Healey Center Speeds ALS Research for Patient Therapies

Getting promising new treatments to patients with amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, can take years. Scientists at Massachusetts General Hospital are working to dramatically change that.

Merit Cudkowicz, MD, MSc, chief of the Department of Neurology and director of the Neurological Clinical Research Institute, leads the Sean M. Healey & AMG Center for ALS at Mass General. The center's researchers collaborate with ALS scientists worldwide to discover novel treatments. The team is spearheading efforts to accelerate the ALS drug development process by creating the first adaptive ALS Platform Trial.

"There are amazing advances in the science of ALS," says Dr. Cudkowicz. "We want to accelerate translating those advances into therapies for patients with ALS all over the world."

The Healey Center funds its own lab-based scientists and also provides a grant program to support young investigators worldwide (Healey Scholars) who study the basic biology of ALS and investigate new treatments. Current research priorities include:

• Identifying disease targets and ways to modulate those targets
• Developing biomarkers for tailored treatments, faster treatment screening and earlier diagnosis
• Creating a transformative new approach to clinical trial design

Identifying and Modulating Targets of ALS

The Healey Center supports laboratories at Mass General where researchers are working to understand the basic biology of ALS. Clotilde Lagier-Tourenne, MD, PhD, assistant professor in neurology, is exploring how damage to cell protein TDP-43 can lead to motor neuron death.

Research has shown that TDP-43 is mislocated in the motor neurons of 98% of people with ALS. The protein should be in the nucleus, but instead aggregates in the cytoplasm. Depleted nuclear TDP-43 also damages other components in motor neuron cells, resulting in cell dysfunction and early cell death.

Dr. Lagier-Tourenne is investigating what causes loss of nuclear TDP-43 and subsequent damage. She found that depleted nuclear TDP-43, in turn, depletes the level of another protein, stathmin-2, which is critical in determining how nerve axons survive. Dr. Lagier-Tourenne has also found a way to repair the damage: restoration of stathmin-2 levels alone rescues nerve axons' regeneration ability, regardless of TDP-43 status. This evidence supports the rescue of stathmin-2 levels as a potential therapeutic approach for ALS and presents an avenue to pursue in future studies.

In another Mass General lab, Brian Wainger, MD, PhD, assistant professor of neurology and anesthesiology, has found a treatment that can reduce abnormal motor neuron excitability in people with ALS. Dr. Wainger discovered that motor neurons in people with ALS are hyperexcitable because of a problem with the potassium channel in cell membranes. He evaluated drugs that could correct that problem and identified Potiga (ezogabine), a now-discontinued drug to treat epilepsy.

Dr. Wainger tested ezogabine in a clinical trial with 65 people with ALS. Using transcranial magnetic stimulation and threshold tracking nerve conduction studies, he found that treatment with the drug reduced motor neuron excitability. Dr. Wainger's findings contribute to scientists' understanding of neuron hyperexcitability, an important ALS disease pathway, and additional therapeutic possibilities for research and clinical treatment.

Dr. Wainger’s lab group focuses on bettering human stem cell models of ALS. Because other non-motor neuron cell types, such as astrocytes and microglia, contribute substantially to the disease, the lab has developed an organoid model with a goal of capturing broader cellular disease processes. Through this approach, the lab is constructing more robust human stem cell models, both for improved disease mechanistic understanding and for drug screens to identify compounds that block or mitigate motor neuron death.

Developing Biomarkers in ALS

Researchers in the Healey Center work closely with the Athinoula A. Martinos Center for Biomedical Imaging faculty to develop imaging markers for ALS. Healey Center investigators are also exploring fluid based biomarkers in blood, urine and spinal fluid.

"Patients often see several doctors before they get to a neurologist who can confirm ALS, which takes about 12 months," says Dr. Cudkowicz. "That's 12 months without intervening, so we have several studies to develop earlier diagnostic markers."

Diagnostic biomarkers can also shorten the time it takes to diagnose ALS. With a simple lab test or imaging study, primary care physicians will have the information they need to refer their patients to a neurologist for specialized care.

Biomarkers also enable researchers to identify the specific biology in each individual with ALS and how that biology changes through various phases of the disease. They can then develop novel drugs to target individual biology throughout disease progression. Researchers will also be able to screen treatments faster using surrogate biomarkers to measure disease progression and therapeutic efficacy. The use of surrogate markers can shorten the time required for FDA drug approval.

Transformative New Approach to ALS Clinical Trial Design

Mass General has been at the forefront of international ALS research for decades. In 1993, Robert H. Brown, Jr., MD, led the international team that discovered the first ALS-associated gene. In 1995, Mass General was a founding member of the Northeast ALS (NEALS) Consortium, which has since grown to more than 130 academic research centers worldwide. Now, the Healey Center is taking that framework to the next level by leading the process to start the first adaptive ALS Platform Trial.

Traditionally, each clinical trial evaluates only one experimental treatment at a time. Platform trials, instead, are trials where multiple treatments are tested in parallel, using a common infrastructure and specialized statistical tools. New treatments can be added to the platform as they become available thereby decreasing the gap in time from identification of a rationale therapy to testing. This approach allows investigators to test more agents, faster, and using fewer resources.

In addition to operational efficiencies, the platform approach comes with several scientific efficiencies. Because different treatments are tested using a shared infrastructure and a common master protocol, data from participants in all placebo groups can be pooled resulting in high statistical power to see a treatment effect between each treatment and the pooled placebo group, even though each participant’s individual chance of being on placebo is much lower than in traditional trials.

"This design can cut the time to find an effective treatment in half, and it can cut costs by a third or more," says Dr. Cudkowicz. "It's also really good for patients because it optimizes their chances of getting the drug, provides answers faster, and ensures we keep learning about the disease."

The ALS Platform Trial includes several promising biomarkers and novel outcome measures. ALS trial endpoints have historically been based on estimates of function or survival. While important, these clinical measures require long trials with prolonged follow-up of participants. The ALS community recently developed novel endpoints, such as measures of muscle strength and speech analysis, that can potentially provide answers faster.

The adaptive ALS Platform Trial will include both traditional and novel endpoints and will be an engine to further develop these novel exciting tools.

“We are thrilled to be in a position to test several candidate therapeutics for ALS and, at the same time, facilitate the development of biomarkers that can more quickly predict therapeutic success,” says Sabrina Paganoni, MD, PhD, a physician scientist and faculty at the Healey Center. “In this new paradigm, more patients will have access to promising therapies and the trial will provide important contributions to our knowledge about ALS.”

Worldwide Collaboration in ALS Research

Dr. Cudkowicz and her team collaborate with ALS researchers from around the world. The Healey Center's Science Advisory Council, which comprises a global team of investigators, advises the center's leadership on areas where its support could truly make a difference in accelerating ALS treatments to market. The Science Advisory Council met for the first time one day after the launch of the Healey center.

“We discuss with the Science Advisory Council members new areas of research where our support would accelerate translation to treatment for people with ALS, ideas on granting mechanisms, recommendations for treatments to bring forward in the ALS Platform Trial and advice on partnerships with other funding organizations," Dr. Cudkowicz says.

To attract young scientists to ALS research, the Healey Center is developing Scholar grants to support investigators at Mass General and elsewhere. The Healey Center will also provide an annual Innovation Prize to be awarded at the International MND Symposium.

"I feel blessed to be part of our patients' lives," Dr. Cudkowicz says. "As an ALS doctor, I am really very engaged with the person with the illness and their family. This merging of research and clinical care, to change the landscape for the future, inspires and motivates me each day."

Learn more about the Sean M. Healey & AMG Center for ALS

Learn more about ALS Research at Mass General