The Wainger Lab

The Wainger Lab approaches the study of neurodegenerative diseases with a translational focus, bridging basic science and patient care. Led by Dr. Wainger, a physician-scientist dedicated to advancing treatments for ALS, frontotemporal dementia, chronic pain, and other neurodegenerative conditions, the research group aims to drive meaningful clinical outcomes. The vibrant community and extensive facilities at Mass General Brigham provide nearly limitless opportunities for collaboration and access to core facilities to aid and partner in research. While all the research in our group aims to address neurodegeneration through prevention or treatment, it spans both preclinical research, using animal and cell culture models, and clinical research, where we work directly with patients to accelerate the translation of new therapies.

In the Wainger Lab, we strive to foster Diversity, Equity, Inclusion and Belonging, and we support the MGH statement: “Diversity is the richness of human differences. Inclusion is when everyone feels connected, valued and engaged. At Massachusetts General Hospital, we believe that because of diversity we excel; through inclusion we respect; focused on equity we serve, heal, educate and innovate.”

Preclinical research

ALS

Amyotrophic lateral sclerosis (ALS), often referred to as Lou Gehrig’s disease, is a devastating neurological disease of the motor nervous system. Within a few short years, its victims fall from good health—often in the prime of life—and ultimately perish due to progressive motor neuron deterioration. ALS is surprisingly common: people have a lifetime risk of about 1 in 400. Our goal is to identify and test novel therapeutics for rapid translation of ALS treatments.

Our team is part of the MGH Healey Center for ALS Research. We previously identified abnormalities in the electrical activity of motor neurons derived from ALS patients using stem cell technology. The research culminated in identifying the importance of Kv7 channels as drivers of hyperexcitability in ALS and successfully demonstrating that Kv7 agonist retigabine (also called ezogabine) reduces this pathological hyperexcitability in a phase 2, 12-site clinical trial of ALS subjects.

As part of our ongoing efforts, our lab focuses on investigating the molecular mechanisms driving ALS initiation and progression. By using iPSC-derived motor neurons, organoids, muscles, and mouse models, we explore how ALS mutations impact motor neuron function, neuromuscular junction (NMJ) integrity, and neuroinflammation.

Molecular mechanisms of ALS

In the lab, we use iPSC-derived motor neurons, organoids, and mouse models to study the molecular mechanisms of ALS and identify new potential therapeutic targets. A key area of our research is understanding the role of TDP-43 pathology in ALS and exploring strategies to mitigate the neurodegeneration associated with this pathology. A second major area of interest is investigating how the most common familial ALS mutation, a [GGGGCC] repeat expansion in C9ORF72, contributes to neurodegeneration. Leveraging our expertise in bioinformatics, iPSC technologies, high-content imaging, and high-throughput screening, we strive to identify novel therapeutic targets and hopefully develop more effective treatments for ALS and neurodegenerative diseases.

Neuromuscular junction integrity

Our lab is particularly interested in the neuromuscular junction (NMJ) and how its degeneration occurs in motor neuron diseases, including ALS. To that end, we have developed two distinct iPSC systems for studying the NMJ. The first is an organoid system containing several cell types, including muscle, neurons (sensory and motor), astrocytes, and microglia. This model more closely mirrors the in vivo context, and we have used this approach to study how ALS mutations interfere with NMJ structure and function. The second approach is a more streamlined additive system where we differentiate motor neurons and muscle separately and then add them together in a co-culture. This additive system allows us to mix and match cells of different genotypes to interrogate which cell types contribute to NMJ defects in ALS.

STING pathway and neuroinflammation

The Simulator of Interferon Genes (STING) pathway has emerged as a key player in neuroinflammation through its activation in nervous system immune cells called microglia. Our lab has uncovered that STING activation extends beyond immune cells and also occurs directly in neurons. Intriguingly, we observed STING signaling activation in neurons that are vulnerable to neurodegeneration in ALS (upper and lower motor neurons) but not in neurons and brain regions relatively spared in the disease (e.g. sensory neurons, occipital cortex). Ongoing work in this area aims to 1) uncover the precise mechanisms and downstream consequences of STING activation across different cell types in ALS and 2) explore its potential as a therapeutic target for novel treatment strategies in neurodegenerative diseases like ALS.

Chronic Pain

Chronic pain causes profound impairments in quality of life, mood and functioning. It affects over one quarter of adult Americans and is one of the most common reasons for physician visits, lost productivity and disability. While the vast majority of pain conditions are focal, most current pain treatments are systemic, leading to side effects and risk of addiction. The lack of effective treatments, especially for chronic pain, has led to the opioid epidemic. Evidence from human genetics and mouse models supports that silencing first-order pain sensing neurons (nociceptors) leads to reduced experience of pain. Given the recent successes of gene-therapy based strategies in medicine, we have made novel advances to selectively modify the excitability of pain neurons, without the side effects that result from a less targeted strategy. This strategy is being developed with a goal of clinical translation. The Wainger lab is well-positioned to contribute to advances in this field with our deep background in electrophysiological techniques such as patch clamp, our prior development of a high-content optical rheobase assay of neuronal excitability, our experience with rodent pain models, and our strength in bioinformatics and molecular biology.

CLINICAL RESEARCH

Our group is performing two studies within the NIH HEAL Initiative using neurophysiological techniques to help identify mechanism-based biomarkers in chronic pain. The combination of specialized clinical and research training places the group in a prime position to investigate disease-related research questions and find practical and promising ways to directly advance the application of basic science research to clinical medicine.

Spinal Cord Stimulator

This project is investigating mechanisms of spinal cord stimulator reduction in pain and will include measurements of nerve excitability using threshold tracking and microneurography as well as PET imaging of neuroinflammation in the brain. This study is led by our group, Dr. Roy Freeman, and Dr. Marco Loggia, and is a collaboration including researchers and clinicians at Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Brigham and Women’s Hospital.

Biomarkers of Myofascial Pain

This project, led by Dr. Seward Rutkove and our group, is investigating physiological and ultrasound biomarkers of myofascial pain (pain in the muscle and fascia - thin connective tissue surrounding the muscle). Myofascial pain is a common type of chronic pain. Some therapies such as trigger-point injection, dry needling, and myofascial release provide some relief to patients, however the mechanism of their action is poorly understood. This study aims to identify biomarkers of myofascial pain to allow for improved diagnostic capability as well as to quantify the effect of treatment. The study is a collaboration between Beth Israel Deaconess Medical Center and Massachusetts General Hospital.