Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

References

• Johnston S, Brenu EW, Staines DR, et al. The adoption of chronic fatigue syndrome/myalgic encephalomyelitis case definitions to assess prevalence: a systematic review. Ann Epidemiol. 2013;23:371–376.
   PubMed Web of Science ®Google Scholar
• Jason LA, Benton MC, Valentine L, et al. The economic impact of ME/CFS: individual and societal costs. Dyn Med. 2008;7:6. doi:10.1186/1476-5918-7-6.
   PubMedGoogle Scholar
• Jason LA, Corradi K, Gress S, et al. Causes of death among patients with chronic fatigue syndrome. Health Care Women Int. 2006;27:615–626.
   PubMedGoogle Scholar
• Komaroff AL, Buchwald DS. Chronic fatigue syndrome: an update. Annu Rev Med. 1998;49:1–13.
   PubMed Web of Science ®Google Scholar
• Komaroff AL. Is human herpesvirus-6 a trigger for chronic fatigue syndrome? J Clin Virol. 2006;37(Suppl 1):S39–S46.
   PubMedGoogle Scholar
• Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry. 2003;60:221–236.
   Web of Science ®Google Scholar
• Poeschla B, Strachan E, Dansie E, et al. Chronic fatigue and personality: a twin study of causal pathways and shared liabilities. Ann Behav Med. 2013;45:289–298.
   PubMed Web of Science ®Google Scholar
• Devanur LD, Kerr JR. Chronic fatigue syndrome. J Clin Virol. 2006;37:139–150.
   PubMed Web of Science ®Google Scholar
• Kerr JR, Petty R, Burke B, et al. Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Infect Dis. 2008;197:1171–1184.
   PubMed Web of Science ®Google Scholar
• Kerr JR, Burke B, Petty R, et al. Seven genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: a detailed analysis of gene networks and clinical phenotypes. J Clin Pathol. 2008;61:730–739.
   PubMed Web of Science ®Google Scholar
• Hornig M, Montoya JG, Klimas NG, et al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. 2015 Feb;1(1):e1400121.
   PubMed Web of Science ®Google Scholar
• [ cited 2015 Dec 21]. Available from: http://www.nytimes.com/health/guides/disease/chronic-fatigue-syndrome/medications.html
   Google Scholar
• Ts’o PO, Alderfer JL, Levy J, et al. An integrated and comparative study of the antiviral effects and other biological properties of the polyinosinic acid-polycytidylic acid and its mismatched analogues. Mol Pharmacol. 1976;12:299–312.
   PubMed Web of Science ®Google Scholar
• Alexopoulou L, Holt AC, Medzhitov R, et al. Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3. Nature. 2001;413:732–738.
   PubMed Web of Science ®Google Scholar
• Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5:987–995.
   PubMed Web of Science ®Google Scholar
• Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–252.
   PubMed Web of Science ®Google Scholar
• Bagchi A, Herrup EA, Warren HS, et al. MyD88-dependent and myD88-independent pathways in synergy, priming, and tolerance between TLR agonists. J Immunol. 2007;178:1164–1171.
   PubMed Web of Science ®Google Scholar
• Gowen BB, Wong MH, Jung KH, et al. TLR3 is essential for the induction of protective immunity against punta toro virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not poly(I:C): differential recognition of synthetic dsRNA molecules. J Immunol. 2007;178:5200–5208.
   PubMed Web of Science ®Google Scholar
• Trumpfheller C, Caskey M, Nchinda G, et al. The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci USA. 2008;105:2574–2579.
   PubMed Web of Science ®Google Scholar
• Mitchell WM, Nicodemus CF, Carter WA, et al. Discordant biological and toxicological species responses to TLR3 activation. Am J Path. 2014;184:1062–1072.
   PubMed Web of Science ®Google Scholar
• [ cited 2015 Oct 4]. Available from: http://www.nytimes.com/ref/health/healthguide/esn-chronicfatigue-ess.html
   Google Scholar
• [ cited 2015 Oct 4]. Available from: http://blogs.fda.gov/fdavoice/index.php/2013/06/fdas-latest-efforts-in-patient-focused-drug-development-now-in-full-swing/
   Google Scholar
• Salit IE. Precipitating factors for the chronic fatigue syndrome. J Psychiatr Res. 1997;31:59–65.
   PubMed Web of Science ®Google Scholar
• Strayer DR, Carter WA, Brodsky I, et al. A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. Clin Infect Dis. 1994;18(Suppl 1):S88–S95.
   PubMed Web of Science ®Google Scholar
• Strauss KI. Elimination and degradation of AMPLIGEN (poly I: polyC12U) in humans after intravenous infusion [Ph.D. thesis]. Philadelphia (PA): Hahnemann University; 1991.
   Google Scholar
• Strauss KI, Strayer DR, Gillespie DH. Detection of poly(I): poly(C12U),mismatched double-stranded RNA, by rapid solution hybridization: blood values after intravenous infusion. J Pharm Pharmacol. 1990;42:261–266.
   PubMed Web of Science ®Google Scholar
• Leonard JN, Ghirlando R, Askins J, et al. The TLR3 signaling complex forms by cooperative receptor dimerization. Proc Natl Acad Sci U S A. 2008;105:258–263.
   PubMed Web of Science ®Google Scholar
• Wang Y, Liu L, Davies DR, et al. Dimerization of toll-like receptor 3 (TLR3) is required for ligand binding. J Biol Chem. 2010;285:36836–36841.
   PubMed Web of Science ®Google Scholar
• Thompson MR, Kaminski JJ, Kurt-Jones EA, et al. Pattern recognition receptors and the innate immune response to viral infection. Viruses. 2011;3:920–940.
   PubMed Web of Science ®Google Scholar
• Muzio M, Bosisio D, Polentarutti N, et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol. 2000;164:5998–6004.
   PubMed Web of Science ®Google Scholar
• Kleinman ME. iRNA via TLR3. Nature. 2008;452:591–597.
   PubMed Web of Science ®Google Scholar
• Yu M. Levine SJ.Toll-like receptor, RIG-I-like receptors and the NLRP3 inflammasome: key modulators of innate immune responses to double-stranded RNA viruses. Cytokine Growth Factor Rev. 2011;22:63–72.
   PubMed Web of Science ®Google Scholar
• Pohar J, Pirher N, Benčina M, et al. The role of UNC93B1 protein in surface localization of TLR3 receptor and in cell priming to nucleic acid agonists. J Biol Chem. 2013;288:442–454.
   PubMed Web of Science ®Google Scholar
• Geiss G, Jin G, Guo J, et al. A comprehensive view of regulation of gene expression by double-stranded RNA-mediated cell signaling. J Biol Chem. 2001;276:30178–30182.
   PubMed Web of Science ®Google Scholar
• Luo J, Obmolova G, Malia TJ, et al. Lateral clustering of TLR3: dsRNAsignaling units revealed by TLR3ecd:3Fabs quaternary structure. J Mol Biol. 2012;421:112–124.
   PubMed Web of Science ®Google Scholar
• Jelinek I, Leonard JN, Price GE, et al. TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection. J Immunol. 2011;186:2422–2429.
   PubMed Web of Science ®Google Scholar
• Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;108:387–389.
   PubMed Web of Science ®Google Scholar
• Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953–959.
   PubMed Web of Science ®Google Scholar
• Carruthers BM, van de Sande MI, de Meirleir KL, et al. Myalgic encephalomyelitis: international consensus criteria. J Intern Med. 2011;270:327–338.
   PubMed Web of Science ®Google Scholar
• Clayton EW. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness. JAMA. 2015;313:1101–1102.
   PubMed Web of Science ®Google Scholar
• Strayer DR, Carter W, Strauss KI, et al. Long term improvements in patients with chronic fatigue syndrome treated with ampligen. J Chronic Fatigue Syn. 1995;1:35–53.
   Google Scholar
• Current Hemispherx Biopharma NDA submission documents.
   Google Scholar
• Strayer DR, Carter WA, Stouch BC, et al. A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. PLoS One. 2012;7(3):e31334. doi:10.1371/journal.pone.0031334
   PubMed Web of Science ®Google Scholar
• Strayer DR, Stouch BC, Stevens SR, et.al. Chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME): characteristics of responders to rintatolimod. J Drug Res Dev. 2015;1. doi:http://dx.doiorg/10.16966/jdrd.103.
   Google Scholar
• Vanness JM, Snell CR, Fredrickson DM, et al. Assessment of functional impairment by cardiopulmonary exercise testing in patients with chronic fatigue syndrome. J Chronic Fatigue Syndrome. 2001;8:103–109.
   Google Scholar
• Schutzer SE, Angel TE, Liu T, et al. Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome. PLoS One. 2011 Feb 23;6(2):e17287. doi:10.1371/journal.pone.0017287.
   PubMed Web of Science ®Google Scholar
• Hickie I, Davenport T, Wakefield D, et al. Infection outcomes study group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006; 333–575. .
   Google Scholar
• Chia JK, Chia LY. Chronic chlamydia pneumoniae infection: a treatable cause of chronic fatigue syndrome. Clin Infect Dis. 1999;29:452–453.
   PubMed Web of Science ®Google Scholar
• Kerr JR, Cunniffe VS, Kelleher P, et al. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clin Infect Dis. 2003;36:100–106.
   PubMed Web of Science ®Google Scholar
• Kerr JR, Gough J, Richards SC, et al. Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Gen Virol. 2010;91:893–897.
   PubMed Web of Science ®Google Scholar
• Chia JK, Chia AY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol. 2008;61:43–48.
   PubMed Web of Science ®Google Scholar
• Vojdani A, Choppa PC, Tagle C, et al. Detection of mycoplasma genus and mycoplasma fermentans by PCR in patients with chronic fatigue syndrome. FEMS Immunol Med Microbiol. 1998;22:355–365.
   PubMed Web of Science ®Google Scholar
• Nijs J, Nicolson GL, De Becker P, et al. High prevalence of mycoplasma infections among European chronic fatigue syndrome patients. Examination of four mycoplasma species in blood of chronic fatigue syndrome patients. FEMS Immunol Med Microbiol. 2002;34:209–214.
   PubMed Web of Science ®Google Scholar
• DeFreitas E, Hilliard B, Cheney PR, et al. Retroviral sequences related to human T-?lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci USA. 1991;88:2922–2926.
   PubMed Web of Science ®Google Scholar
• Lombardi VC, Ruscetti FW, Das Gupta J, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009;326:585–589.
   PubMed Web of Science ®Google Scholar
• Lo SC, Pripuzova N, Li B, et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci USA. 2010;107:15874–15879.
   PubMed Web of Science ®Google Scholar
• Alter HJ, Mikovits JA, Switzer WM, et al. A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus. MBio. 2012;3(5).
   PubMed Web of Science ®Google Scholar
• Buchwald D, Cheney PR, Peterson DL, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med. 1992;116:103–113.
   PubMed Web of Science ®Google Scholar
• Josephs SF, Henry B, Balachandran N, et al. HHV-6 reactivation in chronic fatigue syndrome. Lancet. 1991;337:1346–1347.
   PubMed Web of Science ®Google Scholar
• Nicolson GL, Gan R, Haier J. Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. Apmis. 2003;111:557–566.
   PubMed Web of Science ®Google Scholar
• Barker E, Fujimura SF, Fadem MB, et al. Immunologic abnormalities associated with chronic fatigue syndrome. Clin Infect Dis. 1994;18(Suppl 1):S136–S141.
   PubMedGoogle Scholar
• Strayer D, Scott V, Carter W. Low NK cell activity in Chronic Fatigue Syndrome (CFS) and relationship to symptom severity. J Clin Cell Immunol. 2015;6:4.
   Google Scholar
• Suhadolnik RJ, Reichenbach NL, Hitzges P, et al. Upregulation of the 2-?5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis. 1994;18(Suppl 1):S96–S104.
   PubMedGoogle Scholar
• Suhadolnik RJ, Reichenbach NL, Hitzges P, et al. Changes in the 2-?5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome. In Vivo. 1994;8:599–604.
   PubMedGoogle Scholar
• Snell CR, Vanness JM, Strayer DR, et al. Physical performance and prediction of 2-?5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome. In Vivo. 2002;16:107–109.
   PubMed Web of Science ®Google Scholar
• Shetzline SE, Martinand-Mari C, Reichenbach NL, et al. Structural and functional features of the 37-kDa 2-?5A-dependent RNase L in chronic fatigue syndrome. J Interferon Cytokine Res. 2002;22:443–456.
   PubMed Web of Science ®Google Scholar
• Demettre E, Bastide L, D’Haese A, et al. Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients. J Biol Chem. 2002;277:35746–35751.
   PubMed Web of Science ®Google Scholar
• Frémont M, El Bakkouri K, Vaeyens F, et al. 2ʹ,5ʹ-oligoadenylate size is critical to protect RNase L against proteolytic cleavage in chronic fatigue syndrome. Exp Mol Pathol. 2005;78:239–246.
   PubMed Web of Science ®Google Scholar
• De Meirleir K, Bisbal C, Campine I, et al. A 37 kDa 2-?5A binding protein as a potential biochemical marker for chronic fatigue syndrome. Am J Med. 2000;108:99–105.
   PubMed Web of Science ®Google Scholar
• Frémont M, Vaeyens F, Herst CV, et al. 37-kilodalton/83-kilodalton RNase L isoform ratio in peripheral blood mononuclear cells: analytical performance and relevance for chronic fatigue syndrome. Clin Diagn Lab Immunol. 2005;12:1259–1260.
   PubMedGoogle Scholar
• Vernon SD, Unger ER, Dimulescu IM, et al. Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome. Dis Markers. 2002;18:193–199.
   PubMed Web of Science ®Google Scholar
• Whistler T, Unger ER, Nisenbaum R, et al. Integration of gene expression, clinical, and epidemiologic data to characterize chronic fatigue syndrome. J Transl Med. 2003;1:10.
   PubMedGoogle Scholar
• Whistler T, Jones JF, Unger ER, et al. Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects. BMC Physiol. 2005;5:5.
   PubMedGoogle Scholar
• Whistler T, Taylor R, Craddock RC, et al. Gene expression correlates of unexplained fatigue. Pharmacogenomics. 2006;7(3):395–405.
   PubMed Web of Science ®Google Scholar
• Carmel L, Efroni S, White PD, et al. Gene expression profile of empirically delineated classes of unexplained chronic fatigue. Pharmacogenomics. 2006;7:375–86.
   PubMed Web of Science ®Google Scholar
• Broderick G, Craddock RC, Whistler T, et al. Identifying illness parameters in fatiguing syndromes using classical projection methods. Pharmacogenomics. 2006;7:407–419.
   PubMed Web of Science ®Google Scholar
• Fang H, Xie Q, Boneva R, et al. Gene expression profile exploration of a large dataset on chronic fatigue syndrome. Pharmacogenomics. 2006;7(3):429–440.
   PubMed Web of Science ®Google Scholar
• Fostel J, Boneva R, Lloyd A. Exploration of the gene expression correlates of chronic unexplained fatigue using factor analysis. Pharmacogenomics. 2006;7:441–454.
   PubMed Web of Science ®Google Scholar
• Powell R, Ren J, Lewith G, et al. Identification of novel expressed sequences, up-regulated in the leucocytes of chronic fatigue syndrome patients. Clin Exp Allergy. 2003;33:1450–1456.
   PubMed Web of Science ®Google Scholar
• Gra¨ns H, Nilsson P. Evengard B gene expression profiling in the chronic fatigue syndrome. J Intern Med. 2005;258:388–390.
   PubMed Web of Science ®Google Scholar
• Gra¨ns H, Nilsson M, Dahlman-Wright K. Evenga° rd B reduced levels of oestrogen receptor beta mRNA in Swedish patients with chronic fatigue syndrome. J Clin Pathol. 2007;60:195–198.
   PubMed Web of Science ®Google Scholar
• Kerr JR, Burke B, Petty R, et al. Seven genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: a detailed analysis of gene networks and clinical phenotypes. J Clin Pathol. 2008;61:730–739.
   PubMed Web of Science ®Google Scholar
• Byrd MP, Zamora M, Lloyd RE. Translation of eukaryotic translation initiation factor 4GI (eIF4GI) proceeds from multiple mRNAs containing a novel cap-dependent internal ribosome entry site (IRES) that is active during poliovirus infection. J Biol Chem. 2005;280:18610–18622.
   PubMed Web of Science ®Google Scholar
• Zhang L, Gough J, Christmas D, et al. Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis. J Clin Pathol. 2010;63:156–164.
   PubMed Web of Science ®Google Scholar
• Light AR, Bateman L, Jo D, et al. Gene expression alterations at baseline and following moderate exercise in patients with chronic fatigue syndrome and fibromyalgia syndrome. J Intern Med. 2012;271:64–81.
   PubMed Web of Science ®Google Scholar
• White AT, Light AR, Hughen RW, et al. Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls. Psychosom Med. 2012;74:46–54.
   PubMed Web of Science ®Google Scholar
• Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2:1–16.
   PubMed Web of Science ®Google Scholar
• Behan WM, More IA, Behan PO. Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol. 1991;83:61–65.
   PubMed Web of Science ®Google Scholar
• Fulle S, Mecocci P, Fanó G, et al. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med. 2000;29:1252–1259.
   PubMed Web of Science ®Google Scholar
• Kuratsune H, Yamaguti K, Takahashi M, et al. Acylcarnitine deficiency in chronic fatigue syndrome. Clin Infect Dis. 1994;18(Suppl 1):S62–S67.
   PubMedGoogle Scholar
• Plioplys AV, Plioplys S. Serum levels of carnitine in chronic fatigue syndrome: clinical correlates. Neuropsychobiology. 1995;32:132–138.
   PubMed Web of Science ®Google Scholar
• Zhang C, Baumer A, Mackay IR, et al. Unusual pattern of mitochondrial DNA deletions in skeletal muscle of an adult human with chronic fatigue syndrome. Hum Mol Genet. 1995;4:751–754.
   PubMed Web of Science ®Google Scholar
• Vecchiet L, Montanari G, Pizzigallo E, et al. Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome. Neurosci Lett. 1996 19;208:117–120.
   PubMed Web of Science ®Google Scholar
• Arnold DL, Bore PJ, Radda GK, et al. Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion/fatigue syndrome. A 31P nuclear magnetic resonance study. Lancet. 1984;1:1367–1369.
   PubMed Web of Science ®Google Scholar
• McCully KK, Natelson BH, Iotti S, et al. Reduced oxidative muscle metabolism in chronic fatigue syndrome. Muscle Nerve. 1996;19:621–625.
   PubMed Web of Science ®Google Scholar
• Wong R, Lopaschuk G, Zhu G, et al. Skeletal muscle metabolism in the chronic fatigue syndrome. In vivo assessment by 31P nuclear magnetic resonance spectroscopy. Chest. 1992;102:1716–1722.
   PubMed Web of Science ®Google Scholar
• Carter WA, Strayer DR. Double-stranded ribonucleic acids with rugged physico-chemical structure and highly specific biologic activity. US 8722874 B2: Filing date 3/31/2011/ Award May 13, 2014.
   Google Scholar