Demyelination and Remyelination: From Mechanism to Therapy

Agenda

* Presentation titles and times are subject to change.

Abstracts

Keynote Address: Reversing Myelin Loss— What Are the Challenges?
Robin Franklin, PhD, Wellcome Trust–MRC Cambridge Stem Cell Institute, University of Cambridge

Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, represents one of the most compelling examples of adult multipotent stem cells contributing to regeneration of the injured CNS. This process can occur with remarkable efficiency in clinical disease or injury, and in experimental models, revealing an impressive ability of the adult CNS to repair itself. However, its failure in genetic disorders of myelination (leukodystrophies) and its inconsistency in chronic demyelination diseases such as multiple sclerosis, leading to loss of function and ultimately axons, make enhancement of remyelination an important therapeutic objective. There are two broad approaches—transplantation of myelinogenic cells (exogenous therapies) or promotion of the latent regenerative properties of myelinogenic stem and progenitor cells present within the injured tissue (endogenous therapies). A third option involves transplantation on non-myelinogenic cells (such as mesenchymal stem cells) with a view to influencing the regenerative properties of endogenous cells. This talk will consider which diseases are appropriate for remyelination therapy, and highlight the challenges that will need to be overcome in order to translate promising laboratory studies into the effective treatments in the clinic.

Mechanisms of Myelin Regeneration in the Adult Central Nervous System
Catherine Lubetzki, MD, PhD, Sorbonne Universités UPMC, ICM, Pitié-Salpêtrière Hospital, Paris

Remyelination in the adult CNS is mostly achieved by oligodendrocyte progenitor cells (OPCs). These immature cells are first activated, then migrate to the demyelinated lesion where they differentiate into oligodendrocytes. To gain insight into the initial events of the remyelination process, we recently questioned what distinguishes a "quiescent" adult OPC from an "activated" OPC, engaged in the remyelination process. By combining a new method of adult OPCs purification and gene expression profiling, we demonstrated that adult OPCs have a transcriptome more similar to that of oligodendrocytes than to neonatal OPCs, but revert to a neonatal-like transcriptome when activated. We then showed that part of the activation response involves increased expression of two genes of the innate immune system, IL1β and CCL2, which enhance the mobilization of OPCs. In parallel, we investigated the influence on the recruitment of adult OPCs, of guidance cues known to be involved in OPCs migration during development—class 3 semaphorins and Netrin1. We showed that these guidance cues: i) are upregulated after demyelination in experimental models and in MS lesions; and ii) influence adult OPCs migration/recruitment, with a repellent effect of Semaphorin 3A and Netrin 1, contrasting with an attractant effect of Semaphorin 3F. Finally, we demonstrated that modulation of OPCs recruitment influences remyelination rate, with increased and decreased remyelination with overexpression of semaphorin 3F and Netrin1, respectively. These studies further decipher the mechanisms of the repair process and result in identification of potential therapeutic targets for remyelination strategies in multiple sclerosis patients.

Molecular Mechanisms of Myelination and Repair
Patrizia Casaccia, MD, PhD, Icahn School of Medicine at Mount Sinai, New York

It is well accepted that developmental myelination requires the differentiation of progenitors into myelinating oligodendrocytes, specialized cells that provide insulation and metabolic support to neurons and guarantee proper functioning of the central nervous system. Research into oligodendrocyte development conducted in our lab and others has highlighted the importance between the balance of repression and activation of gene expression, and the genome-wide molecular events underlying this lineage transition will be reviewed. Remyelination addresses the regenerative process involving the differentiation of adult progenitor cells. We have previously addressed the re-enactment of developmental processes in the adult brain, in response to environmental challenges (i.e., behavioral manipulation or disease states) and to the aberrant epigenomic mechanism related to conditions of impaired repair. The translational implications of these studies will be highlighted and potential therapeutic strategies aimed at reversing these epigenomic changes will be discussed.

Reversing Myelin Loss after Preterm Hypoxia
Vittorio Gallo, PhD, Center for Neuroscience Research, Children's National Medical Center, Washington, DC

There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. Failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Therefore, we examined whether enhanced EGFR signaling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioral recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells, or the administration of intranasal heparin binding EGF immediately after injury, decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells, and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioral deficits on white-matter-specific paradigms. Inhibition of EGFR signaling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

Identification of Small Molecule Modulators of Remyelination
Luke L. Lairson, PhD, The Scripps Research Institute, La Jolla; and The California Institute for Biomedical Research, La Jolla

Progressive phases of multiple sclerosis (MS) are associated with inhibited differentiation of the progenitor cell population required for remyelination and disease remission. We performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic nerve-derived progenitor cells, to identify selective inducers of oligodendrocyte differentiation. Amongst the most effective compounds identified was Benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting MS when administered alone or in combination with approved immunosuppressive treatments for MS. Evidence from a Cuprizone-induced model of demyelination, in vitro and in vivo T cell assays, and EAE adoptive transfer experiments indicate that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression.

High-Throughput Screening of Therapeutic Agents for Myelin Repair Using Micropillar Arrays
Jonah R. Chan, PhD, University of California, San Francisco*

Damage to myelin from diseases such as multiple sclerosis (MS) results in the disruption of the nerve signal, damage to the axon, and finally degeneration, ultimately leading to chronic disability. In order to effectively treat these devastating conditions, it is essential that we develop novel methodologies and approaches to promote repair. Functional screening for small molecules or biologicals that promote remyelination represents a major hurdle to the identification and development of rational therapeutics for demyelinating diseases. Therefore, it is imperative to continue to make technical advances in the development of high-throughput screening platforms that will provide insight into the cell-autonomous mechanisms for remyelination. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. As a major breakthrough to conventional methodology, we describe a Binary Indicant for Myelination using Micropillar Arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping, observed as "rings" of myelin. The platform is formatted in 96-well plates, amenable to semi-automated random acquisition and automated detection and quantification. Upon screening 1,000-bioactive molecules, we identify a cluster of anti-muscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a novel high-throughput screening platform for potential regenerative therapeutics in MS.
 
Co-authors: Feng Mei¹*, Stephen P. J. Fancy²*, Yun-An A. Shen¹, Jianqin Niu³, Chao Zhao⁴, Bryan Presley⁵, Edna Miao¹, Seonok Lee¹, Sonia R. Mayoral¹, Stephanie A. Redmond¹, Ainhoa Etxeberria¹, Lan Xiao³, Robin J. M. Franklin⁴, Ari Green¹, and Stephen L. Hauser¹.

1. University of California, San Francisco
2. Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco
3. Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, China
4. Wellcome Trust Medical Research Council Cambridge Stem Cell Institute, University of Cambridge
5. Trianja Technologies, Inc., Allen, Texas

* Authors contributed equally

In Vitro Target Discovery Using a Zebrafish Model
Wendy B. Macklin, PhD, University of Colorado School of Medicine, Aurora

Current therapies to treat demyelinating diseases such as multiple sclerosis (MS) are primarily focused on reducing the immune component and inflammation. The other major element of this disease is demyelination, and demyelination repair is an important goal for MS therapeutics. Very few therapeutics are currently available to mediate repair. There are also no effective treatments for the secondary progressive form of MS characterized predominantly by neurodegeneration, which could potentially be reduced by enhanced remyelination. Remyelination does occur to some extent in MS, but it fails with disease progression. Thus, therapeutics focused on enhancing remyelination are essential. In vivo remyelination assays are crucial for drug discovery, but they are long and expensive. Zebrafish myelination is an excellent animal model with which to address this important issue, since large numbers of rapidly developing transparent embryos are external to the mother, making them ideal for chemical screen. An added advantage is that oligodendrocyte development in zebrafish, which is known to be regulated comparably to rodents and humans, occurs over only a few days allowing for rapid screening. Furthermore, once optimal compounds have been identified that enhance remyelination, the stage at which these compounds act can be established rapidly in zebrafish. The current studies focus on generating a useful screen for investigators to demonstrate at a very early stage of analysis which compounds should be moved forward to in vivo remyelination analyses in rodents, and eventually into clinical trial.
 
Co-author: Marnie A. Preston, PhD, University of Colorado School of Medicine, Aurora.

Identifying Targets for Remyelination from Cultures to Animal Models
Charles ffrench-Constant, PhD, FRCP, MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Scotland

Understanding remyelination, like any other example of regeneration, requires the study of three -ologies: stem cell biology, developmental biology and inflammation biology. Stem cell biology identifies the regulators of the adult precursor cells that generate new oligodendrocytes, while developmental biology defines the mechanisms these newly-formed cells must use to integrate successfully into the damaged CNS. The role of inflammation is important as, unlike development, tissue formation must occur against the background of an inflammatory response to the damage. Indeed, this inflammation mediated by the innate immune system is a key part of the regenerative response and a promising source of targets for drug discovery programs. In MS, however, the situation is complicated by the activity of the adaptive immune system that is responsible for the initial damage. To study these three areas of biology in remyelination we have used a series of models to identify intrinsic and extrinsic factors important in the process and that inform the hunt for targets with which to initiate drug discovery programs.

Novel Tracer for Demyelination and Remyelination
Pedro Brugarolas, PhD¹

Demyelination uncovers axonal K+ channels which causes aberrant leakage of K+ ions and poor axonal conduction. The multiple sclerosis (MS) drug 4-aminopyridine (4-AP) can block these channels and partially restore conduction. Based on this mechanism, we hypothesized that 4-AP would preferentially bind to demyelinated axons over normally myelinated axons and could be turned into a tracer. Using several animal models of MS, including Shiverer, DTA, and lysolecithin injected mice, in combination with autoradiography, we observed that [14C] 4-AP had significantly higher uptake in demyelinated white matter areas than in myelinated white matter areas. We also synthesized several fluorinated derivatives of 4-AP, compatible with fluorine-18 labeling and positron emission tomography (PET), and identified one compound that had very similar pharmacological properties to 4-AP and similar distribution in dysmyelinated brains. To our knowledge, this is the first tracer whose uptake increases with the lack of myelin, providing the foundation for a new type of tracer for MS.
 
Coauthors: Jorge E. Sánchez-Rodríguez, PhD¹, Andrew Caprariello, PhD², Jerome J. Lacroix, PhD¹, Robert Miller, PhD², Francisco Bezanilla, PhD¹, and Brian Popko, PhD^1
1The University of Chicago, Chicago, Illinois, United States
²Case Western Reserve University, Cleveland, Ohio, United States

Neuronal Activity Promotes Oligodendrogenesis and Adaptive Myelination in the Mammalian Brain
Erin M. Gibson, PhD, Stanford University School of Medicine, Stanford, California

Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPC). Electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit. Here we use optogenetic stimulation of premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.
 
Coauthors: David Purger, Christopher W. Mount, Andrea K. Goldstein, Grant L. Lin, Lauren S. Wood, Ingrid Inema, Sarah E. Miller, Gregor Bieri, J. Bradley Zuchero, PhD, Ben A. Barres, MD, PhD, Pamelyn J. Woo, Hannes Vogel, MD, and Michelle Monje, MD, PhD, Stanford University School of Medicine, Stanford, California, United States

Tracking Remyelination Using Magnetic Resonance Techniques
Douglas L. Arnold, MD, McGill University, Montreal Neurological Institute, Montreal, Canada

The efficacy of remyelinating therapies on remyelination cannot be directly inferred from clinical outcomes, which are non-specific. A method of quantifying remyelination in vivo is required. Magnetic resonance imaging (MRI) offers a number of different approaches to accomplish this in vivo, including magnetization transfer ratio (MTR) imaging, quantitative magnetization transfer (qMT) imaging, and multi-component T2 relaxation.  Of these, only MTR imaging is routinely available on commercial scanners, and thus offers a practical option for general use in multicenter clinical trials.  For this reason, we will focus on MTR imaging. MTR provides a semi-quantitative means for assessing myelin density based on the exchange of magnetization between hydrogen nuclei in water with hydrogen nuclei in macromolecules, an effect that, within the brain, is dominated by the constituents of myelin. Changes of MTR in the brain have been shown to be sensitive to changes in myelin content.  At the time of focal inflammation and myelin destruction associated with lesion appearance in MS, there is a major reduction in MTR. Subsequent recovery of mean lesion MTR is variable and can be modeled over time based on serial MTR images. This approach is capable of detecting differences in remyelination of acute lesions in relatively modest numbers of subjects and is amenable to use in clinical trials.

Tracking Remyelination Using Positron Emission Tomography Imaging
Bruno Stankoff, MD, PhD, University Pierre et Marie Curie, UPMC, ICM-INSERM 1127, Paris; and Service Hospitalier Frederic Joiliot, SHFJ, CEA, Orsay

Quantitative imaging of remyelination is crucially needed in multiple sclerosis (MS). Molecular imaging by positron emission tomography (PET) could bring important progress in this field by the use of specific and quantifiable tracers. We have shown that compounds related to the Congo red or thioflavine chemical classes could be used as promising myelin markers. Following radiolabelling, molecules such as ¹¹C-MeDAS (N-methyl-4,4′-diaminostilbene), or ¹¹C-PIB (Pittsburgh B compound) were used to measure the myelin dynamics in several demyelinating rodent models. In humans, ¹¹C-PIB PET allowed for imaging of the white matter and could evaluate the myelin loss in MS white matter lesions. We developed a non-invasive quantification method with Logan graphical analysis using reference regions. A longitudinal clinical study of MS subjects and controls was initiated. At the cross-sectional level, we found a gradient of decrease in ¹¹C-PIB binding from normal appearing white matter to lesion edges, lesion center, and black holes, reminiscent of what is found on histological samples. A voxel-wise analysis provided precise maps of myelin loss in the brain of MS subjects. A longitudinal follow up could evaluate the variability of the method. We therefore analyzed longitudinally the ¹¹C-PIB binding potential changes in MS white matter lesions and found that the proportion of lesion volume that displayed an increase in ¹¹C-PIB binding correlated with clinical parameters. PET with ¹¹C-PIB is a promising biomarker for assessing myelin dynamics in MS lesions. The remyelination index derived from PET images has the potential to predict disease severity, and could be of interest as an outcome measure in clinical trials.
 
Co-authors: B. Bodini^1,2, M. Veronese², D. García-Lorenzo¹, C. Papeix¹, B. Zalc¹, M. C. Lubetzki¹, M. Bottlaender³, and F. Turkheimer².

1. University Pierre et Marie Curie, UPMC, ICM-INSERM 1127, Paris
2. King's College London
3. Service Hospitalier Frederic Joiliot, SHFJ, CEA, Orsay

Human Glial Progenitor Cell-based Treatment and Modeling of Neurological Disease
Steven A. Goldman, MD, PhD, University of Rochester Medical Center; University of Copenhagen

The most abundant precursor cells of the adult human brain are glial progenitor cells, which can give rise to both astrocytes and oligodendrocytes. As a result, diseases of glial cells may provide readily accessible targets for cell-based therapies. The myelin diseases in particular are among the most prevalent and disabling conditions in neurology, and may be especially appropriate targets for glial progenitor cell-based therapy. This talk will focus on the potential utility of human glial progenitor cell transplantation as a means of treating both congenital and acquired diseases of myelin. It will cover both tissue and stem cell-derived glial progenitor cells, as well as the use of human induced pluripotent stem cell (hiPSC)-derived glial progenitors in myelin repair, and the potential limitations on the clinical use of each. In addition, we will consider the molecular control of human glial progenitor cells, from the standpoint of establishing strategies for their mobilization and induced myelination in vivo. The talk will also include a description of the glial chimeric mice that result from the neonatal implantation of human glial progenitors into the mouse brain. In these mice, the human glial progenitors out-compete their murine counterparts to eventually dominate the glial population of the recipient brains. By generating these animals using hiPSC-derived glial progenitors, we may now produce patient-derived and disease-specific human glial chimeras. These mice provide us a new model system within which to study not only the myelin disorders, but the entire range of human neurological and neuropsychiatric diseases in which glia may causally participate.

Myelin Development, Disease and Cell-based Therapy
David H. Rowitch, MD, PhD, University of California, San Francisco

Pelizaeus-Merzbacher Disease (PMD) is a severe congenital leukodystrophy caused by X-linked mutations in the myelin gene, Proteolipid protein (PLP1). PMD can present with severe neurological deficiencies leading to death, and no specific therapies exist, highlighting a critical need to develop new approaches. The rationale for cell-based therapy in PMD is that PLP1 mutations render endogenous oligodendrocyte precursor cells (OPCs) defective. Because OPCs expand and are migratory, integration of donar/exogenous OPCs is predicted to lead to progressive replacement of demyelinated areas. We carried out a Phase I clinical study in which neural stem cells were injected directly into white matter of four boys with severe/early onset PMD. We have observed a reassuring safety profile two years post-transplant and increased fractional anisoptropy by MRI in transplanted regions, consistent with cellular engraftment and the potential production of donor cell-derived myelin. Allogeneic neural progenitors transplant requires an as yet undetermined level of immunosuppression. In contrast, generation of patient-derived induced pluripotent stem (iPS) cells, followed by targeted PLP1 gene correction and differentiation into autologous induced OPCs, might facilitate long-term engraftment without need for immunosuppression, but raises the possibility of other risks. These issues will be discussed in the wider context of oligodendrocyte development and myelin regeneration strategies for white matter diseases.

Clinical Investigation of rHIgM22 as a Potential Remyelinating Agent
Andrew Eisen, MD, PhD, Acorda Therapeutics, Inc., Ardsley, New York

The recombinant human IgM22 (rHIgM22) monoclonal antibody was first described as a potential remyelinating agent in the Theiler's Murine encephalomyelitis virus (TMEV) model of multiple sclerosis by the Rodriguez laboratory at the Mayo Clinic in 2002. The specific antigen recognized by rHIgM22 and the pathways that are activated to promote remyelination remain to be elucidated fully. In addition to these aspects of rHIgM22 biology, the development of remyelination biomarkers are under investigation both at the Mayo Clinic and Acorda Therapeutics, Inc. that would assist in the clinical development of rHIgM22. Acorda is now conducting a Phase 1, multi-center, double-blind, randomized, placebo-controlled, dose-escalation study designed to evaluate safety, tolerability, pharmacokinetics, and immunogenicity of single intravenous (IV) administrations of rHIgM22 in patients with all clinical presentations of multiple sclerosis. In the Dose Escalation phase of the study (Cohorts 1–5) the first 2 eligible patients will be enrolled and randomized 1:1 to receive rHIgM22 or placebo, and monitored for safety for a minimum of 7 days before the remaining 8 patients in the cohort are randomized (7 active: 1 placebo) and dosed. This will be followed by an Expanded Cohort where a new group of 21 patients will be enrolled and randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups: placebo, rHIgM22 at the Maximally Tolerated/Tested Dose (MTD) from the Dose Escalation Phase, or at one full dose level lower than MTD. Additionally, a set of clinical and molecular assessments will explore clinical and biological effects of administering rHIgM22 on parameters that might reflect changes due to remyelination in this patient population.

Anti-LINGO-1 to Target Myelin Repair
Diego Cadavid, MD, Biogen Idec, Cambridge, Massachusetts

LINGO-1 is a leucine-rich repeat and Ig-domain-containing, Nogo receptor interacting protein selectively expressed in the CNS on both oligodendrocytes and neurons. Its expression is developmentally regulated, and is upregulated in CNS diseases and injury. In preclinical models, LINGO-1 expression is upregulated in spinal cord injury, experimental autoimmune encephalomyelitis, 6-hydroxydopamine neurotoxic lesions, and glaucoma models. In humans, LINGO-1 is expressed in oligodendrocyte progenitor cells from demyelinated white matter of multiple sclerosis (MS) post-mortem samples and in neurons and axons from Parkinson’s disease and essential tremor brains. LINGO-1 negatively regulates oligodendrocyte differentiation and myelination, neuronal survival, and axonal regeneration by activating ras homolog gene family member A (RhoA) and inhibiting protein kinase B (Akt) phosphorylation. Across diverse preclinical CNS injury models, inhibition of LINGO-1 promotes neuroaxonal and oligodendrocyte survival, oligodendrocyte differentiation, remyelination, and functional recovery. BIIB033, the first anti-LINGO-1 antibody to enter clinical development, is a fully human, IgG1 monoclonal antibody engineered to have reduced effector functions. Two Phase 1 studies have been completed, a single ascending-dose study in healthy human volunteers and a multiple dose study in subjects with relapsing remitting or secondary progressive MS. They revealed satisfactory safety and tolerability of 1 or 2 doses and linear pharmacodynamics properties with half-life of 2-3 weeks. Two Phase 2 efficacy and safety studies in subjects with first episode of acute optic neuritis (RENEW) and subjects with active relapsing remitting or secondary progressive MS (SYNERGY) are ongoing. LINGO-1 antagonism with BIIB033 presents a novel therapeutic approach for the treatment of CNS diseases.

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