EP3383382A1 - Method for improving cognition - Google Patents
Method for improving cognitionInfo
- Publication number
- EP3383382A1 EP3383382A1 EP16798218.0A EP16798218A EP3383382A1 EP 3383382 A1 EP3383382 A1 EP 3383382A1 EP 16798218 A EP16798218 A EP 16798218A EP 3383382 A1 EP3383382 A1 EP 3383382A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mct
- mcfa
- composition
- fatty acid
- medium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
- A23L33/12—Fatty acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to the use of medium-chain triglycerides (MCTs) or medium- chain fatty acids (MCFAs) for improving cognition which has been impaired by UBE3A deficiency, for example in subjects with cognitive disorders or aging subjects.
- MCTs medium-chain triglycerides
- MCFAs medium- chain fatty acids
- the invention relates to the use of MCTs for treating Angelman syndrome and/or Prader-Willi syndrome.
- UBE3A encodes a ubiquitin E3 ligase that targets specific proteins for degradation (de Bie, P. and Ciechanover A. (201 1 ) Cell Death Differ. 18: 1393-402) and is essential for normal cognitive function due to its role as the major ubiquitin binding protein in the synapse.
- UBE3As ability to clear synaptic signalling proteins e.g. Arc
- Loss of UBE3A expression disrupts long term potentiation via the transcription factor Arc, and also gives rise to dysregulation of glutamate receptor activity. Over time an absence of UBE3A causes synaptic degradation and seizures.
- UBE3A dysfunction has been linked to a reduction of cognitive function. In particular, it has been implicated as causative of certain disorders, such as Angelman syndrome.
- Angelman syndrome is a genetic disorder that results in functionally severe developmental delay, which is characterised by severe speech impairment, movement or balance disorders and odd behaviour.
- Angelman syndrome-associated seizures may sometimes be controlled using drugs or with the ketogenic diet, and a modified Atkins diet has also been tried in this context, however the success of these approaches is variable.
- Prader-Willi syndrome is a genetic disorder related to Angelman syndrome.
- Prader-Willi syndrome patients experience significant cognitive, neurological, endocrine and behavioural abnormalities. Furthermore, patients may have difficulty in feeding in infancy due to hypotonia, leading to growth retardation, however they become obese later in life due to an uncontrollable craving for food.
- Prader-Willi syndrome Approximately 400,000 patients worldwide have Prader-Willi syndrome. Although behavioural therapy and other treatments may reduce the effects of Prader-Willi syndrome, there are no effective treatments for this disease.
- the inventors have unexpectedly shown that a medium-chain triglyceride (MCT) diet increases UBE3A expression in the brain. Moreover, the inventors have shown that an MCT diet improves cognitive performance. Specifically, the inventors found that a diet comprising C8 and/or C10 triglycerides increases UBE3A protein expression in the cortex and hippocampus compared to a control diet. The MCT diet was found to improve UBE3A expression levels in the aged subjects to levels that are comparable or superior to that found in young subjects.
- MCT medium-chain triglyceride
- the inventors further found that the MCT diet gives rise to improved cognitive function in the rat models.
- the observed improvements in cognition may result from the increased levels of UBE3A in the brain causing a down- regulation of basal levels of the transcription factor Arc and/or improved control of Arc homeostasis.
- the invention provides a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) for use in improving cognition which has been impaired by UBE3A deficiency.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- UBE3A deficiency may, for example, result from insufficient UBE3A activity in the brain, for example as a result of inadequate levels of expression of UBE3A or expression of an inactive form of the UBE3A enzyme.
- UBE3A deficiencies may arise with increasing age and/or may be readily assessed by the skilled person using, for example, molecular genetic testing that suggests deficient expression or function (e.g. as described herein).
- the cognition is improved through the use of the MCTs of the invention. In another embodiment, the cognition is improved through the use of the MCFAs of the invention.
- the MCT or MCFA improves cognition in a subject with a cognitive disorder.
- the cognitive disorder may be associated with or resulting from insufficient UBE3A activity in the brain.
- the MCT or MCFA improves cognition in a subject with Angelman syndrome or Prader-Willi syndrome.
- the MCT or MCFA improves cognition in an aging subject.
- the aging subject may, for example, be a human subject over the age of 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 years old.
- the invention provides a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) for use in treating Angelman syndrome or Prader-Willi syndrome.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- the MCT or MCFA may, for example, improve cognition in a subject with Angelman syndrome or Prader-Willi syndrome, and/or reduce the occurrence of seizures.
- the MCT for use according to the invention may, for example, comprise three fatty acid moieties, each of which independently has between 6-12, 6-1 1 , 6-10, 7-12, 7-1 1 , 7-10, 8-12, 8-1 1 or 8-10 carbon atoms.
- the MCT for use according to the invention comprises three fatty acid moieties, each of which independently has between 8-10 carbon atoms.
- the MCT for use according to the invention may, for example, comprise three fatty acid moieties, each of which independently has only 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms.
- the MCT for use according to the invention comprises three fatty acid moieties, each of which independently has only 8 or 10 carbon atoms, i.e. preferably, the MCT for use according to the invention comprises only C8 and/or C10 fatty acid moieties.
- the fatty acid moieties are octanoic acid and/or decanoic acid moieties.
- the MCT for use according to the invention may be a homotriglyceride (i.e. all of the fatty acid moieties of the MCT may be of the same identity, for example a C8 homotriglyceride may comprise 3 octanoic acid moieties).
- the MCT for use according to the invention comprises three fatty acid moieties with only 8 carbon atoms. In a preferred embodiment, all three fatty acid moieties are octanoic acid moieties.
- the MCT for use according to the invention comprises three fatty acid moieties with only 10 carbon atoms. In a preferred embodiment, all three fatty acid moieties are decanoic acid moieties.
- the MCFA for use according to the invention may, for example, have between 6-12, 6-1 1 , 6- 10, 7-12, 7-1 1 , 7-10, 8-12, 8-1 1 or 8-10 carbon atoms.
- the MCFA for use according to the invention has between 8-10 carbon atoms.
- the MCFA for use according to the invention may, for example, have only 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms.
- the MCFA for use according to the invention has only 8 or 10 carbon atoms, i.e. preferably, the MCFA for use according to the invention is a C8 and/or C10 fatty acid.
- the MCFA for use according to the invention has only 8 carbon atoms.
- the MCFA is octanoic acid.
- the MCFA for use according to the invention has only 10 carbon atoms.
- the MCFA is decanoic acid.
- the MCT or MCFA for use according to the invention may be administered enterally or parenterally.
- the MCT or MCFA is administered enterally.
- the MCT or MCFA may be administered in the form of a food stuff or a supplement.
- the MCT or MCFA for use according to the present invention may, for example, be administered in a diet comprising about 1 -10%, 2-10%, 3-10%, 4-10%, 5-10%, 6-10%, 7-10% or 8-10% (w/w) of the MCT and/or MCFA of the invention.
- the MCT or MCFA for use according to the present invention may, for example, be administered in a diet comprising about 1 .5-8% (w/w) of the MCT and/or MCFA of the invention.
- the MCT or MCFA for use according to the present invention is administered in a diet comprising about 3-8% (w/w) of the MCT and/or MCFA of the invention.
- the invention provides a composition comprising a medium-chain triglyceride (MCT) and/or medium-chain fatty acid (MCFA) of the invention for use in improving cognition which has been impaired by UBE3A deficiency.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- the UBE3A deficiency may, for example, result from insufficient UBE3A activity in the brain, for example as a result of inadequate levels of expression of UBE3A or expression of an inactive form of the UBE3A enzyme.
- the composition comprises the MCTs of the invention. In another embodiment, the composition comprises the MCFAs of the invention.
- the composition improves cognition in a subject with a cognitive disorder.
- the cognitive disorder may be associated with or result from insufficient UBE3A activity in the brain.
- the composition improves cognition in a subject with Angelman syndrome or Prader-Willi syndrome.
- the composition improves cognition in an aging subject.
- the aging subject may, for example, be a human subject over the age of 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 years old.
- the invention provides a composition comprising a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) of the invention for use in treating Angelman syndrome or Prader-Willi syndrome.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- the composition may, for example, improve cognition in a subject with Angelman syndrome or Prader-Willi syndrome, and/or reduce the occurrence of seizures.
- the composition of the invention comprises a homotriglyceride comprising C8 fatty acid moieties (i.e. fatty acid moieties with 8 carbon atoms), preferably octanoic acid moieties.
- the composition of the invention comprises a homotriglyceride comprising C10 fatty acid moieties (i.e. fatty acid moieties with 10 carbon atoms), preferably decanoic acid moieties.
- the composition comprises a homotriglyceride comprising C8 fatty acid moieties (i.e. fatty acid moieties with 8 carbon atoms), preferably octanoic acid, and a homotriglyceride comprising C10 fatty acid moieties (i.e. fatty acid moieties with 10 carbon atoms), preferably decanoic acid.
- the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 90:10 (w/w) to about 10:90 (w/w). In another embodiment, the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 80:20 (w/w) to about 20:80 (w/w). In another embodiment, the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 70:30 (w/w) to about 30:70 (w/w). In another embodiment, the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 60:40 (w/w) to about 40:60 (w/w). In another embodiment, the ratio of C8:C10 fatty acid- comprising homotriglycerides is about 50:50 (w/w) to about 40:60 (w/w).
- the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 or 10:90 (w/w).
- the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 50:50 or 40:60 (w/w).
- the composition for use according to the present invention may, for example, comprise about 1 -100%, 1 -50%, 1 -30%, 1 -10%, 2-10%, 3-10%, 4-10%, 5-10%, 6-10%, 7-10% or 8-10% (w/w) of the MCT and/or MCFA of the invention.
- composition for use according to the present invention may, for example, comprise about 1 .5-8% (w/w) of the MCT and/or MCFA of the invention.
- the composition for use according to the present invention comprises about 3-8% (w/w) of the MCT and/or MCFA of the invention.
- the composition for use according to the invention is in the form of a powder.
- the powder may, for example, be a spray-dried powder or a freeze-dried powder.
- the composition for use according to the invention is in the form of an emulsion.
- the emulsion may, for example, be an oil-in-water emulsion.
- the composition for use according to the invention is in the form of a food stuff.
- the food stuff is a human food stuff.
- the food stuff may be enriched with the MCT and/or MCFA of the invention.
- the composition for use according to the invention is in the form of a beverage, mayonnaise, margarine, low fat spread, dairy product, cheese spread, processed cheese, dairy dessert, flavoured milk, cream, fermented milk product, cheese, butter, condensed milk product, ice cream mix, soya product, pasteurised liquid egg, bakery product, confectionary product, confectionary bar, chocolate bar, high fat bar, liquid emulsion, spray- dried powder, freeze-dried powder, UHT pudding, pasteurised pudding, gel, jelly, yoghurt, or a food with a fat-based or water-containing filling.
- a beverage mayonnaise, margarine, low fat spread, dairy product, cheese spread, processed cheese, dairy dessert, flavoured milk, cream, fermented milk product, cheese, butter, condensed milk product, ice cream mix, soya product, pasteurised liquid egg, bakery product, confectionary product, confectionary bar, chocolate bar, high fat bar, liquid emulsion, spray- dried powder, freeze-dried powder, U
- the invention provides the use of a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) of the invention for the manufacture of a medicament or composition for improving cognition which has been impaired by UBE3A deficiency.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- the improvement in cognition may be in a subject with a cognitive disorder; a subject with Angelman syndrome or Prader-Willi syndrome; or an aging subject.
- the invention provides the use of a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) of the invention for the manufacture of a medicament or composition for treating Angelman syndrome or Prader-Willi syndrome.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- the invention provides a method of improving cognition in a subject which has been impaired by UBE3A deficiency comprising administering an effective amount of a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) of the invention or a composition of the invention to the subject.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- the improvement in cognition may be in a subject with a cognitive disorder; a subject with Angelman syndrome or Prader- Willi syndrome; or an aging subject.
- the invention provides a method of treating Angelman syndrome or Prader- Willi syndrome in a subject comprising administering an effective amount of a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) of the invention or a composition of the invention to the subject.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- the invention provides a method of increasing UBE3A expression in a subject comprising administering an effective amount of a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) of the invention or a composition of the invention to the subject.
- the method may, for example, increase UBE3A expression in the brain, but not in other tissues, for example not in the periphery.
- MCT chronic medium-chain triglyceride
- Figure 3 mRNA expression of transcripts associated with UBE3A activity in the prefrontal cortex of 24 month-old rats in medium-chain triglyceride (MCT) treated and control (CON) groups; groups: MCT10 (capric triglyceride), MCT8 (caprylic triglyceride), "mix” (40:60 ratio of MCT8 and MCT10.
- MCT10 capric triglyceride
- MCT8 caprylic triglyceride
- Mix 40:60 ratio of MCT8 and MCT10.
- Arc hipp the MCT 10 treated group decreased compared to the control group, p ⁇ 0.05 (one way ANOVA).
- Snrpn hipp the "mix" MCT8 and MCT10 treated group increased compared to the control group, p ⁇ 0.05 (one way ANOVA).
- Octanoic acid/C8 and decanoic acid/C10 significantly increased UBE3A expression levels in the absence of glucose in the media (normalized to the beta-actin). Decanoic acid/C10 at 5 ⁇ and 50 ⁇ significantly increased UBE3A expression in the presence of low glucose at 4mM (normalized to the beta-actin).
- the invention provides a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) for use in improving cognition which has been impaired by UBE3A deficiency.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- the invention provides a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) for use in treating Angelman syndrome or Prader-Willi syndrome.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- MCTs Medium-chain triglycerides
- MCFAs medium-chain fatty acids
- a triglyceride (also known as a triacylglycerol or a triacylglyceride) is an ester that is derived from glycerol and three fatty acids.
- a medium-chain triglyceride is a triglyceride in which all three fatty acid moieties are medium-chain fatty acid moieties.
- Medium-chain fatty acids are fatty acids that have 6-12 carbon atoms.
- the fatty acid moieties are aliphatic fatty acid moieties.
- a MCT is an ester formed from a glycerol molecule and three medium-chain fatty acid molecules.
- fatty acid moiety refers to the part of the MCT that originates from a fatty acid in an esterification reaction with glycerol.
- esterification reaction between glycerol and only octanoic acid would result in a MCT with octanoic acid moieties.
- the MCT for use according to the invention may, for example, comprise three fatty acid moieties, each of which independently has between 6-12, 6-1 1 , 6-10, 7-12, 7-1 1 , 7-10, 8-12, 8-1 1 or 8-10 carbon atoms.
- the MCT for use according to the invention comprises three fatty acid moieties, each of which independently has between 8-10 carbon atoms.
- the MCT for use according to the invention may comprise three fatty acid moieties, each of which independently has only 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms.
- the MCT for use according to the invention comprises three fatty acid moieties, each of which independently has only 8 or 10 carbon atoms, i.e. preferably, the MCT for use according to the invention comprises only C8 and/or C10 fatty acid moieties.
- the fatty acid moieties are octanoic acid and/or decanoic acid moieties.
- the MCT for use according to the invention may be a homotriglyceride (i.e. all of the fatty acid moieties of the MCT may be of the same identity, for example a C8 homotriglyceride may comprise 3 octanoic acid moieties).
- the MCT for use according to the invention comprises three fatty acid moieties with only 8 carbon atoms. In a preferred embodiment, all three fatty acid moieties are octanoic acid moieties.
- the MCT for use according to the invention comprises three fatty acid moieties with only 10 carbon atoms.
- all three fatty acid moieties are decanoic acid moieties.
- Octanoic acid (also known as caprylic acid) is a saturated fatty acid of the formula CH 3 (CH 2 ) 6 COOH.
- Decanoic acid (also known as capric acid) is a saturated fatty acid of the formula CH 3 (CH 2 ) 8 COOH.
- MCTs are present in low amounts in palm oil and coconut oil, for example. Decanoic acid and octanoic acid form about 5-8% and 4-10% of the fatty acid composition of coconut oil, respectively.
- UBE3A encodes a ubiquitin E3 ligase that targets specific proteins for degradation (de Bie, P. and Ciechanover A. (201 1 ) Cell Death Differ. 18: 1393-402) and is essential for normal cognitive function due to its role as the major ubiquitin binding protein in the synapse.
- UBE3A's ability to clear synaptic signalling proteins e.g. Arc
- the medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) and composition of the invention may be used for improving cognition.
- the MCT and composition of the invention may be used for improving cognition in a subject suffering from or at risk of suffering from a cognitive disorder, Angelman syndrome or Prader-Willi syndrome, and/or an aging subject.
- cognition refers to the set of all mental abilities and processes, including knowledge, attention, long-term memory and working memory, judgment and evaluation, reasoning and "computation”, problem solving and decision making, comprehension and production of language.
- MMSE Mini Mental State Examination
- CANTAB Cambridge Neuropsychological Test Automated Battery
- ADAScog Alzheimer's Disease Assessment Scale-cognitive test
- Wisconsin Card Sorting Test Verbal and Figural Fluency Test and Trail Making Test
- EEG electroencephalography
- MEG Magnetoencephalography
- PET Positron Emission Tomography
- SPECT Single Photon Emission Computed Tomography
- MRI Magnetic Resonance Imaging
- fMRI Magnetic Resonance Imaging
- Cognitive and behavioural tests for assessing Angelman and Prader-Willi syndrome children include tests which measure attention, self-directed behaviour, motor ability and memory such as the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), Bayley, H. (2005); Preschool Language Scale, Fourth Edition (PLS-4),Zimmerman, I.L. et al. (2002); and Vineland Adaptive Behavior Scales, Second Edition (VABS-II), Sparrow, S.S. et al. (2005).
- Improved cognition may, for example, be interpreted as a statistically significant difference from the baseline performance in a suitable test (e.g. based on the Bayley Scales of Infant and Toddler Development). Genetic tests
- Genetic test for Angelman syndrome Diagnosis of Angelman syndrome may be carried out via molecular genetic testing that suggests deficient expression or function of the maternally inherited UBE3A allele. Analysis of parent-specific DNA methylation imprints in the 15q1 1 .2-q13 chromosome region detects approximately 80% of individuals with Angelman syndrome, including those with a deletion, uniparental disomy (UPD) or an imprinting defect (ID); fewer than 1 % of individuals have a cytogenetically visible chromosome rearrangement (i.e. translocation or inversion). UBE3A sequence analysis detects pathogenic variants in an additional approximately 1 1 % of individuals. Therefore, molecular genetic testing (e.g. methylation analysis and UBE3A sequence analysis) may identify alterations in approximately 90% of individuals. Genetic test for Prader-Willi syndrome
- a genetic test for Prader-Willi syndrome may assay the 5' CpG island of the SNRPN locus, which controls UBE3A transcription (via non-coding RNA encoded in the SNRPN transcript).
- the promoter, exon 1 and intron 1 region of SNRPN are un-methylated on the paternally expressed allele and methylated on the maternally repressed allele.
- Subjects with Prader-Willi syndrome have only the maternally methylated allele.
- EEG a measure of electrical activity of the brain, is accomplished by placing electrodes on the scalp at various landmarks and recording greatly amplified brain signals. MEG is similar to EEG in that it measures the magnetic fields that are linked to electrical fields. MEG is used to measure spontaneous brain activity, including synchronous waves in the nervous system.
- PET provides a measure of oxygen utilisation and glucose metabolism.
- a radioactive positron-emitting tracer is administered, and tracer uptake by the brain is correlated with brain activity.
- These tracers emit gamma rays which are detected by sensors surrounding the head, resulting in a 3D map of brain activation.
- the detected radioactivity occurs as a function of regional cerebral blood flow.
- an increase in cerebral blood flow and neuronal glucose metabolism can be detected within seconds.
- Suitable analysis can also be based on neuropsychiatric testing, clinical examinations and individual complaints of loss of cognitive function (e.g. subjective memory loss). Further suitable tests may be based on assessments of locomotion, memory and attention, seizure susceptibility, and social interaction and/or recognition. These tests are particularly suitable for assessing disorders such as Angelman syndrome and/or Prader-Willi syndrome, and the effects of treatments thereon.
- the medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) and composition of the invention may be used to improve cognition in a subject with a cognitive disorder.
- cognitive disorder refers to disorders that give rise to impaired cognition, in particular disorders that primarily affect learning, memory, perception, and/or problem solving.
- the medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) and composition of the invention may be used to improve cognition in a subject with Angelman syndrome or Prader-Willi syndrome.
- the MCT, MCFA and composition of the invention may be used to treat Angelman syndrome or Prader-Willi syndrome.
- Angelman syndrome is a genetic disorder that results in functionally severe developmental delay, which is characterised by severe speech impairment, movement or balance disorders, intellectual disability, epilepsy and odd behaviour. Behavioural signatures of Angelman syndrome children include frequent laughter and/or smiling, and an easily excitable personality, often with hand flapping movements. The majority of Angelman syndrome patients experience seizures, with an onset usually before 3 years of age. Almost all show abnormal electroencephalograms (EEGs), which may be used during diagnosis. Patients with Angelman syndrome often exhibit deficient socialisation and communication in a manner that meets the diagnostic criteria for autism.
- EEGs abnormal electroencephalograms
- Angelman syndrome is caused by dysfunction of UBE3A, a gene located at the q1 1 -q13 region of chromosome 15.
- a mutation in UBE3A can either arise spontaneously or be maternally inherited.
- the UBE3A region is deleted from the maternal chromosome, while the paternal chromosome is intact.
- UBE3A is transcribed from both chromosomes during gestation, but during the first year of life the paternal gene is epigenetically silenced in the brain.
- Angelman syndrome patients express UBE3A in the periphery, but show no UBE3A expression in the brain.
- Prader-Willi syndrome is a genetic disorder related to Angelman syndrome that is caused by lack of expression of a number of genes from the q 1 1 -q 13 region of the paternally inherited chromosome 15.
- the chromosome 15q1 1 -q13 region is subject to epigenetic silencing through imprinting.
- the gene(s) on the maternal chromosome are usually imprinted.
- the paternal gene(s) are dysfunctional, this may give rise to the onset of disease.
- Prader-Willi syndrome patients experience significant cognitive, neurological, endocrine and behavioural abnormalities. Furthermore, patients may have difficulty in feeding in infancy due to hypotonia, leading to growth retardation, however they become obese later in life due to an uncontrollable craving for food.
- the invention provides a composition comprising a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) of the invention for use in improving cognition which has been impaired by UBE3A deficiency.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- the invention provides a composition comprising a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) of the invention for use in treating Angelman syndrome or Prader-Willi syndrome.
- MCT medium-chain triglyceride
- MCFA medium-chain fatty acid
- the composition may comprise a plurality of MCTs and/or MCFAs as defined herein.
- the composition may comprise a concentration of about 5 g/L to 150 g/L of the MCT and/or MCFA of the invention.
- the concentration may be about 5 g/L, 10 g/L, 15 g/L, 20 g/L, 30 g/L, 40 g/L, 50 g/L, 60 g/L, 70 g/L, 80 g/L, 90 g/L, 100 g/L, 1 10 g/L, 120 g/L, 130 g/L, 140 g/L, 150 g/L, 175 g/L, 200 g/L, 225 g/L or 250 g/L of the MCT and/or MCFA of the invention.
- the composition may comprise a homotriglyceride comprising C8 fatty acid moieties (i.e. fatty acids with 8 carbon atoms), preferably octanoic acid moieties.
- C8 fatty acid moieties i.e. fatty acids with 8 carbon atoms
- octanoic acid moieties i.e. fatty acids with 8 carbon atoms
- the composition may comprise a homotriglyceride comprising C10 fatty acid moieties (i.e. fatty acids with 10 carbon atoms), preferably decanoic acid moieties.
- C10 fatty acid moieties i.e. fatty acids with 10 carbon atoms
- decanoic acid moieties i.e. fatty acids with 10 carbon atoms
- the composition may comprise a homotriglyceride comprising C8 fatty acid moieties (i.e. fatty acids with 8 carbon atoms), preferably octanoic acid, and a homotriglyceride comprising C10 fatty acid moieties (i.e. fatty acids with 10 carbon atoms), preferably decanoic acid.
- the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 90:10 (w/w) to about 10:90 (w/w).
- the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 80:20 (w/w) to about 20:80 (w/w).
- the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 70:30 (w/w) to about 30:70 (w/w). In another embodiment, the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 60:40 (w/w) to about 40:60 (w/w). In another embodiment, the ratio of C8:C10 fatty acid- comprising homotriglycerides is about 50:50 (w/w) to about 40:60 (w/w).
- the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 or 10:90 (w/w).
- the ratio of C8:C10 fatty acid-comprising homotriglycerides is about 50:50 or 40:60 (w/w).
- composition may be free from or substantially free from mono- or poly-unsaturated fatty acids.
- the composition may have a ketogenic ratio of 0.2 to 0.3:1 .
- the ratio may be 0.5:1 or 1 :1 to 5:1.
- ketoogenic ratio refers to the weight of lipid to the sum of the weights of carbohydrate and protein.
- composition may be in the form of a tablet, dragee, capsule, gel cap, powder, granule, solution, emulsion, suspension, coated particle, spray-dried particle or pill.
- the composition may be in the form of a powder.
- the powder may, for example, be a spray- dried powder or a freeze-dried powder.
- the composition may be in the form of an emulsion.
- the emulsion may, for example, be an oil-in-water emulsion.
- the composition may be usable for reconstitution in water.
- the composition may be inserted or mixed into a food substance.
- the composition may be in the form of a food stuff.
- the food stuff is a human food stuff.
- the composition may be in the form of a nutritional supplement.
- nutritional supplement refers to a product which is intended to supplement the general diet of a subject.
- composition may be in the form of a complete nutritional product.
- complete nutritional product refers to a product which is intended to be the sole item, meal or diet consumed by a subject.
- the composition may be in the form of a beverage, mayonnaise, margarine, low fat spread, dairy product, cheese spread, processed cheese, dairy dessert, flavoured milk, cream, fermented milk product, cheese, butter, condensed milk product, ice cream mix, soya product, pasteurised liquid egg, bakery product, confectionary product, confectionary bar, chocolate bar, high fat bar, liquid emulsion, spray-dried powder, freeze-dried powder, UHT pudding, pasteurised pudding, gel, jelly, yoghurt, or a food with a fat-based or water-containing filling.
- a beverage mayonnaise, margarine, low fat spread, dairy product, cheese spread, processed cheese, dairy dessert, flavoured milk, cream, fermented milk product, cheese, butter, condensed milk product, ice cream mix, soya product, pasteurised liquid egg, bakery product, confectionary product, confectionary bar, chocolate bar, high fat bar, liquid emulsion, spray-dried powder, freeze-dried powder, UHT pudding,
- the composition may be an infant formula.
- the composition may be enriched with a MCT and/or MCFA of the invention.
- enriched means that the MCT and/or MCFA has been added to the composition.
- the MCT and/or MCFA may be spiked (i.e. added within or into) the composition.
- enriched with a MCT or MCFA means that the enriched composition comprises a greater amount of the MCT or MCFA than occurs natively in the composition.
- an enriched composition, food or food extract may comprise at least 1.5-, at least 2-, at least 5-, at least 10-, at least 20-, at least 50- or at least 100-fold more MCT and/or MCFA of the invention than an equivalent native composition, food or food extract which has not been enriched.
- the invention provides the use of a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) of the invention for the manufacture of a medicament or composition for improving cognition which has been impaired by UBE3A deficiency.
- the invention also provides the use of a medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) of the invention for the manufacture of a medicament or composition for treating Angelman syndrome or Prader-Willi syndrome.
- the term “medicament” includes a composition as described herein, including a nutritional supplement and a complete nutritional product.
- the medicament may comprise suitable pharmaceutically acceptable carriers, diluents and/or excipients.
- the medium-chain triglyceride (MCT) or medium-chain fatty acid (MCFA) and compositions of the invention may be administered enterally or parenterally.
- the MCT, MCFA or composition is administered enterally.
- the MCT or MCFA may be administered in the form of a food stuff or a supplement.
- administration of the MCT, MCFA or composition of the invention may, for example, be by an oral route or another route into the gastro-intestinal tract, for example the administration may also be by gastric tube feeding.
- the invention relates to the treatment of Angelman syndrome or Prader- Willi syndrome.
- the treatment may, for example, improve cognition in a subject with Angelman syndrome or Prader-Willi syndrome, and/or reduce the occurrence of seizures.
- all references herein to treatment include curative, palliative and prophylactic treatment; although in the context of the invention references to preventing are more commonly associated with prophylactic treatment. Treatment may also include arresting progression in the severity of a disease.
- the subject to be treated may, for example, be a child or an infant.
- the rats were randomised into four groups according to cognition and body weight. Baseline cognition was tested via social recognition, using the procedure described below.
- Rats were single-housed in standard cages with free access to food and water, and were kept at a 12 hour light cycle period, at a temperature between 20-24°C and a relative humidity between 50-60%. Rats were given a diet of 5% medium-chain triglycerides (MCTs): caprylic triglyceride (C8); capric triglyceride (C10); a 40:60 combination of C8 and C10 triglycerides; or control (5% sunflower oil) via specially formulated animal chow for 8 weeks.
- MCTs medium-chain triglycerides
- Rats were tested for behavioural effects of MCT via a social interaction test 3 days before sacrifice. This test involved introduction of an unfamiliar juvenile rat into the home cage of the test rat for 4 minutes. The amount of touching, sniffing and general exploration of the juvenile rat is recorded, and the total time period of social interaction was used as an index of sociality and anxiety. After 1 h the previously explored juvenile and a new juvenile was introduced into the home cage for 4 minutes and social recognition was calculated by the amount of time spent exploring the new juvenile over the total amount of time spent exploring both juveniles (JNEW/(JNEW+JOLD)), which is termed "novel vs total exploration of the juveniles".
- Rat-Arc-F acagacacagcagatccagc (SEQ ID NO: 2) ;
- Rat-Arc-R tgagtcatggagccgaagtc (SEQ ID NO: 3)
- Rat-Actin-F gtcgtaccactggcattgtg (SEQ ID NO: 4) ;
- Rat-Actin-R ctctcagctgtggtggtgaa (SEQ ID NO: 5)
- Rat-Snrpn-F TTGGTTCTGAGGAGTGATTTGC (SEQ ID NO: 6)
- Rat-Snrpn-R CCTTGAATTCCACCACCTTG (SEQ ID NO: 7)
- Rat-Ube3a-F GGCACCCTTGTTTGAAACTT (SEQ ID NO: 8)
- Rat-Ube3a-R GCTCATGACCCTGTCCTTTC (SEQ ID NO: 9) Results
- the rats were randomised into four groups according to cognition and body weight. Baseline cognition was tested via social recognition, using the procedure described for Example 1.
- Rats were single-housed in standard cages with free access to food and water, and were kept at a 12 hour light cycle period, at a temperature between 20-24°C and a relative humidity between 50-60%. Rats were given a diet of 5% medium-chain triglycerides (MCTs): caprylic triglyceride (C8); capric triglyceride (C10); a 50:50 combination of C8 and C10 triglycerides; or control (sunflower oil) for 8 weeks.
- MCTs medium-chain triglycerides
- UBE3A expression was analysed in immature mice that were exposed to a caprylic homotriglyceride (MCT8) diet during gestation and weaning (via nursing).
- MCT8 caprylic homotriglyceride
- mice Female C57 mice were mated and pregnancy tracked via vaginal smearing. MCT8 was mixed in animal chow (1.5%) and administered to pregnant mouse females between day 10 of gestation and postnatal day 28 while pregnant mice received chow supplemented with 1 .5% sunflower oil (control) . At postnatal day 28, pup brains and livers were collected, fixed, frozen and processed for UBE3A expression.
- mice were tested at postnatal day 60 in a Morris Water Maze task.
- the apparatus used for behaviour consisted of a gallon tank with a platform placed in one of the quadrants.
- the tank was filled with warm water (24°C), made opaque.
- a video camera recorded animal movement within the tank. Visual cues were placed in several quadrants of the tank.
- Human iCell neurons (Cellular Dynamics International) were plated in 24 well plates and were grown to neuronal maturity by culturing for 2 weeks. Cells were then treated with octanoic or decanoic acid (100 ⁇ ) for 6 days, where fresh medium-chain fatty acid (MCFA) was added to the wells every 2 days. Cells were scraped and stored in Trizol, and mRNA extracted. qPCR was performed to probe UBE3A and GRIN1 levels according to the protocol referred to above.
- mice Male Sprague-Dawley rats (8 MCT treated and 8 sunflower oil control) were acclimated for at least 5 days. Animals of all groups were provided with tap water ad libitum during the whole study. A standard diet (RM1 , SDS Dietex) was provided also to the animals during the whole study. Oral administrations (P.O.) were performed on un-anaesthetized animals using an oral gavage probe.
- Example 6 Human iCell neurons (Cellular Dynamics International) were plated in 24-well plates and were cultured for 2 weeks. Cells were then treated with octanoic (C8) or decanoic acid (C10) at different concentrations (C8: 0.25 ⁇ , 2.5 ⁇ , 25 ⁇ ; C10: 0.5 ⁇ , 5 ⁇ , 50 ⁇ ) at 3 different glucose concentrations (25mM, 4mM, OmM) for 3 days. Cells were harvested and processed for real-time PCR. The following probes were used: UBE3A and beta-actin.
- Octanoic acid/C8 and decanoic acid/C10 significantly increased UBE3A expression levels in the abscence of glucose in the media (normalized to the beta-actin).
Abstract
Description
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CN110427536B (en) * | 2019-08-12 | 2022-03-04 | 深圳忆海原识科技有限公司 | Brain-like decision and motion control system |
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