Michel Geffard

Publications (12)25.39 Total impact

• Article: GEMSP: a new therapeutic approach to multiple sclerosis.

  Michel Geffard, Sebastien Duleu, Alban Bessede, Valerie Vigier, Dominique Bodet, Arturo Mangas, Rafael Covenas
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  ABSTRACT: A new therapeutic approach called Endotherapia (GEMSP) for the treatment of Multiple Sclerosis (MS) is suggested. Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self-antigens modified by free radicals. GEMSP is a "tailor-made" combination of small molecules (fatty acids, antioxidants, radical scavengers, amino acids) linked to a non-immunogenic linear chain of poly-L.lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. GEMSP inhibits brain leukocyte infiltration and abolishes episodes of experimental autoimmune encephalomyelitis. In a clinical trial with 102 MS patients treated with GEMSP Endotherapia, 28% of them showed a worsening of their state; 20% showed a decrease in the progression of the disease; 17% showed disease stabilization; and 35% showed a reversal of the evolution of disease; i.e., an improvement in their disease state. In 72% of the cases, a positive evolution of the state of the MS patients treated with Endotherapia was observed (a decrease or stabilization of disease evolution or an improvement). Endotherapia is very safe and no side-effects were reported for GEMSP. Moreover, GEMSP showed no toxicity either in experimental animals or in humans. It seems that Endotherapia is a promising therapy for MS, with no side-effects, which should be considered in the management of long-term pathologies.
  Central Nervous System Agents in Medicinal Chemistry(Formerly Current Medicinal Chemistry - Central Nervous System Agents) 04/2012; 12(3):173-81.
• Article: In utero and early-life exposure of rats to a Wi-Fi signal: screening of immune markers in sera and gestational outcome.

  Saliha Aït-Aïssa, Bernard Billaudel, Florence Poulletier de Gannes, Gilles Ruffié, Sébastien Duleu, Annabelle Hurtier, Emmanuelle Haro, Murielle Taxile, Axel Athané, Michel Geffard, Tongning Wu, Joe Wiart, Dominique Bodet, Bernard Veyret, Isabelle Lagroye
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  ABSTRACT: An experimental approach was used to assess immunological biomarkers in the sera of young rats exposed in utero and postnatal to non-ionizing radiofrequency fields. Pregnant rats were exposed free-running, 2 h/day and 5 days/week to a 2.45 GHz Wi-Fi signal in a reverberation chamber at whole-body specific absorption rates (SAR) of 0, 0.08, 0.4, and 4 W/kg (with 10, 10, 12, and 9 rats, respectively), while cage control rats were kept in the animal facility (11 rats). Dams were exposed from days 6 to 21 of gestation and then three newborns per litter were further exposed from birth to day 35 postnatal. On day 35 after birth, all pups were sacrificed and sera collected. The screening of sera for antibodies directed against 15 different antigens related to damage and/or pathological markers was conducted using enzyme-linked immunosorbent assay (ELISA). No change in humoral response of young pups was observed, regardless of the types of biomarker and SAR levels. This study also provided some data on gestational outcome following in utero exposure to Wi-Fi signals. Mass evaluation of dams and pups and the number of pups per litter was monitored, and the genital tracts of young rats were observed for abnormalities by measuring anogenital distance. Under these experimental conditions, our observations suggest a lack of adverse effects of Wi-Fi exposure on delivery and general condition of the animals.
  Bioelectromagnetics 01/2012; 33(5):410-20. · 1.84 Impact Factor
• Article: Frontiers in vitamin research: new antibodies, new data.

  Rafael Coveñas, Arturo Mangas, Dominique Bodet, Sébastien Duleu, Pilar Marcos, Begum Karakas, Michel Geffard
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  ABSTRACT: Since 2004, the anatomical distribution of vitamins in the monkey brain, studied using immunohistochemical techniques and new tools (specific antisera that discriminate different vitamins reasonably well), has been an ongoing research field. The visualization of immunoreactive structures containing vitamins (folic acid, riboflavin, thiamine, pyridoxal, and vitamin C) has recently been reported in the monkey brain (Macaca fascicularis), all these vitamins showing a restricted or very restricted distribution. Folic acid, thiamine, and riboflavin have only been observed in immunoreactive fibers, vitamin C has only been found in cell bodies (located in the primary somatosensory cortex), and pyridoxal has been found in both fibers and cell bodies. Perikarya containing pyridoxal have been observed in the paraventricular hypothalamic nucleus, the periventricular hypothalamic region, and in the supraoptic nucleus. The fibers containing vitamins are thick, smooth (without varicosities), and are of medium length or long, whereas immunoreactive cell bodies containing vitamins are round or triangular. At present, there are insufficient data to elucidate the roles played by vitamins in the brain, but the anatomical distribution of these compounds in the monkey brain provides a general idea (although imprecise and requiring much more study) about the possible functional implications of these molecules. In this sense, here the possible functional roles played by vitamins are discussed.
  TheScientificWorldJOURNAL 01/2011; 11:1226-42. · 1.66 Impact Factor
• Article: Endotherapia: a new frontier in the treatment of multiple sclerosis and other chronic diseases.

  Michel Geffard, Laetitia de Bisschop, Sébastien Duleu, Nadine Hassaine, Arturo Mangas, Rafael Coveñas
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  ABSTRACT: Currently, several drugs are accessible for the treatment of many chronic diseases (multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, etc.), but most of them have a large list of side effects. Here, we propose a new therapeutic approach called Endotherapia for the treatment of chronic diseases. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self-antigens modified by free radicals. The therapy proposed here is a "tailor-made" combination of small molecules (e.g., fatty acids and vitamins) linked to a non-immunogenic chain of poly-L.Lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. Endotherapia also involves clinical aspects, allowing an exact diagnosis of the disease and the identification of specific circulating antibodies in the serum of patients in several clinical trials (e.g., multiple sclerosis). Endotherapia has been shown to be very safe. In summary, Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. In light of the results obtained, it seems that Endotherapia is a promising therapy for chronic diseases, with no side effects, which is evidently mandatory in the management of long-term pathologies.
  Discovery medicine 11/2010; 10(54):443-51.
• Article: New drug therapies for multiple sclerosis.

  Arturo Mangas, Rafael Coveñas, Michel Geffard
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  ABSTRACT: Multiple sclerosis (MS) is an autoimmune and inflammatory disease of the central nervous system (CNS) that causes neurological disability in young adults and that to date has no cure. Until now, expensive and only partially efficacious therapies have become available. For this reason, researchers, clinicians and pharmaceutical companies are currently investigating new drugs for the treatment of MS. Here, we review the most recent data on drug candidates for MS. In the preclinical phase, such drug candidates have shown a beneficial effect on the onset of experimental autoimmune encephalomyelitis (microtubule-stabilizing drugs, MS14, Lithium, GEMSP...), a decrease in CNS cell infiltrates (recombinant T cell receptor ligand, lovastatin-rolipram, ribavirin, GEMSP...), prevention of demyelination (lovastatin-rolipram, calpain inhibitor, lithium...); and a reduction of axonal loss (phenytoin, lovastatin-rolipram, calpain inhibitor). In clinical trials, drug candidates against MS have shown safety (rituximab, ustekinumab, intravenous immunoglobulin, laquinimod, BHT-3009, fumarate, chaperonin 10, GEMSP...), an improvement of gadolinium-enhanced lesions (protiramer, fingolimod, laquinimod, BHT-3009, fumarate, daclizumab...), and an improvement of the relapse rate (fingolimod, fumarate...). Future research into MS should focus on a combination of therapies and on the development of drugs directed against the remitting and progressive phases of the disease. In this sense, MS is a very complex multifactorial disease that requires treatment able to cover all the aspects of MS and not only the anti-inflammatory aspect.
  Current opinion in neurology 04/2010; 23(3):287-92. · 5.43 Impact Factor
• Article: A new drug candidate (GEMSP) for multiple sclerosis.

  Arturo Mangas, Rafael Coveñas, Dominique Bodet, Sebastien Duleu, Michel Geffard
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  ABSTRACT: GEMSP is a mixture of functional polypeptides: fatty acids linked to poly-L-Lysine (PL), antioxidants linked to PL, free radical scavengers linked to PL, and amino acids linked to PL (patent numbers 6114388 (USA) and 792167 (EU)). In this review, we update the data on this new drug reported in the literature. There is evidence suggesting that GEMSP is a good candidate for the treatment of multiple sclerosis (MS), an inflammatory and neurodegenerative disease of the central nervous system characterized by focal leukocyte inflammation, demyelization and axonal degeneration, resulting in nerve cell dysfunction. Experimental autoimmune encephalomyelitis (EAE) is the main animal model used in the study of MS, a T cell-mediated autoimmune disease of the central nervous system. EAE has many clinical and histopathological similarities to MS. In this model, preclinical studies on GEMSP have demonstrated that the drug strongly inhibits brain leukocyte infiltration and completely abolishes EAE episodes and clinical scores, and it also appears that GEMSP preserves myelin integrity. In general, treatment with the free constituents of GEMSP (not linked to the inert carrier protein) is poorly active against brain leukocyte infiltration in EAE-immunized animals. This means that free molecules (not linked to PL) exert a very poor action on such infiltration and that these molecules are either rapidly incorporated into the metabolism or are degraded. Moreover, with immunocytochemical techniques, it has been demonstrated that one component of GEMSP, the methionine compound, is stored inside the motoneurons of the ventral horn of the spinal cord. However, this component of GEMSP has not been found in the brain. The new candidate for MS therapy has shown no toxicity either in experimental animals or in humans. An open clinical trial in humans has demonstrated that GEMSP is completely safe. In addition, the approved drugs for the treatment of MS exert marked side effects, but no side effects have been reported following the administration of GEMSP. The results obtained at six months of treatment with low doses of GEMSP (0.75 mg/day) in that open clinical trial in humans were as follows: 55% of the patients maintained a stable expanded disability status scale (EDSS) value and 18% of the patients had a decreased EDSS value instead of a normal progression of 0.25 point on the mean EDSS scale. We focus our review on the following topics: 1) EAE models and clinical evaluation; 2) the synthesis of GEMSP; 3) the effects of GEMSP dosage on EAE; 4) the effects of GEMSP on brain leukocyte infiltration; 5) GEMSP inside motoneurons; 6) the role of the components of GEMSP; and 7) GEMSP in MS patients, GEMSP toxicity, and side effects. In conclusion, all the data reported indicate that GEMSP is a new potential drug candidate for the treatment of MS.
  Current Medicinal Chemistry 10/2009; 16(25):3203-14. · 4.86 Impact Factor
• Article: Circulating antibodies directed against "polycyclic aromatic hydrocarbon-like" structures in the sera of cancer patients.

  Olivier Pouns, Arturo Mangas, Rafael Coveñas, Michel Geffard
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  ABSTRACT: An increase in immunoglobulin (Ig) A isotype directed against benzo(a)pyrene (BP) structure has previously been described in sera of cancer patients. In this study, new polycyclic aromatic hydrocarbon (PAH) conjugates were synthesized in order to more closely mimic the endogenous ligands of the cytosolic aryl hydrocarbon receptor (AhR). PAH [benzo(a)pyrene; 1,2-benzanthracene; dibenz[a,c]anthracene; 7,12-dimethylbenza[a]anthracene; benzo(ghi)perylene] were bound to protein carriers such as bovine serum albumin (BSA) via N-acetyl-cysteine (NAC). The levels of circulating antibodies (Abs) directed against PAH-NAC conjugates in the sera of cancer patients were evaluated using an Enzyme-Linked Immunosorbent Assay (ELISA) with these new conjugates. The avidity (IC(50)) and specificity of these circulating Abs were assessed via competition experiments. An increase in Ig directed against these PAH-NAC conjugates was found in the sera of cancer patients, irrespective of the state and stage of the tumors. These Ig were principally of the A isotype. Sera from cancer patients had significantly higher optical density (OD) ranges than the controls, p<0.0001. The ELISA test for breast cancer (n=155) and ovarian cancer (n=62) identified 82% and 92% of positive patients, respectively. The percentage positive in the control group (n=60) was around 5%. Moreover, competition experiments with the different PAH-NAC conjugates and NAC-BSA revealed an estimated avidity of 10(-6)M for the circulating IgA antibodies. The Abs discriminated between the different PAH-NAC conjugates and NAC-BSA. Therefore, these Abs recognize a carcinogenic PAH-NAC structure and not only a BP structure. These markers may be useful in the future for monitoring cancer evolution and recurrence.
  Cancer epidemiology. 08/2009; 33(1):3-8.
• Article: Amyotrophic lateral sclerosis (ALS) and extremely-low frequency (ELF) magnetic fields: a study in the SOD-1 transgenic mouse model.

  Florence Poulletier de Gannes, Gilles Ruffié, Murielle Taxile, Elodie Ladevèze, Annabelle Hurtier, Emmanuelle Haro, Sébastien Duleu, Renaud Charlet de Sauvage, Bernard Billaudel, Michel Geffard, Bernard Veyret, Isabelle Lagroye
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  ABSTRACT: There is some evidence from epidemiological studies of an association between occupational exposure to electromagnetic fields and Amyotrophic Lateral Sclerosis (ALS). Our aim was to perform, for the first time, an animal study in a controlled magnetic environment. We used the SOD-1 mouse model to assess the possible effect of ELF magnetic fields on development of the disease. Seven mice per group were exposed to 50 Hz magnetic fields at two intensities (100 and 1000 microT(rms)) before the onset of the clinical signs of ALS. Exposure lasted 7 weeks, and body weight, motor performance and life span were monitored. Our results did not reveal any evidence of a link between ELF exposure and ALS in this transgenic animal model.
  Amyotrophic Lateral Sclerosis 01/2009; 10(5-6):370-3. · 3.40 Impact Factor
• Article: Gemals, a new drug candidate, extends lifespan and improves electromyographic parameters in a rat model of amyotrophic lateral sclerosis.

  Charles Nicaise, Jerome Coupier, Marie-Pierre Dabadie, Robert De Decker, Arturo Mangas, Dominique Bodet, Luc Poncelet, Michel Geffard, Roland Pochet
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  ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal disease involving selective and progressive degeneration and death of motor neurons. ALS is a multifactorial disease in which oxidative stress, glutamate excitotoxicity, intracellular aggregates, neurofilamentous disorganization, zinc excitotoxicity, mitochondrial damage, neuroinflammation, abnormalities in growth factors and apoptosis play a role. Any therapeutic approach to delay or stop the evolution of ALS should therefore ideally target these multiple pathways leading to motor neuron death. We have developed a combination therapy (Gemals) composed of functional polypeptides (fatty acids, free radical scavengers and amino acids linked to poly-L-lysine), chosen according to their known potentiality for regeneration or protection of neuronal components such as myelin, axon transport and mitochondria. We found that Gemals significantly extended lifespan and improved electromyographic parameters in a SOD1(G93A) rat model. The use of two drug concentrations indicated a possible dose dependence. These initial findings open the way to further investigation necessary to validate this new drug as a candidate for ALS treatment.
  Amyotrophic Lateral Sclerosis 05/2008; 9(2):85-90. · 3.40 Impact Factor
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  Available from: Bernard Veyret

  Article: Evidence for nitric oxide involvement in experimental autoimmune encephalomyelitis and adjuvant-induced arthritis in Lewis rat

  Sanie Mnaimneh, Mona Damaj, Rola Barhoumi, Youssef Mouneimne, Michel Geffard, Bernard Veyret, Philippe Vincendeau
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  ABSTRACT: Nitric oxide (NO) has been implicated as an important pathogenic mediator in several inflammatory and autoimmune diseases. We have developed experimental autoimmune encephalomyelitis (EAE) and adjuvant-induced arthritis in the Lewis rat as experimental models for multiple sclerosis, and rheumatoid arthritis, respectively, in order to investigate the role of NO in the inflammatory process. We have used the monoclonal antibody anti-NO-cysteine (Cys)-G-bovine serum albumin (BSA) developed in our laboratory as an inhibitor of the toxic effect of NO to determine the implication of NO in the creation of neoepitopes and therefore in the symptomatology of these two diseases. In addition, we have detected a significant level of circulating endogenous antibodies directed against nitrosylated and nitrated epitopes in the sera of preimmunized rats. Our data demonstrate the ability of the monoclonal anti-NO-Cys-G-BSA antibody to modulate these diseases through NO neutralization, and further provide evidence for the in vivo synthesis of nitrosylated and nitrated neoepitopes that are stable enough to be highly immunogenic, thereby inducing inflammatory injuries and a humoral immune response. Our findings provide further evidence for the implication of the NO pathway in the pathogenesis of EAE and adjuvant-induced arthritis.
  The Pain Clinic 07/2004; 16(3):229-243.
• Article: Effects of GSM-900 microwaves on DMBA-induced mammary gland tumors in female Sprague-Dawley rats.

  Rachid Anane, Pierre-Emmanuel Dulou, Murielle Taxile, Michel Geffard, François-Lucien Crespeau, Bernard Veyret
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  ABSTRACT: The aim of this investigation was to test the hypothesis that sub-chronic whole-body exposure to GSM-900 microwaves had an effect on tumor promotion and progression. Mammary tumors were induced by ingestion of a single 10-mg dose of 7,12-dimethylbenz(a)anthracene (DMBA) in female Sprague-Dawley rats (Ico:OFA-SD; IOPS Caw). In two independent experiments, DMBA-treated animals were divided into four groups: sham-exposed (16) and exposed (three groups of 16 animals). The specific absorption rates (SARs), averaged over the whole body, were 3.5, 2.2 and 1.4 W/kg in the first experiment (May-July) and 1.4, 0.7 and 0.1 W/kg in the second experiment (September-November). Exposure started 10 days after DMBA treatment and lasted 2 h/day, 5 days/week for 9 weeks. Animals were exposed to plane waves with the electric field parallel to the long axis of the animals. Body weight and the number, location and size of the tumors were recorded at regular intervals. Rats were killed humanely 3 weeks after the end of exposure. The results are negative in terms of latency, multiplicity and tumor volume. With regard to tumor incidence, in the first experiment there was an increase in the rate of incidence at 1.4 W/kg but less at 2.2 W/kg and none at 3.5 W/kg. Overall, these results, which are rather inconsistent, do not bring new evidence of a co-promoting effect of exposure to GSM-900 signals using the DMBA rat model.
  Radiation Research 11/2003; 160(4):492-7. · 2.68 Impact Factor
• Article: Circulating antibodies directed against nitrosylated antigens in trypanosome-infected mice.

  Sanie Mnaimneh, Mona Damaj, Rola Barhoumi, Youssef Mouneimne, Bernard Veyret, Michel Geffard, Philippe Vincendeau
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  ABSTRACT: Nitric oxide has been implicated as an effector cytotoxic molecule in trypanosomiasis. In this work, we investigated the presence of circulating antibodies directed against nitrosylated epitopes as biological indicators for nitric oxide (NO) production in the sera of trypanosome-infected mice. We tested these sera with synthetic antigens, such as S-nitrosated protein or nitrosylated conjugates of amino acids that possess a high affinity to NO, by an immunoenzymatic assay. We detected antibodies directed against nitroso epitopes in the sera of infected mice, as compared to non-infected control mice. The antibody response was linked to the IgM isotype. Our results indicate the production of NO and its derivatives in trypanosomiasis. This production may potentially induce the synthesis of nitroso epitopes in vivo and favor the development of a humoral immune response.
  Experimental Parasitology 105(3-4):241-7. · 2.12 Impact Factor