Michael W. Lawlor MD, PhD
Assistant Professor of Pathology;
Director, Pediatric Pathology Neuromuscular Laboratory
Dr. Lawlor’s clinical responsibilities include the diagnosis of nerve, muscle, brain and spinal cord specimens from surgical and autopsy material, with an emphasis on pediatric muscle and nerve biopsies. His research laboratory studies animal models of congenital myopathy (X-linked myotubular myopathy, in most cases) in an effort to further understand these diseases and develop new treatments.
- Pediatric muscle disease (X-linked myotubular myopathy)
- Preclinical trials of novel therapeutic agents
- Skeletal muscle pathology
- Skeletal muscle physiology
- In vitro models of skeletal muscle function and disease
- Assistant Professor, Department of Pathology, Medical College of Wisconsin / Children’s Hospital of Wisconsin (2001 – Present)
- BS, Marquette University, Milwaukee, Wisconsin (1993 – 1996)
- MD, PhD, Loyola University Chicago, Maywood, IL (1997 – 2004)
- Anatomic Pathology Residency, Massachusetts General Hospital, Harvard Medical School, Boston, MA (2004 – 2006)
- Neuropathology Fellowship, Massachusetts General Hospital, Harvard Medical School, Boston, MA (2006 – 2008)
- Research Fellowship, Human Molecular Genetics, Children’s Hospital Boston, Harvard Medical School, Boston, MA (2008 – 2001)
- Anatomic Pathology
1. Advancing understanding of the pathogenesis of X-linked myotubular myopathy (XLMTM): My postdoctoral work in Dr. Alan Beggs’ laboratory at Children’s Hospital Boston focused on performing treatment trials in murine models of XLMTM. During the course of this work, we performed comprehensive behavioral and pathological analyses on the Mtm1 knockout (KO) and Mtm1 p.R69C mouse models of XLMTM and applied that knowledge to the evaluation of skeletal muscle pathology in canine and human XLMTM. Our initial anti-myostatin trial showed that the myofiber smallness seen in XLMTM was a reversible phenotype in many fibers, but that myofiber hypertrophy in XLMTM was not useful by itself. Follow up functional studies investigated the contributions of myofiber smallness, contractile dysfunction, and “membranous processes” (including excitation contraction coupling (ECC)), and further confirmed that ECC was likely a major and overwhelming cause of weakness in XLMTM. Pilot enzyme replacement studies in this paper revealed improvement of weakness and reversal of sarcotubular pathology after just two weeks of treatment using a non-optimized dose and therapeutic protocol. Additionally, we identified satellite cell depletion as a process occurring in XLMTM mouse models that may contribute to disease progression. Our findngs in in these studies have contributed to the current design of preclinical and clinical trial studies in the field of XLMTM. This work has been supported by funding from NIAMS and the Children’s Hospital of Wisconsin Research Institute and through collaborations with Acceleron Pharma, Audentes Therapeutics, and Valerion Therapeutics.
2. Evaluation of treatment options for XLMTM: My work in the Beggs laboratory and in my own laboratory has focused extensively on testing treatments for XLMTM in animal models, and we now are in the process of translating this knowledge for the planning of human clinical trials. Our first projects focused on the evaluation of myostatin inhibition as a treatment for XLMTM, in which we found 1) that myostatin inhibition using ActRIIB-mFc produced myofiber hypertrophy without extensive increases in strength (due to the ECC problems mentioned above), 2) that only specific fiber types and muscles were responsive to ActRIIB-mFc treatment in murine XLMTM models, and 3) that specific abnormalities of satellite cell behavior or hypertrophic pathway signaling may account for fiber type and muscle specific treatment responses in XLMTM mouse models. This all led us to refocus our XLMTM work on agents that would reconstitute or improve ECC, and we performed a pilot trial of a targeted enzyme replacement agent for XLMTM and acted as the study pathology group for a gene therapy trial in XLMTM canines. This collaborative work also led us to develop standard strategies for the training of investigators handling muscle tissue at distant sites (as well as recovery of inappropriately handled tissue) and in the reporting of muscle biopsy findings in accordance with the NIH Common Data Elements guidelines that I helped develop. I currently continue to work as the study pathologist and site PI for gene therapy studies in canine XLMTM while also coordinating the translation of pathological studies for the XLMTM human clinical trial being organized by Audentes Therapeutics. This work has been supported by funding from NIAMS, the Children’s Hospital of Wisconsin Research Institute, and Audentes Therapetuics and through collaborations with Acceleron Pharma, Audentes Therapeutics, and Valerion Therapeutics.
3. Advancing understanding of the pathogenesis of nemaline myopathy (NM): As we worked on XLMTM, we participated in a number of projects related to NM that focused on the identification of potentially relevant disease processes. NM is a congenital myopathy that is a significant cause of weakness and disability in children and adults and that is characterized by the presence of needle-like inclusions within myofibers. My first paper in the Beggs laboratory was focused on the genetic and pathological features of patients with NM or congenital fiber type disproportion (CFTD) due to mutations in TPM3. This offered my first opportunity to work collaboratively with NM experts around the world, and I participated in studies focused on the cause of weakness in mice or tissue from human patients harboring mutations in the nebulin gene. We have further worked to characterize the pathological phenotypes of nemaline myopathy models that have yet to be published, and this work has cemented productive working relationships with NM investigators worldwide. Our current work in NM is focused on looking at protein expression abnormalities in animal models of NM, while also assessing the potential of myostatin inhibition therapy in mouse NM models using agents from Acceleron Pharma and Pfizer. This work has been supported by funding from NIAMS, the Children’s Hospital of Wisconsin Research Institute, the Clinical and Translational Science Institute of Southeastern Wisconsin, A Foundation Building Strength, and the Muscular Dystrophy Association. Key collaborating companies include Acceleron Pharma and Pfizer.
4. Pathological characterizations of veterinary neuromuscular models and human disease: Our laboratory performs high-quality processing and analysis of skeletal muscle, brain, and visceral organ tissues using the Histology Core Facility at the Children’s Hospital of Wisconsin Research Institute. We have characterized new disease models being developed worldwide, particularly in the field of skeletal muscle disease. Examples of assessments we have performed include our work using Neb(Exon55) NM mice, selenoprotein N deficiency mice, and in human disease states including myofibrillar myopathy and critical care myopathy. This work has been supported by funding from NIAMS, the Children’s Hospital of Wisconsin Research Institute, the Clinical and Translational Science Institute of Southeastern Wisconsin, A Foundation Building Strength, and the Muscular Dystrophy Association.
5. Improving myofiber length to enhance function after limb: In collaboration with Dr. Danny Riley at MCW, we are pursuing studies to generate models and assess treatment efficacy for congenital contractures. Congenital contractures are produced as a result of insufficient movement during the terminal development of the musculoskeletal system, which occurs in the third trimester of fetal development in humans and in the first 3 weeks of postnatal life in rodents. Contractures in humans cause life-long disability, and there is evidence that current stretch therapies used in the pediatric population may actually worsen disease due to differences in the response to stretch when comparing mature vs. developing muscles. Our project will optimize a casting or splinting model for the study and treatment of muscle contractures, and then will assess the effectiveness of stretch, electrical stimulation, and local myostatin inhibition in the rehabilitation of these contractures. This work has been supported by NIAMS, the Neuroscience Research Center at MCW, and the Children’s Hospital of Wisconsin Research Institute and in collaboration with Acceleron Pharma.
6. Automation of muscle biopsy analysis: The pathological analysis of muscle tissue involves the assessment of a number of specific features, and the regional variability between muscles and even within the same muscle makes the process of accurate quantitation of these features very labor-intensive. In collaboration with Lin Yang from the University of Florida, this project will generate computer algorithms that will quickly and accurately provide quantitative measurements of features within skeletal muscle. Additional studies related to the training of computer software to automatically screen for diagnostically relevant patterns or specific abnormalities are also in progress. This work is currently funded by NIAMS.
7. Congenital Muscle Disease Tissue Repository (CMD-TR): This project focuses on the centralization of tissue storage to facilitate research related to congenital muscle diseases using human tissue. The CMD-TR enrolls patients who are interested in donating tissue for research purposes, including prior muscle biopsies or current/future biopsy or autopsy tissue. The CMD-TR then provides access to this de-identified tissue to researchers performing relevant projects, which decreases the burdens associated with patient consenting and regulatory compliance on the part of the researchers. The CMD-TR is funded by a group of patient families and non-profit entities with ties to congenital muscle disease, including Cure CMD, A Foundation Building Strength, Where There’s A Will There’s A Cure, and The Joshua Frase Foundation.
8. Use of electron paramagnetic spectroscopy (EPR) in the characterization and diagnosis of mitochondrial disease: In collaboration with Drs. Brian Bennett (Marquette University) and David Dimmock (MCW), we are pursuing studies to characterize several rat models of mitochondrial disease using standard methods and a spectroscopy technique called EPR. The eventual goal of these studies is to optimize and validate EPR as a diagnostic tool for mitochondrial disease, since the current diagnostic workup for these disorders is not very reliable. We are currently pursuing pilot funding for this work.