US20100063147A1 - Anaplerotic Therapy of Huntington Disease and Other Polyglutamine Diseases - Google Patents

Anaplerotic Therapy of Huntington Disease and Other Polyglutamine Diseases Download PDF

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US20100063147A1
US20100063147A1 US12/516,486 US51648607A US2010063147A1 US 20100063147 A1 US20100063147 A1 US 20100063147A1 US 51648607 A US51648607 A US 51648607A US 2010063147 A1 US2010063147 A1 US 2010063147A1
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disease
precursor
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Alexandra Durr
Fanny Mochel
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Institut National de la Sante et de la Recherche Medicale INSERM
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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
    • A61K31/21—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
    • A61K31/225—Polycarboxylic acids
    • 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
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A23L29/04—Fatty acids or derivatives
    • 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
    • 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
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to the treatment and the prevention of Huntington disease and other polyglutamine diseases.
  • HD Huntington disease
  • a method for treating and/or preventing a polyglutamine disease comprising the step of administering an effective amount of a precursor of propionyl-CoA to an individual in need thereof.
  • the present invention provides a method for treating and/or preventing a polyglutamine disease, comprising the step of administering an effective amount of a precursor of propionyl-CoA to an individual in need thereof.
  • Polyglutamine diseases constitute a class of nine genetically distinct disorders that are caused by expansion of translated CAG repeat. These include Huntington disease (HD), dentatorubralpallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA) and spinocerebellar ataxia 1, 2, 3, 6, 7 and 17.
  • HD Huntington disease
  • DRPLA dentatorubralpallidoluysian atrophy
  • SBMA spinal and bulbar muscular atrophy
  • spinocerebellar ataxia 1, 2, 3, 6, 7 and 17.
  • the polyglutamine disease is selected from the group consisting of Huntington disease (HD), dentatorubralpallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia 1, 2, 3, 6, 7 and 17.
  • HD Huntington disease
  • DPLA dentatorubralpallidoluysian atrophy
  • SBMA spinal and bulbar muscular atrophy
  • spinocerebellar ataxia 1, 2, 3, 6, 7 and 17.
  • the polyglutamine disease is Huntington disease.
  • propionyl-CoA By precursor of propionyl-CoA, it is meant a substance from which propionyl-CoA can be formed by one or more metabolic reactions taking place within the body.
  • precursors of propionyl-CoA are shown in FIG. 5 .
  • Typical examples of precursors of propionyl-CoA are odd-medium-chain fatty acids, in particular seven-carbon fatty acid, triheptanoin (triheptanoyl-glycerol), heptanoate, C5 ketone bodies, (e.g. ⁇ -ketopentanoate (3-ketovalerate), and ⁇ -hydroxypentanoate (3-hydroxyvalerate)) (Kinman 2006, Am J Physiol Endocrinol Metab 291 (4): E860-6, Brunengraber and Roe 2006, J Inherit Metabol Dis 29 (2-3): 327-31).
  • the examples of precursors of propionyl-CoA described above include the compounds themselves, as well as their salts, prodrugs, solvates, if applicable.
  • prodrugs include esters, oligomers of hydroxyalkanoate such as oligo(3-hydroxyvalerate) ( Seebach 1999, Int J Biol Macromol 25 (1-3): 217-36) and other pharmaceutically acceptable derivatives, which, upon administration to a individual, are capable of providing propionyl-CoA.
  • a solvate refers to a complex formed between a precursor of propionyl-CoA described above and a pharmaceutically acceptable solvent.
  • pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.
  • a very practical dietary source of propionyl-CoA is triheptanoin (triheptanoyl-glycerol).
  • heptanoate After intestinal hydrolysis of triheptanoin, heptanoate is absorbed in the portal vein. In the liver, it is partially converted to the C5 ketone bodies ⁇ -ketopentanoate (3-ketovalerate), and ⁇ -hydroxypentanoate (3-hydroxyvalerate).
  • the C5-ketones bodies are also precursors of propionyl-CoA in peripheral tissues.
  • peripheral tissues receive two precursors of propionyl-CoA, i.e., heptanoate and C5-ketone bodies.
  • CS- like C4-, ketone bodies are natural substrates for the brain and can target physiological receptors at the surface membrane of the blood brain barrier.
  • the precursor of propionyl-CoA is triheptanoin, heptanoic acid or heptanoate.
  • Triheptanoin has already been used in the anaplerotic treatment of a few pathologies having in common a decrease in ATP production in spite of ample supply of acetyl-CoA to the citric acid cycle (CAC), and a normal respiratory chain.
  • Such pathologies include cardiac reperfusion injury (Reszko 2003, JBC 278: 34959-65), long-chain fatty acid oxidation disorders (FOD) (Roe 2002,JCI 110: 259-69 and WO 0045649); pyruvate carboxylase deficiency (Mochel 2005, Mol Genet Metab 84: 305-12) and glycogen storage disease type 11 (Roe and Mochel 2006, J Inherit Metab Dis 29 (2-3): 332-40)
  • Triheptanoin is a triglyceride made by the esterification of three n-heptanoic acid molecules and glycerol.
  • heptanoic acid, heptanoate, and triheptanoin may be used interchangeably in the following description.
  • heptanoic acid, heptanoate; and triheptanoin are exemplary precursors of propionyl-CoA of the invention.
  • Substituted, unsaturated, or branched heptanoate, as well as other modified seven-carbon fatty acids can be used without departing from the scope of the invention.
  • Heptanoic acid is found in various fusel oils in appreciable amounts and can be extracted by any means known in the art. It can also be synthesized by oxidation of heptaldehyde with potassium permanganate in dilute sulfuric, acid (Ruhoff, Org Syn Coll. voIII, 315 (1943)). Heptanoic acid is also commercially available through Sigma Chemical Co. (St. Louis, Mo.).
  • Triheptanoin can be obtained by the esterification of heptanoic acid and glycerol by any means known in the art. Triheptanoin is also commercially available through CondeaChemie GmbH (Witten, Germany) as Special Oil 107.
  • Unsaturated heptanoate can also be utilized in the present invention.
  • substituted, unsaturated, and/or branched seven-carbon fatty acids which readily enter the mitochondrion without special transport enzymes can be utilized in the present invention.
  • 4-methylhexanoate, 4-methylhexenoate, and 3-hydroxy-4-methylhexanoate are broken down by normal b-oxidation to 2-methylbutyric acid with final degradation accomplished via the isoleucine pathway.
  • 5-methylhexanoate, 5-methylhexenoate, and 3-hydroxy-5-methylhexanoate are broken down by normal b-oxidation to isovaleric acid with final degradation accomplished via the leucine pathway.
  • Precursors of propionyl-CoA of the present invention can be administered orally, parenterally, or intraperitoneally. Preferably, it can be administered via ingestion of a food substance containing a precursor of propionyl-CoA such as triheptanoin at a concentration effective to achieve therapeutic levels. Alternatively, it can be administered as a capsule or entrapped in liposomes, in solution or suspension, alone or in combination with other nutrients, additional sweetening and/or flavoring agents. Capsules and tablets can be coated with sugar, shellac and other enteric agents as is known. Typically medicaments according to the invention comprise a precursor of propionyl-CoA, together with a pharmaceutically-acceptable carrier. A person skilled in the art will be aware of suitable carriers. Suitable formulations for administration by any desired route may be prepared by standard methods, for example by reference to well-known text such as Remington; The Science and Practice of Pharmacy.
  • FIG. 1 Partial least square (PLS) analyses of NMR spectra of plasma samples from HD patients with no or little signs of the disease and controls.
  • Three groups of premanifest, early and mildly affected HD patients were constituted on the basis of their UHDRS scores, as described in the methods.
  • the first and second components in the X space (NMR spectrum) are denoted PC[1] and PC[2] respectively.
  • PLS score plots (PC[1]/PC[2]) of pair-wise compared groups show the greater variation within the NMR spectrum according to a priori classification with UHDRS.
  • FIG. 2 Plasma relative concentrations of branched chain amino acids are responsible for separation between HD groups.
  • PLS-contribution plot allows comparison between plasma metabolic profiles from early affected HD patients to premanifest carriers.
  • FIG. 3 The levels of branched chain amino acids are significantly different in HD patients and controls.
  • the concentrations of valine, leucine and isoleucine in plasma were determined by ion exchange chromatography. Comparisons of means (ANOVA) were made between men or women with HD and their respective controls.
  • FIG. 4 Plasma branched chain amino acids are negatively correlated with disease progression in HD.
  • Principal component analysis (PCA) loading plot shows the relative importance of each variable from the study and the correlation between these variables. The more the loading (p) of each variable diverges from zero, the more this variable is important in the explained variance of the given component (expressed by R2x). The explained variance of all data reach 44% in the first component and 22% in the second component. There is strong negative correlation between clinical markers (the size of the abnormal CAG repeat expansion, disease severity measured by the
  • FIG. 5 Diagram depicting the metabolic pathway of triheptanoin.
  • FIG. 6 Purkinje cell survival 12 days and 20 days following infection with the lentiviral vectors. 100Q: ATXN7T-100Q-GFP. 10Q: ATXN7T-10Q-GFP. GFP: control vector expressing GFP alone.
  • the Purkinje cell survival is expressed as the percentage of Calbindin-positive cells in infected cultures compared to non-infected cultures. 12 days after infection by ATXN7T-100Q-GFP, Purkinje cell survival is reduced to ⁇ 30% and further decreases to ⁇ 15% after 20 days demonstrating the high and progressive neurotoxicity of the mutant protein, which is clearly distinct from the toxicity of the viral vector alone (GFP condition).
  • HD Huntington disease
  • UHDRS Unified Huntington disease rating scale
  • ppm parts per million
  • PCA principal components analysis
  • PLS partial least square
  • Huntington disease is an autosomal dominant neurodegenerative disorder in which an energy deficiency is thought to play a role. Patients consistently lose weight, although the reason for this is unknown.
  • premanifest carriers in HD we performed a multiparametric study in a group of 32 individuals with no sign or little of the disease compared to 21 controls. Weight loss was observed even in premanifest carriers in the HD group, although their caloric intake was higher. Inflammatory processes were ruled out, as well as primary hormonal dysfunction, including ghrelin and leptin balance. Proton nuclear magnetic resonance spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and premanifest carriers from controls.
  • BCAA branched chain amino acids
  • IGF1 insulin growth factor type 1
  • PCA on plasma NMR spectra identified no outliers in both the control and HD dataset.
  • PLS analyses could distinguish HD individuals at different stages of the disease, meaning that underlying plasma metabolites behaved differently.
  • the difference between premanifest carriers and early HD was evident ( FIG. 1 a ), and extended to more advanced stages of the disease ( FIG. 1 b ).
  • controls and premanifest carriers did not have the same metabolic profile, despite some overlap ( FIG. 1 c ).
  • FIG. 2 The spectral region that contributed to differences among the HD groups determined from PLS contribution plots is shown in FIG. 2 .
  • Plasma metabolic profile from early affected HD patients to premanifest carriers was compared, as well as from mildly to early affected HD patients. There was a significant (>2SD) decrease along with disease progression in the plasma concentrations of a group of variables from the buckets located between 0.9 to 1.05 ppm on the NMR spectrum. These peaks correspond to the branched chain amino acids (BCAA), valine, leucine and isoleucine. No other significant differences among the groups were detected in the spectra even though very small buckets (0.02 ppm) were analyzed. This indicates that a selective decrease in BCAA concentrations accompanies the progression of the disease, and even distinguishes premanifest carriers from both controls and early HD patients. Plasma BCAA levels appear, therefore, to be relevant biomarkers of HD.
  • BCAA BCAA are affected in HD.
  • valine When comparing premanifest carriers to controls, the plasma levels of valine (228 ⁇ 50 versus 245 ⁇ 44), leucine (130 ⁇ 24 versus 144 ⁇ 23) and isoleucine (62 ⁇ 12 versus 68 ⁇ 15) were lower in the former group, although not significantly. This is likely due to the heterogeneity of the premanifest group in which the estimated time to disease onset is expected to vary between individuals, so that the metabolic profile of some premanifest carriers can be similar to controls.
  • a multivariate PCA confirms that there is a strong negative correlation between clinical markers (abnormal CAG repeat expansion size, UHDRS scores, depression scores) and weight parameters ( FIG. 4 ).
  • Low BCAA values appear to be the strongest variables that are negatively correlated with HD and positively correlated with weight loss.
  • BMI lean and fat body mass
  • IGF1 is also a more sensitive indicator of nutrient repletion than albumin, prealbumin or orosomucoide, as observed in our study.
  • huntingtin is a substrate of the serine-threonine Akt pathway, which is activated by IGF1 (Humbert et al. 2002). Altered activation of the Akt pathway has been shown to decrease phosphorylation of the mutated huntingtin, resulting in an increased neuronal toxicity (Rangone et al. 2005). Low levels of IGF1 in HD patients might therefore provide an explanation of the alteration in Akt activation observed in HD cellular models. Consequently, increasing BCAA levels to correct the deficit in IGF1, should favor the phosphorylation of mutated huntingtin, thereby decreasing its toxicity.
  • anaplerotic therapies represent promising molecules for reversing the energy deficiency associated with neurodegenerative diseases and thereby correcting some if not all clinical manifestations of these diseases.
  • Weight loss was calculated by subtracting current weight from the weight of the patient 5 years before inclusion in the study. This information was obtained during the interview and was verified retrospectively from the patients' medical files.
  • the body mass index is (BMI) was obtained by dividing weight (in kilograms) by height (in meters) squared.
  • Bioelectrical impedance (Tanita®) was measured to evaluate the lean mass and fat mass of all participants (Segal et al. 1988).
  • a standardized protocol was designed to thoroughly evaluate all possible causes of weight loss and to avoid biases related to food intake and circadian changes. It included sequentially: (i) a minimal 12 hours fast the night preceding the examination, (ii) and morning blood and urine collection at the same hour (9 am) Samples were stored on ice for immediate analyses or frozen at ⁇ 80° C. for further analyses.
  • the evaluation of inflammation included determination of the erythrocyte sedimentation rate (ESR) and quantification of C-reactive protein (CRP) and the serum interleukins IL1 ⁇ and IL6 by ELISA (Diaclone, Besancon, France).
  • ESR erythrocyte sedimentation rate
  • CRP C-reactive protein
  • IL1 ⁇ and IL6 serum interleukins IL1 ⁇ and IL6 by ELISA (Diaclone, Besancon, France).
  • the basic endocrine evaluation included measurements of fasting serum cortisol (at 9am), tetraiodothyronine (T4L), thyroid stimulating hormone (TSH) and insulin (Elisa Access ultrasensitive insulin, Beckman Coulter, Roissy, France).
  • TSP- 2 H 2 O Aldrich
  • the pH of the ultrafiltrate was adjusted to 2.50 ⁇ 0.05 with concentrated HCl. Finally, 500 ⁇ l of the sample was placed in a 5 mm NMR tube (Wilmad Royal Imperial).
  • the 1 H NMR spectra were determined on an Avance-500 SB spectrometer (Bruker, France) equipped with a 5 mm BBI inverse) probe; samples were not spun. Spectra were collected at 25° C. and consisted in 32K data points with a spectral width of 6,000 Hz and a total acquisition times of 27 min. A 90° radiofrequency pulse, following a water signal presaturation of 10s, was used for each 128 scans. Shimming of the sample was performed automatically on the deuterium signal.
  • the resonance line widths for TSP and metabolites were ⁇ 1 Hz.
  • the phase and the baseline were corrected manually using the spectrometer software (X-Win NMR 3.5, Bruker, France). NMR spectra were first analyzed individually in order to detect abnormal signals—i.e. treatment or special food—that could further interfere with global analyses.
  • spectra were data reduced in numerical format by integrating spectral regions (buckets) every 0.02 ppm and scaled to the total intensity of the spectrum with Amix 3.6.8 software (Bruker Analytician Messtechnik, Germany) from 0.8 to 8.6 ppm, the water peak area being excluded from each spectrum (4.4 to 5.2 ppm). Accordingly, each bucket from the NMR spectrum corresponded to a single variable.
  • PCA principal components analysis
  • PLS partial least squares analysis
  • PLS is a regression extension of PCA and best describe the variation within the data according to a priori classification, corresponding to a Y variable, which was the UHDRS score in our study.
  • PLS was used to identify principal components maximizing the covariance between all X (NMR spectrum) and Y (UHDRS) variables. The greatest dispersion of the spectral profiles is usually best observed in the two first components of the analyses.
  • the first and second components in the X space (NMR spectrum) were denoted PC[1] and PC[2] respectively. Therefore, PLS score plot (PC[1]/PC[2]) of pair-wise compared groups displayed the greater variation within the NMR spectrum according to UHDRS. The validity of each component was obtained by cross validation. Contribution plot was then analyzed in order to determine the respective weight of variables contributing most to the separation between groups.
  • IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt.” Dev Cell 2 (6): 831-7.
  • a pilot study is conducted to test the effect of dietary triheptanoin therapy versus control diet on selected strains of HD R6/2 mice (Mangariani 1996, Cell 87: 493-506, Kosinski 1999, Neuroreport 10: 3891-6).
  • the study includes (i) measuring rates of cerebral anaplerosis from heptanoate and brain ATP in R6/2 mice of different ages and in control mice in order to demonstrate the ability of triheptanoin metabolites to cross the blood brain barrier of R6/2 mice and to reverse central energy deficit; (ii) assessing, the therapeutic efficacy of triheptanoin by accurate behavioral testing, in vivo brain microdialysis (to assay neurotransmitters, triheptanoin metabolites, and BCAA) and neuropathological examination; (iii) metabolomic analyses on mouse plasma and urine.
  • R6/2 and control mice, on triheptanoin-enriched and control diets, are infused sequentially—at 4, 8 and 12 weeks—with various doses of [5,6,7- 13 C 3 ] heptanoate (by gavage or by intravenous infusion) for 1 hr before brain sampling, in order to follow the kinetics of anaplerosis in the brain (using the assay of anaplerotic CoA esters).
  • concentrations of ATP, ADP, and AMP are assayed in all brain samples, as well as in muscle of R6/2 mice.
  • GABA neurotransmitters generated by anaplerosis
  • Behavioral analyses include (i) open field activity monitoring using the TruScan system at 4, 8 and 12 weeks; (ii) RotaRod analysis performed using the AccuScan system equipped with a shockable floor at 6 and 12 weeks; (iii) and the Morris Water Maze, the most popular task in behavioral neuroscience used to assess spatial learning and memory at 12 weeks. Other primary endpoints from the study are weight loss and survival.
  • All right side regions are processed for analysis of DA, 5-hydroxytryptophane (5-HT) and norepinephrine (NE) and related metabolites (3-dihydrophenylacetic acid, homovalinic acid, 3-methoxytyramine and 5-hydroxyindolacetic acid) by HPLC with electrochemical detection.
  • Acetylcholine (Ach) is also measured in frontal posterior cortex tissue by HPLC with electrochemical detection.
  • Branched chain amino acids is measured by HPLC and triheptanoin metabolites by mass spectrometry.
  • Neuropathology, and especially nuclear neuronal inclusions, is performed on the left side regions.
  • a second group of animals is prepared for in vivo microdialysis to monitor in-vivo release of DA, 5-HT by potassium and Ach release by scopolamine in the striatum. Changes in the extracellular concentrations of DA, 5-HT and Ach is compared by three ways ANOVA (time x genotype x diet) with repeated measures.
  • the cells were infected at DIV1 (1st Day In Vitro) with lentiviral vectors carrying truncated forms of normal and mutant ataxin 7 (ATXN7T: amino acids 1-232) fused to GFP (ATXN7T-10Q-GFP, ATXN7T-100Q-GFP).
  • ATXN7T normal and mutant ataxin 7
  • GFP GFP
  • ATXN7T-10Q-GFP ATXN7T-10Q-GFP
  • ATXN7T-100Q-GFP ATXN7T-100Q-GFP
  • This model is used to assess the ability of anaploretic molecules to rescue Purkinje cells infected by ATXN7T-100Q-GFP.
  • Two compounds are tested: the 3-ketovalerate and the 3-hydroxyvalerate, which are both be directly incorporated by the cells in culture. These molecules are added in the culture medium on the same day when, the cells are infected and half of the medium is replaced every 4 days. The cultures are maintained for 20 days and the potential rescue of Purkinje cells is quantified as described above.
  • mice From 5 weeks of age, these mice develop progressive weight loss, ptosis, visual impairment, tremor, ataxia, muscle wasting, kyphosis and finally die at around 14-19 weeks of age.
  • Sca7 266Q5Q mice manifested coordination impairment in the rotarod test by 5 weeks. By 8-9 weeks, gait ataxia is apparent and motor coordination further deteriorates.
  • neuropathological studies revealed progressive NIs formation in many brain regions. Although no neuronal loss is observed, in the brain, Purkinje cells that are one of the most commonly affected cells in SCA7, have a decreased body cell size.
  • the SCA7 knock-in mice show a severe progressive weight loss already significant at the onset of the motor phenotype.
  • a protocol has been set up to measure food and beverage intake in correlation with weight evolution of these mutant mice compared to wild-type ones. This protocol is tested on a group of 3 knock-in females and 3 wild-type females from the same litters. The animals are kept one per cage and they are given a definite amount of food and beverage. Then, their intake and their weight are measured four times a week. Preliminary results show that this procedure is efficient to evidence progressive weight loss and food intake evolution ( FIG. 7 ).
  • Metabolic impairment in HD and other related diseases have been proposed to result from dysregulation of major metabolic pathways at the transcriptional level (Mochel 2007 PLoS ONE, 2(7): e647; Cui 2006 Cell 127: 59-69).
  • the transcriptome of the cerebellum of 4-5 knock-in mice versus 4-5 wild-type mice is analysed at two early stages before onset (post-natal day 10 and post-natal day 22) and one late symptomatic stage (11 weeks of age).
  • Day 1 (i) an extended neurological and general clinical examination; (ii) a global metabolic workup (blood and urine samples) to have an overview of the metabolic profile of HD patients at baseline; (iii) a skin biopsy to test in vitro the ability of triheptanoin to generate energy from the Krebs cycle and the respiratory chain; (iv) the measurement of 5′AMP-activated protein kinase (5′AMPK) activity in patients' fibroblasts, as a reflection of the levels of intracellular energy metabolism; and (v) a 31 P-NMR spectroscopy on patients' muscle in order to assess their skeletal muscle ATP production.
  • 5′AMP-activated protein kinase 5′AMP-activated protein kinase
  • Day 2 an oral loading test of a meal enriched with triheptanoin, together with urine and blood samples before and after meal to determine:
  • triheptanoin 1g/Kg
  • triheptanoin is usually administrated together with a dairy product.
  • Repeated blood samples are collected before and, sequentially, after meal (30, 60, 90, 120 and 180 minutes after triheptanoin ingestion) for assessment of redox status and acylcarnitines profile.
  • Urine is also collected before and after the triheptanoin load (90 and 180 minutes) for analyses of organic acids.
  • HD patients pursue an isocaloric diet enriched with triheptanoin (1g/Kg/day divided in 3 to 4 meals).
  • Fasting plasma BCAA, serum IGF1 and urinary urea are analyzed daily and neurological examination is repeated with UHDRS and TFC scoring.
  • muscle 31 P-NMR spectroscopy is repeated in order to determine the relative concentrations of inorganic phosphate, phosphocreatine and ATP levels after triheptanoin administration.
  • UHDRS score ranging 15 and 50, corresponding to patients at an early to moderate stage of the disease, in order to facilitate the compliance of patients to dietary treatment;

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US12/516,486 2006-12-04 2007-12-03 Anaplerotic Therapy of Huntington Disease and Other Polyglutamine Diseases Abandoned US20100063147A1 (en)

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EP06291873A EP1929995A1 (fr) 2006-12-04 2006-12-04 Thérapie anaplerotic de la maladie de Huntington et d'outres maladies à polyglutamine
PCT/EP2007/063181 WO2008068230A1 (fr) 2006-12-04 2007-12-03 Thérapie anaplérotique de la maladie de huntington et d'autres maladies liées à la polyglutamine

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US14/308,966 Active US9717705B2 (en) 2006-12-04 2014-06-19 Anaplerotic therapy of huntington disease and other polyglutamine diseases
US15/640,018 Active US10220014B2 (en) 2006-12-04 2017-06-30 Anaplerotic therapy of huntington disease and other polyglutamine diseases
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US15/640,018 Active US10220014B2 (en) 2006-12-04 2017-06-30 Anaplerotic therapy of huntington disease and other polyglutamine diseases
US16/267,210 Abandoned US20190365695A1 (en) 2006-12-04 2019-02-04 Anaplerotic therapy of huntington disease and other polyglutamine diseases

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US9717705B2 (en) 2006-12-04 2017-08-01 Institut National De La Sante Et De La Recherche Medicale Anaplerotic therapy of huntington disease and other polyglutamine diseases
US9833430B2 (en) * 2013-11-14 2017-12-05 The University Of Queensland Neurodegenerative disorders and methods of treatment and diagnosis thereof
US10111848B2 (en) 2012-12-13 2018-10-30 National Institute Of Health And Medical Research Triheptanoin for the treatment of glucose transport 1 deficiency

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US10220014B2 (en) 2006-12-04 2019-03-05 Inserm (Institut National De La Sante Et De La Recherche Medicale) Anaplerotic therapy of huntington disease and other polyglutamine diseases
US10111848B2 (en) 2012-12-13 2018-10-30 National Institute Of Health And Medical Research Triheptanoin for the treatment of glucose transport 1 deficiency
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US20190365695A1 (en) 2019-12-05
HK1223829A1 (zh) 2017-08-11
DK2097064T3 (en) 2015-11-23
US20180021287A1 (en) 2018-01-25
SI2097064T1 (sl) 2016-01-29
EP1929995A1 (fr) 2008-06-11
US9717705B2 (en) 2017-08-01
EP2097064A1 (fr) 2009-09-09
EP2097064B1 (fr) 2015-08-19
ES2552843T3 (es) 2015-12-02
US20120165405A1 (en) 2012-06-28
HUE026217T2 (en) 2016-05-30
CY1116938T1 (el) 2017-04-05
EP3009135A1 (fr) 2016-04-20
US10220014B2 (en) 2019-03-05
EP3009135B1 (fr) 2020-02-05
WO2008068230A1 (fr) 2008-06-12
ES2778525T3 (es) 2020-08-10
PL2097064T3 (pl) 2016-02-29
PT2097064E (pt) 2015-11-25

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