists for $400K Assistive Technology Challenge

New UBQLN2 ALS Mouse Model Replicates Many Key Disease Features

An ALS Association-funded research team led by Mervyn Monteiro, Ph.D., Professor at the University of Maryland School of Medicine in Baltimore, has developed a new mouse model that faithfully replicates many aspects of the disease, including the formation of characteristic aggregates of an ALS-linked protein called TDP-43. The new model was created by inserting a mutant ubiquilin 2 (UBQLN2) gene, an important contributor to protein recycling, according to a new study published this week in the Proceedings of the National Academy of Sciences. The new model will help decipher how mutations in UBQLN2 cause ALS in people, and more generally how defects in protein recycling contribute to neurodegeneration.

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which leads to total paralysis and death, usually within two to five years of diagnosis. For unknown reasons, veterans are twice as likely to develop ALS as the general population. There is no cure, and only one drug approved by the U.S. Food and Drug Administration (FDA) modestly extends survival.

UBQLN2 acts as a shuttle, ferrying misfolded proteins to the cell’s protein recycling machinery. Mutations in UBQLN2 were discovered in 2011 as a rare cause of ALS-frontotemporal dementia (FTD), a related neurodegenerative disease. In the new study, Dr. Monteiro and the three primary co-authors Nhat Le, Ph.D., Lydia Chang, Ph.D. and Irina Kovlyagina, Ph.D. inserted the mutant UBQLN2 gene into mice. The mice developed progressive muscle weakness and paralysis, as well as memory deficits. Analysis of brain and spinal cord tissue showed the development of characteristic protein aggregates similar to those seen in human disease, including aggregates containing TDP-43, which are common to almost all forms of ALS.

“This new mouse model is an excellent tool that mimics many of the components of ALS,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D., M.B.A., “and in combination with other models, is likely to help us develop new therapies.”

Because this mouse model develops TDP-43 aggregates, it may be especially important for determining whether and how these widespread protein inclusions contribute to disease. This information should be directly useful for deciding whether to target TDP-43 aggregates in treatment development.

ALS Gene C9orf72 Study Published in Journal “Neuron”

Pictured above: Dr. Gao’s laboratory team

A new disease pathway for C9orf72-related ALS was revealed in journal Neuron in a study led by principle investigator Dr. Fen-Biao Gao from the University of Massachusetts Medical School in Worcester, Mass. The research team found that the C9orf72 expansion leads to DNA damage, signifying another potential ALS therapeutic target. The ALS Association supported this encouraging study that also included current and past Milton Safenowitz Postdoctoral Fellows Dr. Dejun Yang (2015 recipient) and Dr. Helene Tran (2012 recipient).

Continue reading ALS Gene C9orf72 Study Published in Journal “Neuron”

FDA Approves Clinical Trial of Novel Stem Cell and Gene Therapy to Stall Progression of ALS

Washington, D.C. (October 24, 2016) — Last week, regenerative medicine investigators at Cedars-Sinai Medical Center in Los Angeles, Calif. received approval from the U.S. Food and Drug Administration (FDA) to test a combination stem cell-gene therapy in a clinical trial designed to test the safety of this therapeutic approach, supported by The ALS Association since 2003, to potentially stall the progression of amyotrophic lateral sclerosis (ALS). This study is the first clinical trial to use neural stem cells to deliver GDNF for ALS, an approach developed by Clive Svendsen, Ph.D., from Cedars-Sinai. It will be conducted at the ALS clinic at Cedars-Sinai Medical Center and led by Robert Baloh, M.D., Ph.D. and Peggy Allred, P.T., D.P.T. and the neurosurgical team will be led by J. Patrick Johnson, M.D., M.S.

Continue reading FDA Approves Clinical Trial of Novel Stem Cell and Gene Therapy to Stall Progression of ALS

ALS Gene C9orf72 Damages DNA Revealing a New Disease Pathway

The most commonly inherited gene in familial ALS, C9orf72, points to DNA damage causing oxidative stress, according to a new study funded by The ALS Association. The study was published in the journal Neuron and led by principle investigator Fen-Biao Gao, Ph.D. and first author Rodrigo Lopez-Gonzalez, Ph.D. from the Department of Neurology at University of Massachusetts Medical School in Worcester, Mass. Findings from this paper point to DNA damage as a disease pathway of C9orf72-related ALS.

Continue reading ALS Gene C9orf72 Damages DNA Revealing a New Disease Pathway