US20180296647A1 - Prophylactic and therapeutic agent for rett syndrome (rtt) comprising ghrelin as active ingredient - Google Patents

Prophylactic and therapeutic agent for rett syndrome (rtt) comprising ghrelin as active ingredient Download PDF

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US20180296647A1
US20180296647A1 US15/768,101 US201615768101A US2018296647A1 US 20180296647 A1 US20180296647 A1 US 20180296647A1 US 201615768101 A US201615768101 A US 201615768101A US 2018296647 A1 US2018296647 A1 US 2018296647A1
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ghrelin
rtt
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patients
administration
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Toyojiro Matsuishi
Masayasu Kojima
Kotaro YUGE
Munetsugu HARA
Yushiro YAMASHITA
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Kurume University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • 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

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  • the present invention relates to a novel use of ghrelin in the clinical field. Specifically, the present invention relates to a prophylactic and therapeutic agent for Rett Syndrome (RTT) comprising ghrelin as an active ingredient.
  • RTT Rett Syndrome
  • RTT Rett Syndrome
  • MECP2 methyl-CpG binding protein 2
  • RTT develops mainly in female infants, who exhibit hypotonia and autistic tendencies in early infancy and then impaired locomotion, such as crawling and walking, retardation of language development and, finally, severe intellectual disabilities. From infancy to early childhood, there is a loss of purposeful motor functions of the hand, such as in hand washing, kneading, handwringing or bringing one hand to the mouth while pounding on the chest, with distinctive hand stereotypies. These symptoms are almost always present in typical RTT cases.
  • RTT is understood to be a neurodevelopmental, rather than a neurodegenerative, disorder.
  • Angela J McArthur et al., Developmentulhledicitie & Crash Neirrology 1998, 40, 186-192 (Non-patent reference 1); Carolyn Ellaway et al., Brain & Development 23 (2001) S101-S103 (Non-patent reference 2); Yoshiko Nomura, Brain & Development 27 (2005) S35-S42 (Non-patent reference 3); Deidra Young et al., Brain & Development 29 (2007) 609-616 (Non-patent reference 4); Meir Lotan et al., The Scientific World Journal (2006) 6, 1737-1749 (Non-patent reference 5); Flavia Schwartzman et al., Arq Gastroenterol v. 45, no. 4, Jul. set. 2008 (Non-patent reference 6); Kathleen J. Mo
  • Brain injury secondary to trauma (perinatally or postnatally), neurometabolic diseases or severe infection causing neurological problems, grossly abnormal psychomotor development in the first six months of life
  • IGF-1 was administered to six patients with RTT, ages 4-11 years. The IGF-1 was administered twice per day for 6 months at 0.05 mg/kg. The International Severity Score was ameliorated in three patients, the test could be performed safely and drug tolerability was confirmed (Autism Research and Treatment, Volume 2012, Article ID 679801, 14 pages (Non-patent reference 13)).
  • JP 2010-526089 Patent reference 1
  • JP 2012-131815 Patent reference 2
  • JP 2012-503009 Patent reference 3
  • JP 2014-196331 Patent reference 4
  • JP 2015-145407 Patent reference 5
  • JP 2014-508744 Patent reference 6
  • Ghrelin is a peptide hormone first detected in the stomach as an endogenous ligand of GHS receptor, an orphan receptor without known ligand (Kojima M et al., Nature 402, 656-660 (1999) (Non-patent reference 18); Kojima M et al., Trends Endocrinol Metab 12, 118-122 (2001) (Non-patent reference 19).
  • Human ghrelin is a 28 amino acid peptide in which the side chain of the 3rd amino acid residue, serine, is modified with the fatty acid octanoic acid (N-GSSFLSPEHQRVQQRKESKKPPAKLQPR-C).
  • ghrelin is transformed into an active form by octanoylation to exhibit its physiologic activities. Ghrelin was identified in fish, amphibian, birds and many mammalian species and has a fatty acid at the 3rd serine or threonine residue.
  • the ghrelin producing cells in the stomach are called X/A-like cells, function of which is not known up till the present.
  • production of ghrelin though in lesser amounts, is observed in tissues including the intestinal tract, hypothalamus, pituitary gland, pancreas, kidney, placenta and testes.
  • Plasma ghrelin levels increase with fasting and decrease with food intake. Plasma ghrelin levels are lower in obese individuals and higher under lean conditions. Ghrelin acts in the pituitary gland to stimulate GH secretion. This activity is synergistic with that of growth hormone-releasing hormone (GHRH).
  • GHRH growth hormone-releasing hormone
  • Ghrelin also acts in the hypothalamus to stimulate food intake and, thus, acts as a feeding promoting peptide. Weight gain and increased adipose tissue is observed after ghrelin administration. Therefore, ghrelin is considered to be a hormone antagonistic to leptin, an anti-obesity hormone produced in fat cells.
  • ghrelin is mainly produced in gastric endocrine cells and has an important activity in regulating energy metabolism such as feeding promotion, weight gain and regulation of gastrointestinal function. It is, so far, the only peptide hormone produced in the periphery with feeding promoting activity. Ghrelin is secreted in the stomach when hunger signals are transmitted to the brain via the afferent vagus nerve. Ghrelin acts in the hypothalamus, which is the central region for regulating feeding and GH secretion.
  • Ghrelin is present in the a cells which produce glucagon in the pancreatic islets.
  • the ghrelin receptor gene is expressed in both ⁇ and ⁇ cells.
  • Ghrelin at physiological concentrations (10 ⁇ 12 to 10 ⁇ 11 M) increases intracellular Ca 2+ levels in pancreatic ⁇ cells isolated from rats under hyperglycemic conditions, promoting insulin secretion.
  • ghrelin does not affect intracellular Ca 2+ levels or insulin secretion in pancreatic ⁇ cells.
  • Another possible effect is that ghrelin modifies insulin activity in the liver and is involved in glucose metabolism.
  • Ghrelin when intravenously administered to healthy subjects, decreases average arterial blood pressure without changing heart rate and increases cardiac output.
  • ghrelin When ghrelin is continually administered in a rat model for heart failure after cardiac infarction, ghrelin levels are increased in the left ventricular ejection fraction together with an increase in serum GH and alleviation of cachexia. These observations suggested the usefulness of ghrelin as a drug to treat heart failure because of its amelioration of cardiac dysfunction and malnutrition. Furthermore, when ghrelin was administered to patients with chronic heart failure, increased cardiac index and improved hemodynamics were reported.
  • Munetsugu Hara et al. measured plasma ghrelin levels in 27 patients with RTT and 53 healthy controls. The plasma levels of both total ghrelin and active ghrelin with octanoyl modification were lower in patients with RTT than in healthy controls (Int. J. Devl Neuroscience 29 (2011) 899-902 (Non-patent reference 23)). In addition, plasma levels of total ghrelin were positively correlated with serum IGF-1 levels and head circumference. There was also a correlation between decreased plasma levels of total and active ghrelin and eating difficulties and constipation, as well as between decreased plasma levels of active ghrelin and eating difficulties.
  • Munetsugu Hara et al. reported comparison between plasma levels of ghrelin, GH and IGF-1 with anthropometric data (weight, height, BMI and head circumference) in 22 patients with RTT, associated with MECP2 gene mutations, and 14 age- and gender-matched healthy controls (Brain & Development 36 (2014) 794-800 (Non-patent reference 25)). To subdivide the patients with (RTT) and without (non-RTT) MeCP2 mutations in the group with epilepsy and intellectual disabilities, those with RTT had significantly lower BMI values and heights than those in the non-RTT group. More significantly, there was an inverse correlation between plasma ghrelin levels and head circumference in the RTT group.
  • Toyojiro Matsuishi et al. reviewed an interim report that plasma levels of total ghrelin were lower in patients with RTT than in healthy controls. This suggested that ghrelin plays an important role in the pathophysiology of RTT (Brain & Development 33 (2011) 627-631 (Non-patent reference 26)).
  • Toyojiro Matsuishi reviewed the discovery of RTT, discovery of its causative gene, establishment of an animal model and current therapeutic candidates identified using model animals and presented therapeutic agents and future perspectives animals or human (Japanese Journal of Clinical Medicine, Vol. 71, No. 11 (2013) 2043-2053) (Non-patent reference 27)).
  • RTT is a neurodevelopmental disorder with various symptoms such as neurological symptoms including dystonia, seizures, sleep disturbances, eating disorders and emaciation. A therapeutic agent for ameliorating these symptoms is needed.
  • the present inventors conducted research to identify an effective therapeutic method for RTT. As a result, they found that ghrelin levels decreased in patients with RTT in an age-dependent manner and were correlated with gastrointestinal symptoms such as feeding and constipation, and autonomic nervous symptoms, thereby completing the present invention.
  • the present invention relates to pharmaceutical composition comprising ghrelin and a pharmaceutically acceptable carrier.
  • the present invention relates to a prophylactic and therapeutic agent for RTT comprising a therapeutically effective amount of ghrelin.
  • ghrelin was actually administered to patients with RTT to prove its effectiveness.
  • the prophylactic and therapeutic agent for RTT of the present invention comprising a therapeutically effective amount of ghrelin can be administered to patients safely without severe side effects and exerts the effects of increased GH secretion and amelioration of constipation, sleep, muscle tone and dystonia.
  • FIG. 1-1 shows amelioration symptoms in patients with RTT after administration of ghrelin.
  • FIG. 1-2 shows amelioration of symptoms in patients with RTT after administration of ghrelin.
  • FIG. 1-3 shows amelioration of symptoms in patients with RTT after administration of ghrelin.
  • FIG. 2 shows changes in plasma ghrelin levels with the passage of time in patients with RTT after administration of ghrelin.
  • FIG. 3 shows changes in growth hormone secretion with the passage of time in patients with RTT after administration of ghrelin.
  • FIG. 4 shows changes in blood glucose with the passage of time in patients with RTT after administration of ghrelin.
  • FIG. 5-1 shows time-dependent changes in thermography in patients with RTT after administration of ghrelin.
  • FIG. 5-2 shows time-dependent changes in surface temperature in patients with RTT after administration of ghrelin.
  • FIG. 5-3 shows time-dependent changes in surface temperature and deep body temperature in patients with RTT after administration of ghrelin.
  • FIG. 6 shows chest and abdominal movements in patients with RTT after administration of ghrelin.
  • FIG. 7 shows the results of a test investigating effects on breathing before and after intravenous administration of ghrelin in patients with RTT.
  • FIG. 8-1 shows the results of autonomic analysis (Holter electrocardiography) in patients with RTT after administration of ghrelin.
  • FIG. 8-2 shows the results of autonomic analysis (Holter electrocardiography) in patients with RTT after administration of ghrelin.
  • FIG. 9 shows that cortisol awaking response (CAR) was ameliorated by administration of ghrelin in patients with RTT.
  • FIG. 10 shows the results of melatonin measurements in the saliva of patients with RTT after administration of ghrelin.
  • FIG. 11 illustrates symptomatic progress in patients of interest with RTT, shown in the chronological order of symptom development.
  • FIG. 12-1 shows time-dependent changes in VAS in patients with RTT after administration of ghrelin.
  • FIG. 12-2 shows time-dependent changes in VAS in patients with RTT after administration of ghrelin.
  • FIG. 13 shows amelioration of dystonia by VAS in patients with RTT after administration of ghrelin.
  • FIG. 14-1 shows the sleep diary of a patient (Case 1) with RTT before and after administration of ghrelin.
  • FIG. 14-2 shows the sleep diary of a patient (Case 4) with RTT before and after administration of ghrelin.
  • ghrelin is undergoing clinical testing for gastrointestinal symptoms such as anorexia nervosa and cardiovascular disorders and for use after total gastrectomy. These tests are performed without showing significant side effects.
  • Ghrelin as used herein is active ghrelin showing its original physiological activities wherein the side chain of the 3rd amino acid residue in a peptide consisting of 28 amino acid residues is modified with octanoic acid.
  • Ghrelin as used herein may be a ghrelin derivative where any one to several of the 28 amino acid residues is deleted, substituted or added, a ghrelin derivative substituted with, lauric acid or palmitic acid in place of octanoic acid, a ghrelin derivative substituted with an unsaturated fatty acid or a branched fatty acid (e.g.
  • Ghrelin as used herein may be obtained by isolating the natural peptide or may be prepared in a conventional manner using a peptide synthesizer.
  • a method for preparing ghrelin as used herein is not particularly limited.
  • ghrelin as used herein may be prepared by isolation from ghrelin producing cells of the human gastric corpus or by a gene recombination technique.
  • ghrelin may be purified by chromatography.
  • ghrelin may be purified by gel filtration, two ion exchange HPLCs, and reverse phase HPLC.
  • Ghrelin as used herein may also be purified by affinity chromatography using a suitable carrier to which an antibody to ghrelin is bound.
  • ghrelin is dissolved in a solvent and the solution is aseptically filtered and transferred to an ample or vial to prepare the composition of the present invention.
  • a solvent distilled water for injection, saline, 0.01 M to 0.1 M phosphate buffer and the like may be used, if necessary, in admixture with ethanol, glycerol, etc.
  • the solution is aseptically filtered, transferred to an ample, a vial etc. and lyophilized to prepare the pharmaceutical composition of the present invention.
  • the therapeutic agent of the present invention may also be mixed with sugars such as mannitol, glucose and lactose, salts such as common salt and sodium phosphate, and the like, as additives.
  • sugars such as mannitol, glucose and lactose, salts such as common salt and sodium phosphate, and the like.
  • the pharmaceutical composition of the present invention in a dissolved state usually has a pH ranging from 6.8 to 7.5, preferably 7.3 to 7.4, more preferably 7.35.
  • the route of administration of the pharmaceutical composition of the present invention is not particularly limited and is in accordance with common practice including, for instance, oral administration, intraperitoneal injection, intratracheal injection, intrabronchial injection and direct intrabronchial instillation, subcutaneous injection, transdermal delivery, intra-arterial injection, intravenous injection, nasal administration and the like. However, it is preferably administered via parenteral administration, namely, subcutaneous, intradermal or intravenous injection.
  • the pharmaceutical composition for parenteral administration includes a solution of ghrelin of the present invention dissolved in a commonly acceptable carrier, preferably an aqueous carrier.
  • aqueous carriers all known in the art, including, for instance, water, buffer, brine, glycine and the like. These solutions are sterilized and generally contain no particulate substances. These pharmaceutical compositions may be sterilized by a method for sterilization well known in the art.
  • composition of the present invention may be supplemented with a commonly used additive, for instance, a stabilizing agent (arginine, polysorbate 80, macrogol 4000, etc.), an excipient (mannitol, sorbitol, sucrose, etc.) and the like, and formulated for injection or in preparations that can be administered transmucosally (nasally, orally or sublingually) by procedures such as sterile filtration, dispersion, lyophilization, etc.
  • a stabilizing agent arginine, polysorbate 80, macrogol 4000, etc.
  • excipient mannitol, sorbitol, sucrose, etc.
  • a therapeutically effective amount of ghrelin may vary depending on the severity of disease state, age, body weight etc. of the subject and is ultimately determined at the discretion of the physician.
  • ghrelin may be administered once at a dose of 0.03 ⁇ g/kg/day to 10 ⁇ g/kg/day, preferably 1 ⁇ g/kg/day to 5 ⁇ g/kg/day, more preferably 1 ⁇ g/kg/day to 3 ⁇ g/kg/day.
  • a dose of 3 ⁇ g/kg/day is the most preferable.
  • a skilled person could determine the necessary procedural regimen, depending on the severity of a specific disease and condition to be treated, using a standard pharmacological method.
  • a visual analog scale with 5 as the baseline, 10 as the best and 0 as the worst may be used by parents or physical therapists.
  • dystonia was assessed using the international BFMDRS.
  • the VAS assesses appetite, bowel movement, dystonia, vasomotor reflex, sleep, swallowing etc.
  • Test items evaluated in patients with RTT are the following: As test items, cortisol in saliva, ghrelin, growth hormone, IGF-1, blood glucose in blood etc. were measured in addition to breathing and cardiac function. Sleep was assessed with a sleep diary and by actigraphy. Day-long EEG video monitoring was also used for assessment, before and after ghrelin administration.
  • Breathing pattern chest/abdominal sensor, SpO 2 monitor Circulation: 12-lead electrocardiogram Temperature: surface temperature, deep body temperature, thermography Sleep: sleep diary, actigraphy Blood test: ghrelin, growth hormone, blood glucose, IGF-1 etc. Saliva: cortisol, melatonin, MHPG etc. Electroencephalogram (EEG): 24-hour EEG video monitoring Autonomic nervous system: Holter electrocardiography
  • Ghrelin has a variety of physiological activities besides appetite promotion and GH secretion. It is known that ghrelin alleviates and modulates sympathetic hypertonic autonomic nerves and impaired autonomic nerve imbalances are observed in RTT. Patients with RTT having eating disorders exhibit significantly lower levels of both total ghrelin and active ghrelin than do controls. Lower total ghrelin levels are significantly correlated with constipation. RTT model animals have lower brain weights than control animals, with microcephalic tendencies and also have lower plasma ghrelin levels.
  • Informed Consent After approval of the ethics committee of Kurume University, the test was conducted after obtaining Informed Consent (IC) from the patients' parents. Four patients aged 21 years old (case 1), 12 years old (case 2), 22 years old (case 3) and 32 years old (case 4), each with the MECP2 mutation and a definitive diagnosis, were subjected to the test (Table 1). Ghrelin was intravenously administered in the morning, after fasting for 3 days. For clinical data, RTT Behavioral Questionnaire, Burke-Fahn-Marsden Dystonia Rating Scale, VAS (Visual Analog Scale; 5: baseline before treatment; 10: markedly improved; 0: markedly worsened) evaluated by their parents, and a sleep diary were used. For biochemical data, plasma levels of ghrelin, GH, blood glucose, saliva cortisol and melatonin were obtained. For physiological data, electroencephalogram, respiration sensor, Holter electrocardiography and actigraphy were used.
  • Intravenous line saline with heparin lock
  • Ghrelin blood sampling before, immediately after, 30 minutes after and 60 minutes after ghrelin administration
  • GH blood sampling before, immediately after, 30 minutes after, 60 minutes after and 90 minutes after ghrelin administration
  • Saliva sampling at bedtime of the 1st day in the hospital and immediately after awakening on the 2nd day, thereafter every 3 hours until bedtime Assessment: neurological examination on admission to the hospital
  • Central nervous system seizure frequency, dystonia Neurological Test Chart check, etc.
  • Autonomic nervous system Holter electrocardiography: RR interval, sympathetic thermography, deep body temperature measurement Others: constipation status, duration of eating (mean duration of eating time in the morning, afternoon and evening), sleep, respiratory abnormalities, scoliosis, grinding of the teeth, developmental psychomotor milestones, and other clinical parameters
  • the patients were admitted to the hospital in the morning after their histories were taken, wore actigraphy devices until dinner, and had saliva sampled with cotton swabs and sample tube for collecting and storing samples.
  • venous line maintained with saline (with heparin lock) was inserted and ghrelin was administered at 3 ⁇ g/kg/day.
  • Blood sampling for ghrelin and growth hormone (GH) measurements was performed and saliva was successively sampled to measure cortisol, neurotransmitter and the like.
  • Ghrelin was administered before breakfast on 3 consecutive days, a total of 3 administrations.
  • the amount of blood sampled for ghrelin measurements was 2 ml each, a total of 8 ml, and sampling was done before, immediately after, 30 minutes after and 60 minutes after administration of ghrelin, a total of 4 times.
  • GH sampling was conducted a total of 5 times on the first day in the hospital.
  • the amount of blood collected for GH measurements was 0.5 ml whole blood per sampling, a total of 2.5 ml, and blood samples were collected once between 9:00 and 9:30 a.m. before the initiation of the test, and immediately after, 30 minutes after, 60 minutes after and 90 minutes after ghrelin administration, a total of 5 times.
  • Saliva samples were collected 30 minutes after awakening and then 3 hours later before bedtime at 21 o'clock in the evening. The amount of each saliva sample was approximately 500 al. On the day of release from the hospital, the short-term effects of ghrelin were assessed and each patient was informed of the next appointment day.
  • the plasma ghrelin levels increased immediately after administration and returned to baseline levels after about 60 minutes ( FIG. 2 ).
  • GH levels reached a peak of secretion (30 to 175 times higher than baseline level) at 30 minutes after ghrelin administration (G in the figure) at 3 ⁇ g/kg ( FIG. 3 ).
  • Blood glucose levels increased slightly at 30 to 60 minutes-after ghrelin administration ( FIG. 4 ).
  • Ghrelin administration did not affect surface temperature or deep body temperature ( FIG. 5 ). The temperature tended to once decrease and then increase. It was difficult to keep environmental conditions constant, such as room temperature, clothes and bed/couch, making these temperature assessments difficult. Most of the patients with RTT showed respiratory abnormalities such as hyperventilation and/or apnea.
  • FIGS. 6 and 7 There were no significant changes in breathing or chest movements after ghrelin administration ( FIGS. 6 and 7 ). Breathing was monitored in the waking state and compared before and after intravenous ghrelin administration. Apnea for 10 seconds or more, its frequency and total time, hypopnea for 10 seconds or less, its frequency and total time, were assessed but no significant effects on breathing abnormalities were observed.
  • the results of autonomic analysis (Holter electrocardiography) are shown in FIG. 8 .
  • Cortisol awaking response (CAR) reflecting awaking rhythm and the autonomic nerves, is seen in healthy adults at 30 minutes after awakening and is regarded as an important reaction predominantly of the sympathetic nervous system. CAR was not observed in the patients with RTT ( FIG. 9 ).
  • FIG. 10 The results of saliva melatonin measurements are shown in FIG. 10 .
  • FIG. 11 illustrates symptomatic progress in one of the patients.
  • Time-dependent changes in VAS and amelioration of dystonia by VAS are shown in FIGS. 12-1 and 12-2 and FIG. 13 , respectively.
  • a sleep diary before and after ghrelin administration is shown in FIG. 14 . Improvement of sleep rhythms was reported in the sleep diary.
  • the mother of the 21 year old female patient made the following remarks: “she became calm and peaceful; I'm glad that she looks merry; she got to be able to sleep, no longer needs melatonin, and more active during the day; her duration of eating became shorter; she got to have formed stool (I was afraid of worsening of diarrhea); dystonia was ameliorated; she got to be able to open the mouth at the dental checkup; PT was surprised; tremor of the head decreased and hair sprouted; vasomotor nerve reflex was ameliorated (frequency became lowered, time was reduced by half (from 20 minutes to 10 minutes), she got no longer sweaty).” In the 32-year-old female, dystonia was ameliorated, it became easier for her to open her mouth and she became able to eat large amounts of solid foods.
  • the prophylactic and therapeutic agent for RTT of the present invention comprising a therapeutically effective amount of ghrelin can be administered to patients safely without severe side effects and can be used effectively for therapy of RTT, such as increasing GH secretion and ameliorating constipation, sleep, muscle tone and dystonia.

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