Novel siRNAS and methods of use thereof

Abstract

The invention relates to compounds, in particular siRNAs, which inhibit the expression of specific human genes. The invention also relates to pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier. The present invention also provides a method of treating and / or preventing the incidence or severity of various diseases or conditions associated with the genes and / or symptoms associated with such diseases or conditions comprising administering to a subject in need of treatment for such disease or condition and / or symptom the compound or the pharmaceutical composition in a therapeutically effective dose so as to thereby treat the subject. The invention also provides antibodies which inhibit specified human polypeptides and pharmaceutical compositions comprising one or more such antibodies.

Description

[0001]This application claims the benefit of U.S. Provisional patent application No. 60 / 854,503 filed Oct. 25, 2006, and of U.S. Provisional patent application No. 60 / 930,493 filed May 15, 2007, both of which are hereby incorporated by reference in their entirety.[0002]Throughout this application various patents and publications are cited. The disclosures of these documents in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.FIELD OF THE INVENTION[0003]The present invention relates to compounds, pharmaceutical compositions comprising same and methods of use thereof for the inhibition of certain genes, including pro-apoptotic genes. The compounds and compositions are thus useful in the treatment of subjects suffering from diseases or conditions and or symptoms associated with such diseases or conditions in which gene expression has adverse consequences. In particular embodiments, t...

AI Technical Summary

Benefits of technology

The siRNA-based approach effectively reduces apoptosis in targeted cells, offering a therapeutic means to treat conditions like hearing loss, renal failure, and respiratory distress by inhibiting the expression of pro-apoptotic genes, potentially reversing or preventing tissue damage and improving patient outcomes.

Problems solved by technology

The ototoxic effects of various therapeutic drugs on auditory cells and spiral ganglion neurons are often the factor limiting their therapeutic usefulness.

For example, antibacterial aminoglycosides such as gentamycin, streptomycin, kanamycin, tobramycin, and the like are known to have serious toxic side effects, particularly ototoxicity and nephrotoxicity, which reduce their value as therapeutic agents (see Goodman and Gilman's The Pharmacological Basis of Therapeutics, 6th ed., A. Goodman Gilman et al., eds; Macmillan Publishing Co., Inc., 1980.

Thus, ototoxicity is a recognized dose-limiting side-effect of antibiotic administration.

Studies have shown that from 4 to 15% of patients receiving one gram per day for greater than one week develop measurable hearing loss, which gradually worsens and can lead to permanent deafness if treatment continues.

Unfortunately, they too have ototoxic side effects including tinnitus (“ringing in the ears”) and temporary hearing loss.

Moreover, if the drug is used at high doses for a prolonged time, hearing impairment can become persistent and irreversible.

Therefore, a loss of hair cells will result in profound and irreversible deafness.

Unfortunately, there are presently no effective therapies to treat the cochlea and reverse this condition.

Death of the sensory cell can lead to progressive Wallerian degeneration and loss of primary auditory nerve fibers.

In mammals, auditory hair cells are produced only during embryonic development and do not regenerate if lost during postnatal life, therefore, a loss of hair cells will result in profound and irreversible deafness.

Unfortunately, at present, there are no effective therapies to treat the cochlea and reverse this condition.

Today, there is no specific treatment for established ARF.

However, when these drugs were tested in clinical trials no benefit was shown and their use for treating ARF has not been approved.

In conclusion, there are no currently satisfactory modes of therapy for the prevention and / or treatment of acute renal failure, and there is a clear need to develop novel compounds for this purpose.

Delayed graft function (DGF) is the most common complication of the immediate postoperative period in renal transplantation and results in poor graft outcome (Moreso et al.

Although the incidence and definition of DGF vary among transplant centers, the consequences are invariable: prolonged hospital stay, additional invasive procedures, and additional cost to the patient and health-care system.

One of the most common forms of glaucoma, known as primary open-angle glaucoma (POAG), results from the increased resistance of aqueous humor outflow in the trabecular meshwork (TM), causing IOP elevation and eventual optic nerve damage.

It is characterized by inflammation of the lung parenchyma leading to impaired gas exchange with concomitant systemic release of inflammatory mediators which cause inflammation, hypoxemia and frequently result in failure of multiple organs.

This condition is life threatening and often lethal, usually requiring mechanical ventilation and admission to an intensive care unit.

Acute allograft rejection remains a significant problem in lung transplantation despite advances in immunosuppressive medication.

Rejection, and ultimately early morbidity and mortality may result from ischemia-reperfusion (I / R) injury and hypoxic injury.

Spinal cord injury or myelopathy, is a disturbance of the spinal cord that results in loss of sensation and / or mobility.

It contributes to increased acute rejection and impaired long-term allograft function.

Lung transplantation, the only definitive therapy for many patients with end stage lung disease, has poor survival rates in all solid allograft recipients.

With unrelieved pressure, tissue ischemia can develop resulting in the accumulation of metabolic waste in the interstitial tissue, resulting in anoxia and cellular death.

This pressure-induced ischemia also leads to excessive tissue hypoxia, further promoting bacterial proliferation and tissue destruction.

The newly formed blood vessels are excessively leaky.

This leads to accumulation of subretinal fluid and blood leading to loss of visual acuity.

While dry AMD patients may retain vision of decreased quality, wet AMD often results in blindness.

In the proliferative stage the disease is characterized by extensive neovascularization, vessel intrusion into the vitreous, bleeding and fibrosis with subsequent retinal traction, which leads to severe vision impairment.

Routine activities such as eating, drinking, swallowing, and talking may be difficult or impossible for subjects with severe oral mucositis.

Dry eye syndrome is a common problem usually resulting from a decrease in the production of tear film that lubricates the eyes.

Most patients with dry eye experience discomfort, and no vision loss; although in severe cases, the cornea may become damaged or infected.