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#3 - A method of treating an enzyme deficiency disorders which causes neurodegeneration with small molecule
Long Title: Therapeutic Compounds Targeting Infantile Neuronal Ceroid-Lipofuscinosis (INCL) and Other Disorders Caused by Thioesterase Deficiency Disorders
NIH Reference No.: E-157-2011
Executive Summary
General Description
Clinically known as infantile NCL (INCL), commonly known as infantile Batten disease is a rare neuron-killing disease and one of the more than 50 LSDs. Although INCL is a rare (1 in >120,000 births) disease, it belongs to a group of the most common (1 in 12,500 births) inherited pediatric neurodegenerative disorders. INCL is caused by mutations in the CLN1 or PPT1 gene, which encodes palmitoyl-protein thioesterase-1 (PPT1), a lysosomal enzyme. Although children afflicted with INCL are normal at birth they manifest psychomotor retardation around 11-18 months of age. At around 2 years of age these children are completely blind and around 4 years of age these children show no brain activity. They remain in this vegetative state for several more years before eventual death. Currently, there is no effective treatment for INCL and for that matter for any of the Batten disease group of diseases. The delivery of potential macromolecular drugs to the brain is difficult because of the blood-brain-barrier, as result of this the development of effective therapies remain challenging.
Scientific Progress
Dr. Mukherjee and his colleagues of NICHD identified and characterized N-tert (Butyl)hydroxylamine (NtBuHA), a chemical derivative of hydroxylamine (HA), which mimics the action of PPT1 enzyme. PPT1-deficiency impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases and consequently, leads to accumulation of lipofuscin-like material in lysosomes and tissues leading to INCL pathogenesis. Compared to hydroxylamine, NtBuHA has been shown to be non-toxic in Ppt1-/- mice, which represent a reliable animal model of INCL. In addition, NtBuHA exhibits potent antioxidant property, crosses the blood-brain-barrier, retards progression of brain atrophy, extends the life of the diseased mice (n=80, NtBuHA-treated vs. n=110, untreated control), prevents neurodegeneration. Thus, NtBuHA has not only shown promise as a potential therapeutic agent for INCL but also may be effective in as yet unidentified diseases caused by any thioesterase deficiency in general.
Future Direction
Dr. Mukherjee and his team are gathering further experimental data required for filing an IND application for approval by the FDA. Obtaining FDA approval of an IND is essential for conducting a clinical trial to determine whether NtBuHA treatment is beneficial for the patients with INCL.
Strengths
Weaknesses
Patent Status
Relevant Publications
Sarkar C., et al. Nat Neurosci. 2013 Nov;16(11):1608-17 (PMID: 24056696)
Sarkar C., et al. Mol Genet Metab 2011;104:338-345. (PMID: 21704547)
Zhang Z., et al. Hum Mol Genet. 2006 Jan 15;15(2):337-46. (PMID: 16368712)
Inventor Bios
Anil Baran Mukherjee, M.D., Ph.D.
Dr. Anil Mukherjee received his Ph.D. from the University of Utah in Salt Lake City and underwent postdoctoral training in Human Genetics at Columbia University College of Physicians and Surgeons in New York. He then served as an Assistant Professor of Pediatrics and Human Genetics at the State University of New York at Buffalo, Buffalo, N.Y. for 4 years following which he became a medical student at the same university and received his M.D. degree. He obtained postgraduate training in Internal Medicine and after that joined the Biochemical and Developmental Genetics Section of the NICHD as a Clinical Associate. Subsequently, he joined the US Public Health Service as a Medical Officer and was tenured to the position he currently holds. He was elected Fellow of the Medical Sciences Section of the American Association for the Advancement of Science for his scientific achievements. He is also a member of the American Society of Biochemistry and Molecular Biology, Society for Neuroscience and the American Human Genetics Society. Dr. Mukherjee received numerous honors and awards, including USPHS Commendation Medal and Lifetime Achievement Award from his Medical School Alumni Association.
NIH Reference No.: E-157-2011
Executive Summary
- Intention Type: Therapeutic/Method
- Patent Status: US Patent Application No. 14/110,393 filed 07 and EP Patent Application No. 12716889.6
- LINK: http://www.ott.nih.gov/technology/e-157-20110
- NIH Reference Number: E-157-2011
- NIH Institute or Center: National Institute of Child Health and Human Development (NICHD)
- Disease Focus: Lysosomal Storage Disorder (LSD), Infantile Neuronal Ceroid-Lipofuscinosis (INCL), Thioesterase deficiency diseases
- Basis of Invention: Thioesterase-Mimetic Small molecule
- How it works: The chemical compound mimics the action of a key enzyme, palmitoyl-protein thioesterase-1 (PPT1), the deficiency of which causes a devastating LSD called INCL.
- Lead Inventor: Anil Baran Mukherjee, M.D., Ph.D.
- Development Stage: In vivo animal data available, ex vivo data available. The compound mediated depletion of lysosomal ceroid deposits and suppressed apoptosis in both cultured cells from INCL patients and in the brain of Ppt1−/− mice.
- Novelty: a first-in-class compound to treat Thioesterase –deficiency diseases including INCL
- Clinical Application: Small molecule therapeutics for INCL and other as yet unrecognized Thioesterase-deficiency disorders.
General Description
Clinically known as infantile NCL (INCL), commonly known as infantile Batten disease is a rare neuron-killing disease and one of the more than 50 LSDs. Although INCL is a rare (1 in >120,000 births) disease, it belongs to a group of the most common (1 in 12,500 births) inherited pediatric neurodegenerative disorders. INCL is caused by mutations in the CLN1 or PPT1 gene, which encodes palmitoyl-protein thioesterase-1 (PPT1), a lysosomal enzyme. Although children afflicted with INCL are normal at birth they manifest psychomotor retardation around 11-18 months of age. At around 2 years of age these children are completely blind and around 4 years of age these children show no brain activity. They remain in this vegetative state for several more years before eventual death. Currently, there is no effective treatment for INCL and for that matter for any of the Batten disease group of diseases. The delivery of potential macromolecular drugs to the brain is difficult because of the blood-brain-barrier, as result of this the development of effective therapies remain challenging.
Scientific Progress
Dr. Mukherjee and his colleagues of NICHD identified and characterized N-tert (Butyl)hydroxylamine (NtBuHA), a chemical derivative of hydroxylamine (HA), which mimics the action of PPT1 enzyme. PPT1-deficiency impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases and consequently, leads to accumulation of lipofuscin-like material in lysosomes and tissues leading to INCL pathogenesis. Compared to hydroxylamine, NtBuHA has been shown to be non-toxic in Ppt1-/- mice, which represent a reliable animal model of INCL. In addition, NtBuHA exhibits potent antioxidant property, crosses the blood-brain-barrier, retards progression of brain atrophy, extends the life of the diseased mice (n=80, NtBuHA-treated vs. n=110, untreated control), prevents neurodegeneration. Thus, NtBuHA has not only shown promise as a potential therapeutic agent for INCL but also may be effective in as yet unidentified diseases caused by any thioesterase deficiency in general.
Future Direction
Dr. Mukherjee and his team are gathering further experimental data required for filing an IND application for approval by the FDA. Obtaining FDA approval of an IND is essential for conducting a clinical trial to determine whether NtBuHA treatment is beneficial for the patients with INCL.
Strengths
- Large scale animal study completed,
- Data being collected in preparation for an IND filing
- Nucleophilic small molecule that functionally mimics all thioesterases
- Non-toxic compared to hydroxylamine, which generates methemoglobin
- NtBuHA is a small molecule
- Orally administrable
- Crosses the blood brain barrier and protects neurons
- Extends lifespan of Ppt1-/- mice, a reliable animal model of INCL
Weaknesses
- NtBuHA is an off-patented compound
- Clinical trials will take longer time in order to identify the effect of drug on life span
- INCL is a rare disease (1 in >100,000 births) and thus, it is difficult to recruit large number of patients in a short time
- Need to prove to the investors that the standard of care for these patients may be significantly reduced if there is an effective treatment for INCL
- Needs to prove to potential investors that the human cost of this disease, aside from dollars and cents, is enormous
Patent Status
- US Patent Application No. 14/110,393 filed 07 Oct 2013
- EP Patent Application No. 12716889.6 filed 07 Oct 2013
Relevant Publications
Sarkar C., et al. Nat Neurosci. 2013 Nov;16(11):1608-17 (PMID: 24056696)
Sarkar C., et al. Mol Genet Metab 2011;104:338-345. (PMID: 21704547)
Zhang Z., et al. Hum Mol Genet. 2006 Jan 15;15(2):337-46. (PMID: 16368712)
Inventor Bios
Anil Baran Mukherjee, M.D., Ph.D.
Dr. Anil Mukherjee received his Ph.D. from the University of Utah in Salt Lake City and underwent postdoctoral training in Human Genetics at Columbia University College of Physicians and Surgeons in New York. He then served as an Assistant Professor of Pediatrics and Human Genetics at the State University of New York at Buffalo, Buffalo, N.Y. for 4 years following which he became a medical student at the same university and received his M.D. degree. He obtained postgraduate training in Internal Medicine and after that joined the Biochemical and Developmental Genetics Section of the NICHD as a Clinical Associate. Subsequently, he joined the US Public Health Service as a Medical Officer and was tenured to the position he currently holds. He was elected Fellow of the Medical Sciences Section of the American Association for the Advancement of Science for his scientific achievements. He is also a member of the American Society of Biochemistry and Molecular Biology, Society for Neuroscience and the American Human Genetics Society. Dr. Mukherjee received numerous honors and awards, including USPHS Commendation Medal and Lifetime Achievement Award from his Medical School Alumni Association.