Methods for delivery of siRNA to the spinal cord and therapies arising therefrom
Inventors
Feinstein, Elena • Grumet, Martin
Assignees
Rutgers State University of New Jersey • Quark Pharmaceuticals Inc
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Publication Number
US-8901097-B2
Publication Date
2014-12-02
Expiration Date
Abstract
The present application relates at least in part to methods for the administration of small interfering RNAs (siRNAs) to the spinal cord of a human or animal patient and also to a method of treatment for spinal cord injury and other diseases and disorders of the CNS. In particular, the application discloses methods to deliver an siRNA compound locally, directly and without the need for transduction vehicles and formulations in effective doses to the injured spinal cord to promote recovery of CNS function and or attenuation of allodynia.
Core Innovation
The invention relates to siRNA/dsRNA therapies for treating neuropathic pain associated with a disease, a disorder or an injury in a subject. It is directed to a RhoA target gene using a double-stranded RNA compound administered in an amount effective to treat the neuropathic pain, with administration one day or more post-onset of the disease or disorder, or post-injury.
The disclosed approach emphasizes local delivery directly to the injured spinal cord, including intraspinal, intraparenchymal, and lumbar intrathecal delivery via lumbar puncture. The therapy uses a vehicle-free delivery approach described for directly targeting the injured spinal cord, and the therapeutic rationale is based on RhoA upregulation after SCI and a defined post-injury timing window for administration.
In addition to RhoA targeting, the document describes targeting of TLR4 and includes a broad target-gene list. The provided rationale and therapeutic outcomes are supported by measures of siRNA/dsRNA uptake, RhoA knockdown, and siRNA stability, with reported effects including attenuating neuropathic pain and allodynia and promoting recovery following spinal cord injury.
Claims Coverage
The partial content provides one independent claim. The inventive coverage centers on administering a double-stranded RNA compound directed to a RhoA target gene to treat neuropathic pain, with post-onset or post-injury timing limitations and dependent refinements that specify timing windows, neuropathic-pain associations, and optional route/site and co-therapy features.
Double-stranded RNA directed to a RhoA target gene for treating neuropathic pain
A method of treating neuropathic pain associated with a disease, a disorder or an injury in a subject by administering an effective amount of a double-stranded RNA compound directed to a RhoA target gene.
Post-onset or post-injury administration timing
Administering the double stranded RNA compound to the subject one day or more post-onset of the disease or disorder, or post-injury.
Intraspinal administration
Administering the double-stranded RNA compound intraspinally.
Administration within a defined post-injury window
Administering the double-stranded RNA to the subject within 48 hours after injury, or up to 14 days after an injury.
Neuropathic pain associated with selected conditions
Where the neuropathic pain is associated with one of the listed conditions including traumatic nerve injury, post-ischemia, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, sciatica, phantom limb pain, diabetic neuropathy, and cancer chemotherapy-induced neuropathic pain.
Optional co-administration with selected pharmacological agents
Administering, in addition to the double-stranded RNA, a selected pharmacological agent chosen from specified anti-inflammatory, antimicrobial, free-radical, anti-cancer/chemotherapeutic agents or combinations, using simultaneous, concurrent, separate, or sequential administration.
Across the independent claim and its dependents, the coverage is directed to double-stranded RNA compounds targeting a RhoA target gene for treating neuropathic pain with administration beginning one day or more after onset or injury. Dependent features further narrow timing windows, specify an intraspinal administration site, enumerate neuropathic-pain associations via listed conditions, and optionally add selected pharmacological co-administration options.
Stated Advantages
Attenuating neuropathic pain and allodynia and promoting recovery after spinal cord injury.
Reducing disease/injury-associated RhoA mRNA/protein levels as a therapeutic outcome.
Preserving white-matter sparing and corticospinal tract fibers and enhancing serotonergic fiber growth.
Reducing ED1+ activated macrophages associated with the injury response.
Documented Applications
Treating neuropathic pain associated with a spinal cord injury (SCI), including attenuating neuropathic pain/allodynia following SCI.
Treating neuropathic pain associated with a disease, disorder or injury when the neuropathic pain is associated with selected conditions listed in the dependent claim, including traumatic nerve injury, post-ischemia, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, sciatica, phantom limb pain, diabetic neuropathy, and cancer chemotherapy-induced neuropathic pain.
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