News Column

Researchers Submit Patent Application, "Novel Therapy for Treatment of Chronic Degenerative Brain Diseases and Nervous System Injury", for Approval

June 19, 2014



By a News Reporter-Staff News Editor at Gene Therapy Weekly -- From Washington, D.C., NewsRx journalists report that a patent application by the inventor MELLON, Synthia (San Francisco, CA), filed on October 24, 2013, was made available online on June 5, 2014 (see also Patents).

No assignee for this patent application has been made.

News editors obtained the following quote from the background information supplied by the inventors: "The present invention relates to methods of providing therapy for nervous system conditions including, but not limited to: degenerative brain diseases, ganglioside storage disorders and inflammatory disorders.

"There are more than 600 known disorders that afflict the nervous system. Nervous system disorders have varied etiologies, but ultimately all have devastating effects on the individuals suffering from them. Nervous system disorders include degenerative conditions such as Parkinson's and Alzheimer's disease; inflammatory diseases such as Multiple sclerosis, spinal cord injury ischemia and stroke, psychiatric disorders such as schizophrenia, and lipid storage disorders such as Neimann-Pick-C, Tay Sachs, Batten, Sandhoff and Gaucher disease.

"Neurological disorders strike an estimated 50 million Americans each year, exacting an incalculable personal toll and an annual economic cost of hundreds of billions of dollars in medical expenses and lost productivity.

"The burden of neurological disease is a burden borne by every segment of society, and people everywhere. Indeed, individuals suffering from nervous system disorders often a require care 24 hours a day, seven days a week. In such cases family members from several households may need to partake in the care, and these caregivers usually have jobs, as well as their own families. Thus, the consequences of neurological disease have far reaching consequences.

"Neurological disorders may be manifest at any stage of life. Some neurological diseases typically exhibit adult onset. These include Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, Multiple Sclerosis, Parkinson's Disease, Stroke, and traumatic brain injury. Adult onset neurological disease accounts for between 13.3 and 16.1 million cases of neurological disorders in the United States. Unfortunately, many of these diseases and disorders are progressive, so that the burden of care for the individual increases with time.

"Other neurological diseases affect infants and children. Indeed, glycosphingolipid storage diseases are a common cause of pediatric neurodegenerative diseases. Although the frequency of individual disorders is not high, together they are a significant group of disorders with a collective frequency of 1 in 18,000 live births.

"Unfortunately, neurologic disease is seldom curable. This is true irrespective of the age at which the neurological disease is manifest. Thus, strategies for the treatment of these debilitating and often fatal diseases often focus primarily on pallative measures. Attempts at curing neurological disease have also been proposed. These treatments have included enzyme replacement therapy, gene therapy, and allogenic bone marrow transplantation. Unfortunately however, the treatments typically do not improve the condition nor alter the ultimate outcome of the disease. Thus, before this invention, symptomatic management was often the only approach available for treating most of these disorders.

"The present inventors have determined for the first time that the use of neuroactive steroids is effective for the treatment of degenerative brain diseases and central nervous system disorders.

"Managing the neuropathologic processes that contribute to the morbidity of neurologic diseases has proven to be a challenging task, since as noted above, there are many factors that can cause, perpetuate, or exacerbate neurological conditions involving the central nervous system. There has been no evidence prior to this invention that neuroactive steroids would provide effective therapy for the treatment of a wide range of neurological diseases, including congenital lipid storage diseases, inflammatory diseases, and chronic degenerative brain disease. The present invention therefore fulfills the need for an effective method of treating neurological disorders by providing methods of administering neuroactive steroids to a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

"FIG. 1: Ganglioside profiles in cortex from Neimann Pick type-C(NP-C) mice treated with allopregnanolone. (a) High-performance TLC profile of gangliosides from untreated (left) and day 7-treated (right) NP-C mice. (b) Quantitative data for gangliosides GM2, GM3 and GM1 in the cortex from untreated, day 10- and day-7-treated NP-C mice. Individual gangliosides are expressed as nanomoles of ganglioside per gram of wet weight of tissue (n=3 untreated, n=2 day 10-treated, and n=4 day 7-treated NP-C mice; data are the mean.+-.s.d.; P

"FIG. 2: Immunostaining for gangliosides GM1 and GM2, and for CD4.sup.+ and for CD8.sup.+ T cells in adult (60-day old) mouse brains. Cerebellum. There is virtually no GM1 or GM2 immunostaining in wild type mouse cerebella, and only slight immunostaining in allopregnanolone-treated mice, while there is GM1 and GM2 immunostaining in untreated NP-C mice. This coincides with a large increase in immunostaining for CD4 and CD8 T cells, seen in the untreated NP-C mice, but absent from both P7 allopregnanolone-treated NP-C mice and wild type mice.

"FIG. 3: Immunostaining for gangliosides GM1 and GM2, and for CD4.sup.+ and for CD8.sup.+ T cells in adult (60-day old) mouse brains. Thalamus/hypothalamus. There is virtually no GM1 or GM2 immunostaining in the thalamus/hypothalamic region of wild type mouse, and only very slight immunostaining in P7-allopregnanolone-treated mice, while there is GM1 and GM2 immunostaining in untreated NP-C mice. This coincides with a large increase in immunostaining for CD4 and CD8 T cells, seen in the untreated NP-C mice, but absent from both P7 allopregnanolone-treated NP-C mice and wild type mice.

"FIG. 4: Immunostaining for MAC1 and for MHCII activated macrophage cells in adult (60-day old) mouse brains. There is immunostaining for both MAC1 and MHC II in the thalamus of untreated NP-C mice, which is substantially reduced in day 7-allopregnanolone-treated NP-C mice. Wh=white matter.

"FIG. 5: Cytokine concentrations in Adult Wild type, Untreated NP-C and allopregnanolone-Treated (day 7) NP-C mice. The cytokines TGF.beta. and IL1.beta. are substantially reduced in day 7-allopregnanolone-treated NP-C mice, in comparison to untreated NP-C mice.

"FIG. 6: Allopregnanolone stimulation of neurotrophin secretion in cultured cells.

"FIG. 7: Effect of ganaxolone on progression of NP-C symptoms: Ganaxolone (25 mg/kg in 20% .beta.-cyclodextrin) was administered subcutaneously in a single injection at P7 (n=12 mice for untreated and wild type; n=4 mice for ganaxolone treatment).

"FIG. 8: Effect of an LXR ligand T0901317, Allopregnanolone, and a combination of both T0901317 plus allopregnanolone on progression of NP-C symptoms. T0901317 was given at 50 mg/kg/day beginning at P (postnatal day) 18. Allopregnanolone (25 mg/kg in 20% .beta.-cyclodextrin) was administered subcutaneously in a single injection at P (postnatal day) 7 (n=12 mice for each treatment). LXR ligand or Allopregnanolone treatment delayed the onset of symptoms, and LXR ligand blunted the decline in symptoms. The combination therapy delayed the onset of symptoms and decline in neurologic function, assessed by rotorod trials. The combination therapy also significantly prolonged the lifepan of the NP-C mice (mean 136 days) compared with allopregnanolone treatment alone (mean 112 days) or LXR ligand alone (mean 80 days), vs. untreated NP-C mouse (mean 74 days)."

As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventor's summary information for this patent application: "The use of neuroactive steroids in the treatment of central nervous system disorders and degenerative brain diseases has not been described previously. However, it has now been discovered that a variety of neurological disorders, including, but not limited to congenital storage diseases, may benefit from treatments with neuroactive steroids. Thus, in one aspect, the invention provides a method to effect treatment of a nervous system condition. The method comprises administering to a patient in need thereof, an effective amount of a composition comprising a compound having a structure according to Formula (I):

"##STR00001##

"wherein R is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl; and X.sup.1 is a member selected from O, S and NR.sup.6. R.sup.6 is a member selected from H, OR.sup.7, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl. R.sup.7 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl. R.sup.1 is a member selected from H, OR.sup.8, NR.sup.8R.sup.9, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl; and R.sup.8 is a member selected from H, C(X.sup.2)R.sup.10, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl. X.sup.2 is a member selected from O, S and NH; R.sup.10 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl; R.sup.9 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are members independently selected from H, substituted or unsubstituted alkyl, and substituted or unsubstituted heteroalkyl. In an exemplary embodiment, the nervous system condition is a lysosomal storage disorder.

"In an exemplary embodiment, R is selected from substituted or unsubstituted alkyl. In another embodiment R is CH.sub.3.

"In other exemplary embodiments the invention provides a method for ameliorating the symptoms or signs of an inflammatory disorder, and/or nervous system conditions characterized by a change in the permeability of the blood brain barrier. In other embodiments, the invention provides therapy for the treatment of Multiple Sclerosis, Alzheimer's Disease, Parkinson's Disease, spinal cord injury, ischemia, and stroke.

"In other exemplary embodiments the invention provides therapy for a lysosomal storage disorder. The lysosomal storage disorder is characterized by abnormalities of cholesterol metabolism. In an exemplary embodiment, the abnormality of cholesterol metabolism is further associated with a cardiovascular disorder. In an exemplary embodiment, the cardiovascular disorder is a member selected from heart disease and atherosclerosis. In an alternative embodiment, the lysosomal storage disorder is a sphingolipid storage disease. Exemplary sphingolipid storage diseases for which the invention provides effective therapy include, but are not limited to: GM1 and GM2 gangliosidosis, Tay Sachs Disease, Batten, Sandhoff, Gaucher disease, Fabry's disease, Niemann Pick A and B, Niemann Pick-C, Schindler Disease, Farber disease, Krabbe Disease, Austin Disease, Sulfatidosis, Fucosidosis, and mucopolysaccharidosis.

"In another exemplary embodiment, the invention provides a method of therapy that ameliorates the signs and symptoms of a neurodegenerative disease. Neurodegenerative diseases for which the invention provides effective therapy include, but are not limited to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.

"In another exemplary embodiment, the invention provides effective therapy for the treatment of a demyelinating disorder which in exemplary instances is manifest as Multiple Sclerosis, optic neuritis, transverse neuritis and/or Guillain-Barre Syndrome.

"In still another exemplary embodiment the invention provides a method for ameliorating the signs and symptoms of a leukodystrophy. The leukodystrophy may include metachromatic leukodystrophy, Krabbe disease, adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Canavan disease, Childhood Ataxia with Central Hypomyelination or CACH (also known as Vanishing White Matter Disease), Alexander disease, Refsum disease, and cerebrotendinous xanthomatosis.

"In another exemplary embodiment, the invention provides an effective treatment for neurological conditions involving disruptions of brain cellular metabolism. Exemplary conditions involving disruptions of brain cellular metabolism include, but are not limited to hypoglycemia, acidosis, hypoxia, or hypercarbia, which may be brought on by extracellular events. An exemplary extracellular event includes, but is not limited to, a disruption of extracellular fluid composition triggered by hypernatremia, hyponatremia, hyperosmolality, hypoosmolality, hypercalcemia, hypocalcemia, hypermagnesemia, hypomagnesemia, hyperphosphatemia, and/or hypophosphatemia.

"In another exemplary embodiment, the invention provides effective therapy for a neurological condition that is a psychiatric condition. Exemplary psychiatric conditions include, but are not limited to, frontotemporal dementias, movement disorders, psychoses, schizophrenia, depression, alcoholism, premenstrual dysphoric disorder, posttraumatic stress disorder, and/or social isolation.

"In another aspect the invention provides a combination therapy for treatment of a nervous system condition. The method comprises administering to a patient in need thereof, effective amounts of a compound according to Formula (I) described above and a Liver X Receptor (LXR) ligand.

"In an exemplary embodiment, the LXR ligand is either an oxysterol or a non-oxysterol. Exemplary oxysterol LXR ligands include, but are not limited to, TO901317, 22-hydroxycholesterol, 24(S)-hydroxycholesterol, 24(S),25-epoxycholesterol, and 27-hydroxycholesterol. Exemplary non-oxysterol LXR ligands include, but are not limited to, Paxilline.

"In still another aspect, the invention provides a pharmaceutical composition comprising effective amounts of a compound according to Formula (I) described above, a LXR ligand, and a pharmaceutically acceptable carrier.

"Additional aspects, advantages and objects of the present invention will be apparent from the detailed description that follows."

For additional information on this patent application, see: MELLON, Synthia. Novel Therapy for Treatment of Chronic Degenerative Brain Diseases and Nervous System Injury. Filed October 24, 2013 and posted June 5, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1727&p=35&f=G&l=50&d=PG01&S1=20140529.PD.&OS=PD/20140529&RS=PD/20140529

Keywords for this news article include: Biotechnology, Stroke, Patents, Dementia, Thalamus, Metabolism, Psychiatric, Tauopathies, Diencephalon, Gene Therapy, Mental Health, Bioengineering, Brain Diseases, Alzheimer Disease, Movement Disorders, Parkinson's Disease, Neurological Disease, Basal Ganglia Diseases, Parkinsonian Disorders, Neurodegenerative Diseases.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC


For more stories covering the world of technology, please see HispanicBusiness' Tech Channel



Source: Gene Therapy Weekly


Story Tools






HispanicBusiness.com Facebook Linkedin Twitter RSS Feed Email Alerts & Newsletters