Matthew Meriggioli

Objective: To describe STRONG, a multicenter, open-label, phase 1 study (NCT03381729) of the safety, tolerability, optimal dose, and efficacy of onasemnogene abeparvovec (AVXS-101) in patients with SMA2. Background: SMA is a rapidly progressing neurodegenerative disease causing loss of motor and respiratory function. The genetic root cause is bi-allelic deletion/mutation of the survival motor neuron 1 gene (SMN1). Disease severity is modified by SMN2 copy number. AVXS-101 comprises an adeno-associated virus serotype 9-encapsulated transcript of human SMN that crosses the blood-brain barrier. In a phase 1 study (NCT02122952) in patients with SMA1, intravenous AVXS-101 demonstrated unprecedented improvements in survival, motor function, and motor milestone achievement Design/Methods: In STRONG, SMA2 patients (bi-allelic SMN1 mutations/deletions, 3 copies of SMN2) who could sit but not stand or walk independently were enrolled in 2 cohorts by age (cohort 1: ≥6 to Results: As of October 12, 2018, 28 patients have been enrolled at 11 sites. Enrollment is complete. To date, no safety or tolerability concerns have been identified. A study update will be provided. Conclusions: Results from STRONG show intrathecal delivery of AVXS-101 in infants is feasible and well tolerated, with no safety concerns to date, and may support AVXS-101 as a promising treatment option for patients with SMA2. Disclosure: Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Novartis, and Roche. Dr. Finkel has received royalty, license fees, or contractual rights payments from Licensing fees from Children’s Hospital of Philadelphia for development of the CHOP-INTEND motor scale. Dr. Finkel has received research support from Ionis Pharmaceuticals, Inc. and Biogen, grants from AveXis and Cytokinetics. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, and Sarepta. Dr. Day has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, and Sarepta. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation, CureSMA, Ionis Pharmaceuticals, Inc., Biogen, AveXis, Cytokinetics, Fibrogen, PTC Therapeutics, Roche, Santhera, Sarepta, and Summit. Dr. Kuntz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Audentes, AveXis, Catalyst, Cytokinetics, Marathon, PTC Therapeutics, and Sarepta Therapeutics. Dr. Kuntz has received research support from AveXis, Audentes, Biogen, Pfizer, Roche and Sarepta Therapeutics. Dr. Connolly has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Sarepta, Astelles, Marathon, Accelleron, Roche, (advisory boards) and Catabasis (DMSB). Dr. Connolly has received research support from Clinical trial site PI for Avexis, Sarepta, Biogen, Cytokinetics, NS Pharma, Pfizer, Roche, Italfarmaco, Fibrogen, and Capricor. Dr. Crawford has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Muscular Dystrophy Association, Novartis, Roche, Sarepta, Scholar Rock, and the Spinal Muscular Atrophy Foundation. Dr. Butterfield has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta Therapeutics and Biogen. Dr. Butterfield has received research support from PTC Therapeutics, Sarepta Therapeutics, Pfizer, and, Biogen. Dr. Shieh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, AveXis, Inc., Biogen, Grifols, PTC Therapeutics and Sarepta. Dr. Shieh has received research support from AveXis, Inc., Audentes, Biogen, Bristol-Myers Squibb, Cytokinetics, Catalyst, Fibrogen, Ionis Pharmaceuticals, Inc., Marathon, Pfizer, PTC Therapeutics, Sarepta, Santhera, Summit, Sanofi/Genzyme and Ultragenyx. Dr. Tennekoon has received research support from Catabasis Pharmaceuticals. Dr. Iannaccone has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Biogen, Sarepta, Capricor. Dr. Iannaccone has received research support from AveXis, Biogen,…

Objective: To investigate the functionality of circulating immune cells in ALS patients. Background Amyotrophic lateral sclerosis (ALS) axonal pathology precedes motoneuron degeneration during disease progression in patients and the mSOD1 mouse model. We and others have shown that a functional immune system is neuroprotective in mSOD1 mice, enhancing survival and promoting facial motoneuron (FMN) survival levels after axotomy. Increased levels of FMN loss after axotomy were seen in immunodeficient mice, but wildtype levels of FMN survival could be restored by adoptively transferring wildtype splenocytes or CD4+ T cells prior to axotomy. Interestingly, the adoptive transfer of mSOD1 whole splenocytes did not rescue axotomy-induced FMN death in immunodeficient mice, but isolated CD4 + T cells (from the splenocyte population) effectively mediated neuroprotection to similar levels as wildtype CD4 + T cells, suggesting that the defect in immune neuroprotection was NOT explained by a functional defect in CD4 + T cells. Previous studies examining the peripheral immune compartment in ALS patients have yielded varied results regarding levels/function of CD4 + T cells. Based on the results above, we hypothesize that the peripheral immune microenvironment in ALS activates CD4 + T cells early on, but the neuroprotective effects of certain T cell subsets are subsequently inhibited by non-Tcell components of the immune system. Design/Methods: In vitro T cell proliferation assays were utilized to assess the function of ALS T cell subsets activated with anti-CD3 stimulation and compared to controls. Results: ALS CD4 + T cell subsets maintain their functional and proliferative capabilities when removed from the ALS microenvironment and activated polyclonally. No differences in T regulatory cell function or FoxP3 expression were detected in ALS samples compared to controls. Conclusions: ALS CD4 + T cells function normally in response to polyclonal stimulation in vitro , suggesting that other components of the ALS immune system (B cells, dendritic cells, or macrophages) underlie the defect in neuroprotective CD4 + T cell functionality. Supported by: The ALS Association (JR). Disclosure: Dr. Mesnard has nothing to disclose. Dr. Muthusamy has nothing to disclose. Dr. Xin has nothing to disclose. Dr. Sheng has nothing to disclose. Dr. Jones has received research support from Veterans Affairs, the National Institutes of Health, and the Les Turneer ALS Foundation. Dr. Prabhakar has received personal compensation for activities with Gliknik Inc. as a consultant.Dr. Prabhakar has received research support from NIH. Dr. Rowin has nothing to disclose. Dr. Meriggioli has received personal compensation for activities with Athena Diagnostics, Talecris Biotherapeutics, Gliknik, and Celegene Corporation. Dr. Meriggioli receives patent payments for a patent on bispecific antibody coated dendritic cells. Dr. Meriggioli has received research support from the NIH/NINDS and the Muscular Dystrophy Association.

A-waves are generally considered a nonspecific finding of unclear electrodiagnostic and clinical significance. We systematically identified A-waves during routine F-wave studies and defined them as supramaximally elicited reproducible intermediate to late responses that are clearly separate from the M-responses. In patients with A-waves, we noted electrophysiologic diagnoses, the nerve in which the A-wave was identified, the presence of A-waves in multiple nerves, and A-wave morphology. In 54 of 1,258 studies performed, A-waves were present in one or more nerves. Electrophysiologic diagnoses in patients with A-waves included diffuse axonal neuropathy (11.5%), demyelinating neuropathy (66.7%), motor neuron disease (6.5%), radiculopathy (3.6%), mononeuropathy (3.9%), and normal (tibial nerve only) 0.7%. A-waves were abnormal when found in any nerve except the tibial nerve. They were particularly prevalent and present in multiple nerves in acquired and hereditary demyelinating neuropathies, and they more often had a complex morphology. We postulate that demyelination is the crucial underlying pathophysiologic correlate of the supramaximally stimulated A-wave.

Myasthenia gravis (MG) is an acquired autoimmune syndrome caused by the failure of neuromuscular transmission, which results from the binding of autoantibodies to proteins involved in signaling at the neuromuscular junction (NMJ). Although the precise origin of the immune response in MG is not known, it remains one of the better characterized autoimmune disorders, and serves as a paradigm not only for understanding autoimmunity but also for the study of the NMJ and ion channels. Earlier diagnosis and the availability of effective treatments have reduced the burden of high mortality and severe disability previously associated with myasthenia gravis. However, diagnosing the disease remains problematic and can be delayed because of its nonspecific and fluctuating symptoms. Furthermore, the management of MG is associated with considerable limitations. Treatment options in related myasthenic disorders are also inadequate. Present treatments for MG are either targeted toward symptoms or involve immunosuppressive therapies that have variable efficacy and that uniformly carry significant risk of infection or malignancy. Conventional treatments result in global, unfocused immunosuppression, rather than targeted inhibition of the autoreactive immune cells. Myasthenia gravis and other disorders of the NMJ are relatively rare and are often neglected by national health authorities and the pharmaceutical industry. Held every five years, the International Conference on Myasthenia Gravis and Related Disorders attracts thought leaders in the field and provides a venue for researchers and clinicians to exchange ideas, establish collaborations, and continue to move the field forward. The international conferences also provide forums for younger investigators to communicate their recent findings. The 12th International Conference on Myasthenia Gravis and Related Disorders was held on May 21–23, 2012 in New York City at the conference center at the New York Academy of Sciences. The meeting was cosponsored by the New York Academy of Sciences and the Myasthenia Gravis Foundation of America, with additional support provided by the NIH/NINDS/NCATS/ORD. Educational grants were received from Alexion Pharmaceuticals and BioMarin Pharmaceutical, Inc.; corporate sponsorships were received from CSL Behring, IBL International, KRONUS, Athena Diagnostics, and Terumo BCT. Nearly 300 scientists and clinicians from around the world attended the meeting. The plenary sessions included 50 presentations. Over 100 abstracts were presented during two poster sessions. The keynote address by Marinos C. Dalakas summarized the evolution of biologics and other novel approaches in the treatment of MG and other immune-mediated neuromuscular disorders. Other highlights included latest developments pertaining to the structure of the NMJ; defects in regulatory T cells; the discovery of low-density lipoprotein receptor-related protein 4 as

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Objective: To evaluate the safety, tolerability, and preliminary efficacy of BVS857 in spinal and bulbar muscular atrophy (SBMA). Background: SBMA is an X-linked neuromuscular disease caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. SBMA is characterized by progressive muscle weakness, atrophy, and fasciculations. Preclinical studies have shown amelioration of disease manifestations with activation of the insulin-like growth factor 1 (IGF-1) pathway. BVS857 is an IGF-1 mimetic; IGF-1 was modified to improve its pharmacological properties. Design/Methods: This study was a double-blind, placebo-controlled study of IGF-1 pathway activation with BVS857 in patients with genetically-confirmed SBMA. Safety and tolerability was first evaluated in Part A with 8 SBMA patients. In Part B, BVS857 was administered as weekly intravenous administration for 12 weeks with a 2:1 drug to placebo randomization in 27 patients. The primary outcome measures included s...

There are very limited data concerning the association of lymphocytic thyroiditis with cardiomyopathy, and there is only one published report of fatal cardiomyopathy associated with autoimmune thyroiditis. An association of Hashimoto encephalopathy (HE) with autoimmune myocarditis has not yet been reported. Here we describe a case of a 31-year-old man with autoimmune thyroiditis complicated by HE, who succumbed to autoimmune myocarditis. This association raises the possibility that HE and myocarditis may share a common pathogenetic mechanism in some cases.

In this study we describe a patient with a prolonged myasthenic crisis refractory to conventional immunomodulatory therapy who was treated with GM-CSF (granulocyte macrophage colony-stimulating factor, sargramostim). T-regulatory cell (Treg) suppressive function and Foxp3 expression were evaluated before and after treatment with GM-CSF. Treatment with GM-CSF was associated with clinical improvement, expansion in the circulating numbers of Foxp3(+) cells, increase in Foxp3 expression levels in Tregs, early improvement in Treg suppressive capacity for AChR-α-induced T-cell proliferation, and subsequent enhancement in Treg suppression of polyclonal T-cell proliferation. Although definitive conclusions cannot be drawn from a single case, the correlation with similar findings in GM-CSF-treated animals with experimental autoimmune myasthenia gravis suggests further exploration of the effects of GM-CSF in myasthenia gravis should be studied in a clinical trial setting.

L'invention concerne une signalisation pro-apoptotique par modulation vers le bas de KIAA0358 ou l'expression d'IG20-SV4, induisant efficacement une apoptose spontanee et une sensibilisation a une apoptose induite par TNF? dans des cellules de neuroblastome. L’invention concerne egalement des procedes et une composition pour ameliorer la mort cellulaire dans des neuroblastomes, ainsi que des procedes et des compositions pour reduire la mort cellulaire dans des troubles neurodegeneratifs.

ObjectiveTo determine the prevalence and clinical features of anti-HMGCR myopathy among patients with presumed limb-girdle muscular dystrophy (LGMD) in whom genetic testing has failed to elucidate causative mutations.MethodsPatients with presumed LGMD and unrevealing genetic testing were selected based on a few clinico-pathologic features and tested for anti-HMGCR autoantibodies (n = 11). These clinico-pathologic features are peak creatine kinase (CK) greater than 1,000 IU/L and at least 3 of the following features: (1) limb-girdle pattern of weakness, (2) selective involvement of posterior thigh on clinical examination or muscle imaging, (3) dystrophic changes on muscle biopsy, and (4) no family history of muscular dystrophy.ResultsSix patients tested positive for anti-HMGCR autoantibodies. In 4, there was a presymptomatic phase, lasting as long as 10 years, characterized by elevated CK levels without weakness. Muscle biopsies revealed variable degrees of a dystrophic pathology wit...

Monoclonal antibodies that target either PD-1 or PD-L1 have recently been approved for treatment of advanced non-small cell lung cancer. These antibodies are immune checkpoint inhibitors which have been shown to exacerbate Myasthenia Gravis (MG) and other autoimmune diseases. While effective in preventing tumor cells from evading immune attack, immune checkpoint inhibitors such as nivolumab, an antibody directed against the programmed cell death protein-1 (PD-1) receptor located on T-cells, may also cause immune dysregulation and could cause or potentiate pre-existing autoimmune conditions. We present a patient with latent ocular MG treated with nivolumab for her stage IV non-small cell lung cancer who developed generalized MG and severe myasthenic crisis. Providers must be aware of the risks inherent to these novel therapies since they can have life-threatening effects.

TED M. BURNS, MD, GORDON A. SMITH, MD, JEFFREY A. ALLEN, MD, ANTHONY A. AMATO, MD, W. DAVID ARNOLD, MD, RICHARD BAROHN, MD, MICHAEL BENATAR, MD, PhD, SHAWN J. BIRD, MD, MARK BROMBERG, MD, NIZAR CHAHIN, MD, EMMA CIAFALONI, MD, JEFFREY A. COHEN, MD, ANDREA CORSE, MD, BRIAN A. CRUM, MD, WILLIAM S. DAVID, MD, ELLIOT DIMBERG, MD, EDUARDO A. DE SOUSA, MD, PETER D. DONOFRIO, MD, P. JAMES B. DYCK, MD, ANDREW G. ENGEL, MD, ERIK R. ENSRUD, MD, MARK FERRANTE, MD, MIRIAM FREIMER, MD, KARISSA L. GABLE, MD, SUMMER GIBSON, MD, JAMES M. GILCHRIST, MD, JONATHAN M. GOLDSTEIN, MD, CLIFTON L. GOOCH, MD, BRENT P. GOODMAN, MD, DMITRI GORELOV, DO, SIDNEY M. GOSPE Jr., MD, PhD, NAMITA A. GOYAL, MD, AMANDA C. GUIDON, MD, JEFFREY T. GUPTILL, MD, LAURIE GUTMANN, MD, LUDWIG GUTMANN, MD, KELLY GWATHMEY, MD, YADOLLAH HARATI, MD, C. MICHEL HARPER Jr., MD, MICHAEL K. HEHIR, MD, LISA D. HOBSON-WEBB, MD, JAMES F. HOWARD Jr., MD, CARLAYNE E. JACKSON, MD, NICHOLAS JOHNSON, MD, SARAH M. JONES, MD, VERN C. JUEL, MD, HENRY J. KAMINSKI, MD, CHAFIC KARAM, MD, KATHLEEN D. KENNELLY, MD, PhD, SAMI KHELLA, MD, JULIE KHOURY, MD, JOHN C. KINCAID, MD, JOHN T. KISSEL, MD, NOAH KOLB, MD, DAVID LACOMIS, MD, SHAFEEQ LADHA, MD, DANIEL LARRIVIERE, MD, JD, RICHARD A. LEWIS, MD, YUEBING LI, MD, WILLIAM J. LITCHY, MD, ERIC LOGIGIAN, MD, JAU-SHIN LOU, MD, PhD, DANIEL J.L. MacGOWEN, MD, RICARDO MASELLI, MD, JANICE M. MASSEY, MD, MICHELLE L. MAUERMANN, MD, KATHERINE D. MATHEWS, MD, MATTHEW N. MERIGGIOLI, MD, ROBERT G. MILLER, MD, JOON-SHIK MOON, MD, PhD, TAHSEEN MOZAFFAR, MD, SHARON P. NATIONS, MD, RICHARD J. NOWAK, MD, LYLE W. OSTROW, MD, PhD, ROBERT M. PASCUZZI, MD, AMANDA PELTIER, MD, KATHERINE RUZHANSKY, MD, DAVID P. RICHMAN, MD, MARK A. ROSS, MD, DEVON I. RUBIN, MD, JAMES A. RUSSELL, DO, GEORGE M. SACHS, MD, PhD, MOHAMMAD KIAN SALAJEGHEH, MD, DAVID S. SAPERSTEIN, MD, STEPHEN SCELSA, MD, DUYGU SELCEN, MD, AZIZ SHAIBANI, MD, PERRY B. SHIEH, MD, NICHOLAS J. SILVESTRI, MD, J. ROB SINGLETON, MD, BENN E. SMITH, MD, YUEN T. SO, MD, PhD, GUILLERMO SOLORZANO, MD, ERIC J. SORENSON, MD, JAYASHRI SRINIVASEN, MD, JINNY TAVEE, MD, RABI TAWIL, MD, PARIWAT THAISETTHAWATKUL, MD, CHARLES THORNTON, MD, JAYA TRIVEDI, MD, STEVEN VERNINO, MD, PhD, ANNABEL K. WANG, MD, TYLER A. WEBB, MD, MICHAEL D. WEISS, MD, ANTHONY J. WINDEBANK, MD, and GIL I. WOLFE, MD

Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle-specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets.

17. Ruyssen-Witrand A, Rouanet S, Combe B, et al. Fcγ receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab. Ann RheumDis. 2012;71(6):875-877. 18. Nakashima I, Takahashi T, Cree BA, et al. Transient increases in anti-aquaporin-4 antibody titers following rituximab treatment in neuromyelitis optica, in association with elevated serum BAFF levels. J Clin Neurosci. 2011;18(7): 997-998.

The recommendations for clinical research standards published in 2000 by a task force of the Medical Sci-entific Advisory Board (MSAB) of the Myasthenia Gravis Foun-dation of America (MGFA) were largely successful in introducing greater uniformity in the recording and reporting of MG clinical trials. Recognizing that changes in clinical trial design and implementation may increase the likelihood that new therapies are developed for MG, the MGFA MSAB Task Force here presents updated recommendations for the design and implementation of clinical trials in MG, including (a) the use of a quantitative measure, such as the MG-Composite, that is weighted for clinical significance and incorporates patient reported outcomes; (b) consideration of nontrial strategies; and (c) development of biomarkers that support mechanistic studies of pharmacotherapies. The hope is that these updated task force recommendations will expedite the development and ac-ceptance of more effective and less noxious th...

Dendritic cells (DCs) have the potential to activate or tolerize T cells in an Ag-specific manner. Although the precise mechanism that determines whether DCs exhibit tolerogenic or immunogenic functions has not been precisely elucidated, growing evidence suggests that DC function is largely dependent on differentiation status, which can be manipulated using various growth factors. In this study, we investigated the effects of mobilization of specific DC subsets-using GM-CSF and fms-like tyrosine kinase receptor 3-ligand (Flt3-L)-on the susceptibility to induction of experimental autoimmune myasthenia gravis (EAMG). We administered GM-CSF or Flt3-L to C57BL/6 mice before immunization with acetylcholine receptor (AChR) and observed the effect on the frequency and severity of EAMG development. Compared with AChR-immunized controls, mice treated with Flt3-L before immunization developed EAMG at an accelerated pace initially, but disease frequency and severity was comparable at the end o...

Skeletal muscle weakness is a leading cause of mobility disability in the elderly (sarcopenia), as a complication of acute or chronic illness (cachexia), and due to inherited or acquired muscle diseases (muscular dystrophies, myositides, etc.). As of now, there are no approved drugs that can reliably increase muscle strength and function. However, with our understanding of the regulation of myocyte signaling and homeostasis evolving rapidly, experimental treatments are now entering the clinic. We review the current status of clinical research in pharmacological therapies for muscle disorders.

Autoimmune myasthenia gravis (MG) is a disorder of the neuromuscular junction caused in the majority of patients by autoantibodies directed against the postsynaptic nicotinic acetylcholine receptor (AChR). The classic clinical presentation of MG has been well characterized as fluctuating muscle weakness affecting particular muscle groups. Selective review of the literature relating to the pathogenesis, diagnosis, and treatment of anti-AChR-positive MG. Approximately 85% of patients with generalized MG and 50% of patients with purely ocular MG have anti-AChR antibodies. A number of clinical MG subtypes may be identified amongst those patients with anti-AChR antibodies, comprising early-onset MG (onset < or = 40 years), late-onset MG (onset after 40 years), thymoma-associated MG, and ocular MG. 'Low-affinity' anti-AChR antibodies may be found in 66% of patients with generalized MG who are negative for anti-AChR and anti-muscle-specific receptor tyrosine kinase antibodies by conventional assays. While pathologic changes in the thymus gland (hyperplasia and neoplasia) almost certainly play a role in the development of MG in patients with early-onset disease and thymomatous MG, the pathogenic role of the thymus remains to be determined in ocular MG, late-onset MG, and generalized MG with low-affinity anti-AChR antibodies. Autoimmune MG with AChR autoantibodies encompasses several disease subtypes defined by clinical presentation and thymic pathology. Treatment options include thymectomy, cholinesterase inhibitors, immunosuppressive drugs and plasma exchange or intravenous immunoglobulin, and are tailored according to the clinical presentation.