Hem Research, Inc.

Hemispherx Biopharma

Hem Pharmaceuticals Corporation

William A Carter

David Strayer

The invention relates to our discovery of a novel double-stranded ribonucleic acid (dsRNA) having specific biological activities, which includes acting as a selective agonist for activation of the Toll-like receptor 3. Its 'rugged' molecular structure as measured by physico-chemical techniques is resistant to molecular unfolding (i.e., denaturation). This structure appears to be responsible for increased efficacy of dsRNA in therapeutic applications and improved biological activity (e.g., used as an immunoregulatory agent). Medicaments, processes for their manufacture, and methods for their use are provided herein.

Double-stranded ribonucleic acids with rugged physico-chemical structure and highly specific biologic activity

A novel form of Rugged dsRNA with a unique composition and physical characteristics was identified with high specificity of binding to TLR3, which conveys an important range of therapeutic opportunities. Unlike the previous known antiviral Ampligen&#xae; (poly I, poly C12,U) the new and improved form (poly I, poly C,U) has a reduced tendency to form branched dsRNA which results in increased bioactivity due to an increased ability to bind TLR3 receptor. Pharmaceutical formulations containing the new nucleic acid as active ingredients and methods of treatment are also provided. The invention also provides a description of the physicochemical properties of this novel form of Rugged dsRNA and a method for its preparation in substantially pure form. DsRNAs acting thru TLR3 receptor activation are potent antiviral compounds as well as anticancer agents; also through secondary immunomodulation they can enhance the bioactivity of vaccines and also treat autoimmune disorders.

An antiviral/immunomodulatory response in an animal is induced by oral administration to an infected animal, including humans, of a human &#x3b1;-interferon. Methods of conferring resistance or mitigating the effects of exposure to a virus including avian influenza are described.

Broad spectrum immune and antiviral gene modulation by oral interferon

Vaccine protection against acute or chronic viral infection is facilitated by using as an adjuvant or immuno-stimulant, a dsRNA together with an anti-influenza vaccine.

dsRNAs as influenza virus vaccine adjuvants or immuno-stimulants

Severe acute respiratory syndrome is treated with a natural human alpha interferon, a dsRNA or both natural human alpha interferon and a dsRNA.

Treating severe acute respiratory syndrome

Virus infections promoting Chronic Fatigue can be diagnosed by assessing the 2'-5'A/RNase L pathway, including measurement of 2'-5'A oligonucleotide levels in the patient's circulating peripheral leucocytes, and comparing these resuls with those of healthy individuals. Double-stranded RNAs, notably mismatched dsRNAs, when administered in appropriate amounts, increase the 2'-5'A and normalize the antiviral pathway in patients with Chronic Fatigue Syndrome and improve the clinical symptoms.

Treating viral infections associated with chronic fatigue with dsRNA

The presence of neuro-cognitive disorders associated with systemic immunological malfunction are assessed in human patients by determining the level of intracellular RNase L in a sample of the patient's peripheral blood and comparing that level to predetermined levels of RNase L in healthy individuals. Aberrant RNase L levels as compared with those in healthy individuals indicate the presence of neuro-cognitive disorders associated with systemic immunological malfunction. This procedure is useful to distinguish systemic immunological malfunction from primary psychological or neuropsychiatric disorders presenting otherwise similar clinical symptoms.

Diagnosis and treatment of neuro-cognitive disorders associated with

Abnormalities in the circulating immune complexes in a patient's blood, such as observed in patients having inflammatory disorders, viral infections, or simply deranged immune function, are restored to normal or viral immunity conferred by the administration of a matched or mismatched dsRNA.

Treatment of hepatitis with mismatched dsRNA

Surfactant-stabilized ternary complexes of dsRNAs in topical pharmaceutical compositions, optionally also including a lymphokine and/or an inhibitor of reverse transcriptase, are applied topically to the affected or exposed area to treat or prevent viral infections, such as herpes virus, and other infectious conditions, particularly venereally transmitted pathogens. Ternary complexes of two strands of complementary RNA plus a compatible surfactant stabilized against temperature-associated enzymatic inactivation are described.

Topically active compositions of mismatched dsRNAs

Parenterally administered systemic dsRNAs release host mediators into various compartmentalized biological fluids to combat various microorganisms, particularly viruses, thereby reducing the infectivity and spread of various organisms including those associated with various diseases such as those caused by venereal warts, herpes and HIV.

Elaboration of host defense mediators into biological fluids by systemic

Hepatitis viral infections are efficaciously treated with mismatched dsRNAs, notably rI.sub.n.r(C.sub.11-14,U).sub.n.

Treatment of viral hepatitis with mismatched dsRNA

Patients having chronic fatigue syndrome having chronic cerebral dysfunction, as characterized by memory lapses occasional seizures and loss of cognitive functions are treated with a dsRNA such as rI.multidot.r(C.sub.11-14,U) to improve the patient's clinical condition.

Treatment of chronic cerebral dysfunction by dsRNA methodology

Hepatitis viral infections are efficaciously treated with mismatched dsRNAs, notably rI.r(C.sub.11-14,U).sub.n, alone or in combination with one or more ganciclovir, coumermycin A1, dideoxyinosine or its nucleoside analogs.

Diagnosis of viral hepatitis

Hepatitis viral infections are efficaciously treated with mismatched dsRNAs, notably rI.multidot.r(C.sub.11-14,.sup.U).sub.n, alone or in combination with one or more of ganciclovir, coumermycin Al, dideoxyinosine or its nucleoside analogs.

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Birchrunville, PA, United States of America

William A Carter