Treatment for hereditary neuropathy with liability to pressure palsies (HNPP)
Inventors
Assignees
US Department of Veterans Affairs • Vanderbilt University
Publication Number
US-10507211-B2
Publication Date
2019-12-17
Expiration Date
2037-07-17
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Abstract
A method of treating demyelinating diseases involves administering a PAK1 inhibitor that is PF-3758309 to a subject in need of such treatment.
Core Innovation
The invention relates to a method of treating demyelinating diseases, including hereditary neuropathy with liability to pressure palsies (HNPP), by administering a PAK1 inhibitor specifically PF-3758309 to subjects in need of such treatment. This approach addresses the disruption of myelin junctions such as tight junctions and adherens junctions which normally seal spaces between myelin lamellae and axolemma, essential for maintaining effective nerve conduction.
HNPP is caused by a heterozygous deletion of the PMP22 gene resulting in partially defective myelin junctions and increased myelin permeability without segmental demyelination, a state referred to as functional demyelination. This abnormal permeability impairs action potential propagation leading to neurological deficits. The problem addressed is the lack of effective treatments for demyelinating diseases that can prevent or reverse this functional demyelination and subsequent conduction failure.
The patent discloses that increased PAK1 activity correlates with increased actin polymerization which disrupts myelin junctions. Pharmacological inhibition of PAK1 with PF-3758309 normalizes actin polymerization levels, preserves myelin junction integrity, improves nerve conduction, and halts disease progression in a Pmp22+/− mouse model of HNPP. The compound PF-3758309 shows unique ability to penetrate peripheral nerves and to be effective at doses much lower than previously used in cancer treatment, representing an unexpected therapeutic advantage.
Claims Coverage
The patent includes one independent claim covering a method for treating HNPP by administering a PAK1 inhibitor, specifically PF-3758309, with various conditions on administration routes and dosages.
Method of treating HNPP using PF-3758309
Administering to a subject in need a therapeutically effective amount of the PAK1 inhibitor PF-3758309 for treatment of hereditary neuropathy with liability to pressure palsies.
Multiple routes of administration
The PAK1 inhibitor PF-3758309 can be administered orally, topically, by intramuscular injection, or by intraperitoneal injection, including formulation into compositions suitable for injection.
Dose ranges of PF-3758309
Administration of PF-3758309 at doses ranging about 0.03 to 3 mg/kg, including narrower ranges such as 0.25-3 mg/kg and 0.03-1 mg/kg, for effective treatment.
Compositions containing PF-3758309 with pharmaceutically acceptable carriers
Providing PF-3758309 in a composition with pharmaceutically acceptable carriers, formulated for injection or unit dose forms.
Monitoring symptoms associated with HNPP
The method may further include monitoring clinical symptoms associated with HNPP such as numbness, loss of reflexes, uncoordinated movements, poorly controlled blood pressure, blurred vision, memory problems, loss of bladder and bowel control, fatigue, pins and needles sensation, tingling, muscle palsy, and pain.
Application to mammalian subjects
The therapeutic method applies to mammalian subjects, including humans.
The independent claim centers on a method of treating HNPP by administering PF-3758309. The claimed inventive features include selection of the PAK1 inhibitor PF-3758309, specific administration routes, defined dosage ranges, pharmaceutical composition formulations, symptom monitoring, and application in mammals.
Stated Advantages
Pharmacological inhibition of PAK1 with PF-3758309 normalizes actin polymerization and prevents progression of myelin junction disruption and nerve conduction failure in the HNPP mouse model.
PF-3758309 demonstrates effective penetration into the peripheral nerve system, unlike other PAK1 inhibitors tested, providing a unique therapeutic modality.
Effective doses of PF-3758309 for treatment of demyelinating diseases are significantly lower—about 100 times lower—than doses used for skin cancer treatment, enhancing safety and reducing side effects.
Treatment with PF-3758309 is effective both in juvenile and adult mice with fully developed pathology, indicating potential for treatment of symptomatic patients.
Documented Applications
Treatment of hereditary neuropathy with liability to pressure palsies (HNPP), an inherited peripheral nerve demyelinating disease.
Treatment of other demyelinating diseases including multiple sclerosis, optic neuritis, neuromyelitis optica (Devic's disease), transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Tabes dorsalis, leukoencephalopathies, progressive multifocal leukoencephalopathy, leukodystrophies, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth disease type I, Leber's Hereditary Optic Neuropathy, copper deficiency associated conditions, and progressive inflammatory neuropathy.
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