Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K35/48—Reproductive organs
  • A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
  • A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

• the present invention relates to methods of treating sexual dysfunction, particularly female sexual dysfunction, and related disorders and conditions pertaining to sexual activity and sexual satisfaction, and methods to enhance sexual satisfaction, particularly female sexual satisfaction by administering therapeutically effective amounts of isolated populations of mesenchymal stem cells.
• Female sexual dysfunction is a prevalent problem, afflicting approximately 40% of women. There are few treatment options. K.H. et ah, Cardiovasc Hematol Agents Med Chem. 7(3 ⁇ 4):260-269 (2009). FSD can be classified under many subtypes.
• female sexual arousal disorder (FS AD) is a disorder characterized by a persistent inability to attain sexual arousal or to maintain arousal until the completion of a sexual activity.
• Female sexual Interest/Arousal Disorder FSIAD is a diagnosis found when a subject experiences a lack of or significantly reduced sexual interest or arousal.
• Female hypoactive sexual desire disorder is a general loss of interest in sexual activity.
• the present invention concerns a method of increasing libido and/or sexual satisfaction in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a population of isolated human mesenchymal stem cells.
• the present invention also concerns a method of treating sexual dysfunction in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a population of isolated human mesenchymal stem cells as either a short-term or a long-term therapy, wherein said sexual dysfunction is a sexual disorder selected from the group consisting of hypoactive sexual desire disorder, orgasmic disorder, and sexual arousal disorder.
• the sexual dysfunction is hypoactive sexual desire disorder.
• the patient is a human.
• the patient is a female.
• the mesenchymal stem cells are bone marrow- derived mesenchymal stem cells, cord blood-derived mesenchymal stem cells, adipose tissue- derived mesenchymal stem cells, or derived from induced pluripotent stem cells (iPSCs).
• the mesenchymal stem cells do not express STRO-1.
• the mesenchymal stem cells do not express CD45.
• the mesenchymal stem cells do not express fibroblast surface markers or have a fibroblast morphology.
• the mesenchymal stem cells are not genetically manipulated.
• the mesenchymal stem cells are allogeneic stem cells. In other embodiments of the invention, the mesenchymal stem cells are autologous stem cells. In yet other embodiments of the invention, a mixture of allogeneic and autologous mesenchymal stem cells are administered to the patient. In yet additional embodiments of the invention, a mixture of mesenchymal stem cells and non-mesenchymal stem cells are administered to the patient.
• the mesenchymal stem cells are administered in a single dose. In another embodiment of the invention, the mesenchymal stem cells are administered in multiple doses, e.g., two or more doses. In another embodiment of the invention, the mesenchymal stem cells are administered at least yearly.
• the mesenchymal stem cells are administered systemically. In one embodiment of the invention, the mesenchymal stem cells are administered by infusion or direct injection. In one embodiment of the invention, the mesenchymal stem cells are administered intravenously, intraarterially, intramuscularly, intraperitoneally, subcutaneously, intradermal.)', orally, transendocardially, or intranasally. In a further embodiment, the mesenchymal stem cells are administered intravenously. In a further embodiment, the mesenchymal stem cells are administered intramuscularly.
• the mesenchymal stem cells are administered at a dose of about 20x10 6 mesenchymal stem cells. In another embodiment of the invention, the mesenchymal stem cells are administered at a dose of about lOOxlO 6 mesenchymal stem cells.
• the mesenchymal stem cells are obtained from a human donor and wherein a step of MHC matching of the human donor to the patient is not employed prior to the administration of the mesenchymal stem cells to the patient.
• the treatment increases libido and/or sexual satisfaction or reduces sexual dysfunction in the patient by 25%.
• FIG. 1 Study Flow Chart The flow chart outlines how patients were screened and randomized for the CRATUS study.
• Embodiments may be practiced without the theoretical aspects presented. Moreover, the theoretical aspects are presented with the understanding that the embodiments are not bound by any theory presented.
• a therapeutically effective amount means an amount that increases libido and/or sexual satisfaction or reduces sexual dysfunction in the patient.
• the dosage and number of doses (e.g., single or multiple dose) administered to the patient will vary depending upon a variety of factors, including the route of administration, patient conditions and characteristics (sex, age, body weight, health, size), extent of symptoms, concurrent treatments, frequency of treatment and the effect desired, and the like.
• the isolated population of mesenchymal stem cells is administered as a single dose. In another embodiment, the isolated population of mesenchymal stem cells is administered in multiple doses, e.g., two or more doses. In other embodiments, the isolated population of mesenchymal stem cells is administered at least yearly.
• the administration of the isolated population of mesenchymal stem cells is repeated, such as at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months after the first administration of the isolated population of mesenchymal stem cells, or repeated at least between 2-4, 2-6, 2-8, 2-10, 3-4, 3-6, 3-8, 3-10, 4-6, 4-8, 4-10, 6-8, 6-10, 6-12, or 12-18 months after the first administration of the isolated population of mesenchymal stem cells.
• the isolated population of mesenchymal stem cells is administered at a dose of about lxlO 6 , 2x10 6 , 5x10 6 , lOxlO 6 , 20x10 6 , 30x10 6 , 40x10 6 , 50x10 6 , 60x10 6 , 70x10 6 , 80x10 6 , 90x10 6 , lOOxlO 6 , llOxlO 6 , 120x10 6 , 130x10 6 , 140x10 6 , 150x10 6 , 160x10 6 , 170x10 6 , 180x10 6 , or 190x10 6 mesenchymal stem cells.
• the isolated population of mesenchymal stem cells is administered at a dose of about 20x10 6 mesenchymal stem cells. In a further embodiment, the isolated population of mesenchymal stem cells is administered at a dose of about lOOxlO 6 mesenchymal stem cells.
• the isolated population of mesenchymal stem cells is administered at a dose of from about 10-lOOxlO 6 , 20-100x10 6 , 50-100x10 6 , 0.1-5x10 6 , 0.1-lOxlO 6 , 0.1- lOOx10 6 , l-50x10 6 , 1-100x10 6 , 0.01-lOxlO 6 or 0.01-100x10 6 mesenchymal stem cells.
• the therapeutically effective amount of the isolated population of mesenchymal stem cells is sufficient to increase the libido and/or sexual satisfaction in the patient, i.e., an increase in libido and/or sexual satisfaction by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, or 500%.
• the therapeutically effective amount of the isolated population of mesenchymal stem cells is sufficient to reduce sexual dysfunction in the patient, i.e., a reduction in sexual dysfunction by at least by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
• administering a composition may be accomplished by any technique known in the art, including, but not limited to, oral administration, injection, infusion, parenteral, intravenous, mucosal, sublingual, intramuscular, intradermal, intranasal, intraperitoneal, intraarterial, subcutaneous absorption or by any method in combination with other known techniques.
• the isolated population of mesenchymal stem cells is administered systemically.
• the isolated population of mesenchymal stem cells is administered by infusion or direct injection.
• the isolated population of mesenchymal stem cells is administered intramuscularly, intravenously, intraarteerially, intraperitoneally, subcutaneously, intradermally, orally, transendocardially, or intranasally.
• the isolated population of mesenchymal stem cells is administered intramuscularly.
• the isolated population of mesenchymal stem cells is administered intravenously.
• the term "patient” as used herein includes, but is not limited to, humans and non- human vertebrates such as wild, domestic, and farm animals. In some embodiments, the term refers to humans, such as elderly humans >65 years of age, or elderly humans 60-95 years of age. In some embodiments, the human patient is a female.
• allogeneic refers to a cell that is of the same animal species but genetically different in one or more genetic loci as the animal that becomes the "recipient host.” This usually applies to cells transplanted from one animal to another non-identical animal of the same species.
• autologous means derived from the same organism.
• the phrase "in need thereof means mat the patient has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the patient can be in need thereof.
• Cells are referred to herein as being positive or negative for certain cellular or protein markers.
• a cell can be negative for CD45, which can also be referred to as CD45-.
• the superscript notation "-" refers to a cell that is negative for the marker linked to the superscript.
• a marker with the "+” refers to a cell that is positive for that marker.
• a cell that is referenced as "CD8+” is positive for CD8.
• a "+” can also be used to reference the marker as positive.
• a "-” can also be used to reference the marker as negative.
• the term “stem cell” refers to a cell from the embryo, fetus, or adult that has, under certain conditions, the ability to reproduce itself for long periods or, in the case of adult stem cells, throughout the life of the organism. It also can give rise to specialized cells that make up the tissues and organs of the body.
• the stem cells are adult stem cells, such as, but not limited to, mesenchymal stem cells, hematopoietic stem cells, neural stem cells, epithelial stem cells, and skin stem cells.
• the stem cells are embryonic stem cells.
• Mesenchymal stem cells are the formative pluripotent blast cells found, inter alia, in bone marrow, blood, dermis, and periosteum that are capable of differentiating into any kind of the specific types of mesenchymal or connective tissues ⁇ i.e., the tissues of the body that support the specialized elements; particularly adipose, osseous, cartilaginous, elastic, and fibrous connective tissues) depending upon various influences from bioactive factors, such as cytokines.
• mesenchymal stem cells are isolated from bone marrow of adult humans.
• the cells are passed through a density gradient to eliminate undesired cell types.
• the cells can be plated and cultured in appropriate media.
• the cells are cultured for at least one day or about three to about seven days, and may include removal of non-adherent cells. The adherent cells can then be plated and expanded.
• Homogeneous human mesenchymal stem cell compositions which serve as the progenitors for all mesenchymal cell lineages.
• Mesenchymal stem cells are identified by specific cell surface markers, which may be identified with unique monoclonal antibodies.
• the homogeneous mesenchymal stem cell compositions are obtained by positive selection of adherent marrow or periosteal cells that are free of markers associated with either hematopoietic or differentiated mesenchymal cells.
• These isolated mesenchymal cell populations display epitopic characteristics associated with only mesenchymal stem cells, have the ability to regenerate in culture without differentiating, and have the ability to differentiate into specific mesenchymal lineages when either induced in vitro or placed in vivo at a site of inflammation.
• pluripotent mesenchymal stem cells are separated from other cells in the bone marrow or other mesenchymal stem cell source.
• Bone marrow cells may be obtained from iliac crest, femora, tibiae, spine, rib, or other medullary spaces.
• Other locations from which human mesenchymal stem cells can be obtained include embryonic yolk sac, placenta, umbilical cord, fetal and adolescent skin, and blood.
• the mesenchymal stem cells are obtained from cord blood, adipose tissue, or induced pluripotent stem cells (iPSCs).
• the human mesenchymal stem cells of the invention are identified by the absence of certain markers.
• human mesenchymal stem cells useful in the invention include those that are negative for STRO-1 and/or negative for CD45.
• human mesenchymal stem cells useful in the invention include those that do not express fibroblast surface markers or have a fibroblast morphology.
• the present invention relates to methods to treat or reduce sexual dysfunction and related disorders pertaining to sexual activity' and sexual satisfaction, and methods to enhance or increase sexual satisfaction, in some embodiments female sexual satisfaction.
• the present disclosure also relates to methods to treat women to reduce time to orgasm, to increase intensity of orgasm, and to improve sexual quality of life.
• female sexual dysfunction refer generally to the impairment of the sexual function in a female.
• Sexual dysfunction in females includes inhibited orgasm.
• Female sexual dysfunction includes, but is not limited to, a number of categories of diseases, conditions and disorders including female hypoactive sexual desire disorder (FHSDD or HSDD, used interchangeably herein), female orgasmic disorder (FOD), sexual anhedonia, female sexual interest/arousal disorder (FSIAD), and female sexual arousal disorder (FSAD).
• Hypoactive sexual desire disorder includes a disorder in which sexual fantasies and desire for sexual activity are persistently or recurrently diminished or absent, causing marked distress or interpersonal difficulties.
• Sexual anhedonia includes decreased or absent pleasure in sexual activity.
• Sexual arousal disorder can be caused by reduced estrogen, illness, or treatment with diuretics, antihistamines, antidepressants, or antihypertensive agents. The woman can experience mild, moderate, or severe FSD.
• FSD, FSAD, FOD and FHSDD are as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM), 4th edition, the contents of which definitions are incorporated herein by reference.
• the disorder is female sexual interest/arousal disorder (FSIAD), which encompasses FSAD and FHSDD.
• FOD and FSIAD are defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM), 5th edition, the contents of which definitions are hereby incorporated herein by reference.
• the diagnostic criteria for FSIAD include a lack of, or significantly reduced, sexual interest/arousal, as manifested by at least three of the following: (1) absent/reduced interest in sexual activity; (2) absent/reduced sexual/erotic thoughts or fantasies; (3) no/reduced initiation of sexual activity, and typically unreceptive to a partner's attempts to initiate; (4) absent/reduced sexual excitement/pleasure during sexual activity in almost all or all sexual encounters; (5) absent/reduced sexual interest/arousal in response to any internal or external sexual/erotic cues; and (6) absent/reduced genital or nongenital sensations during sexual activity' in almost all or all sexual encounters. In FSIAD, these symptoms have persisted for a minimum duration of approximately six months and cause the patient significant distress.
• the diagnostic criteria for FOD are as follows:
• Criterion A The symptoms in Criterion A have persisted for a minimum duration of approximately 6 months.
• Criterion A The symptoms in Criterion A cause clinically significant distress in the individual.
• the sexual dysfunction is not better explained by a nonsexual mental disorder or as a consequence of severe relationship distress (e.g., partner violence) or other significant stressors and is not attributable to the effects of a substance/medication or another medical condition.
• the diagnosis of FOD also asks the clinician to specify whether (1) Lifelong: The disturbance has been present since the individual became sexually active or (2) Acquired: The disturbance began after a period of relatively normal sexual function. Also, the clinician is to specify whether (1) Generalized: Not limited to certain types of stimulation, situations, or partners or (2) Situational: Only occurs with certain types of stimulation, situations, or partners. The clinician is to specify if the patient never experienced an orgasm under any situation.
• a therapeutically effective amount of an isolated population of mesenchymal stem cells is administered to the patient in need thereof.
• a method of treating FSD, FSIAD, FSAD, FSOD, or FHSDD comprising administering to a patient in need of such treatment a therapeutically effective amount of an isolated population of mesenchymal stem cells.
• the invention is directed to methods of increasing female sexual satisfaction, increasing duration of orgasm, reducing time to orgasm, increasing intensity of orgasm and/or increasing oxytocin release related to sexual activity by administering a therapeutically effective amount of an isolated population of mesenchymal stem cells.
• the invention is directed to methods of increasing female sexual self-esteem and/or increasing a female patient's self-perception of kannity by administering a therapeutically effective amount of an isolated population of mesenchymal stem cells.
• Enhancement of female sexual satisfaction, female sexual self-esteem, female self- esteem, and female self-perception of americanity can be measured by patient questionnaires to determine if the patient's quality of life, particularly in sexual matters, is enhanced by the present therapeutic methods. Enhancement can also be determined by a change from baseline in the number of satisfying sexual events (SSE), a change from baseline in the level of sexual interest or desire, a change from baseline in the level of sexual arousal, or a change from baseline in the level of distress from sexual activities.
• Baseline may be defined as a four- week no-treatment phase or a four-week placebo run-in phase. Changes from baseline typically refer to the treatment responses obtained during the last four weeks of a double- blinded treatment period relative to baseline.
• the time period used for assessing baseline should be the same as the time period used for assessing treatment responses (e.g.. four weeks at the end of the treatment period).
• Enhancement of self-esteem or female sexual self-esteem may be measured by any one of the questionnaires and scales available in the art such as, without limitation, those disclosed in Heatherton, T.F. & Polivy, J. J. Personality and Social Psychology, 60:895-910 (1991); Rosenberg's Self-Esteem Scale found on October 30, 2016 at
• the questionnaire is completed by the female patient at a time prior to administration of the therapeutically effective amount of an isolated population of mesenchymal stem cells and prior to one or more episodes of sexual intimacy, and then the questionnaire is completed again by the same patient after the administration of the therapeutically effective amount of an isolated population of mesenchymal stem cells and the occurrence of one or more episodes of sexual intimacy.
• the patients to be treated with the present invention include humans, and in certain embodiments are pre-, per- and post-menopausal women. In one embodiment, the woman is concomitantly on hormone replacement therapy. In another embodiment she is not on concomitant hormone replacement therapy.
• the patients to be treated is a mammal, such as non-human primates (particularly higher primates), sheep, dog, rodent (e.g., mouse or rat), guinea pig, goat, pig, cat, rabbits, cow, and panda. Treatment in non-human mammals may be desirable to accelerate conception during mating.
• the patient to be treated is a human or animal concomitantly taking one or more SSRI or antidepressants, such as antidepressants used in the treatment of major depressive disorder and anxiety disorders.
• SSRIs may cause a variety of sexual dysfunction, such as anorgasmia, erectile dysfunction, diminished libido, genital numbness, and sexual anhedonia (pleasureless orgasm).
• the mesenchymal stem cells of the present disclosure may also be administered to the patient concomitantly with the SSRI therapy.
• SSRIs include the following: citalopram, fluvoxamine, escitalopram, paroxetine, sertraline, fluoxetine, and dapoxetine.
• Hie compositions and methods of the present disclosure may also be used with a patient who concomitantly is taking tricyclic antidepressants or serotonin-noradrenaline reuptake inhibitors (SNRIs).
• SNRIs include the following: venlafaxine; desvenlafaxine, duloxetine, milnacipran, levomilnacipran, and sibutramine.
• the terms “treat,” “treatment,” or “treating” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a disease or condition, e.g., FSD.
• the term “treating” includes reducing or alleviating at least one adverse effect or symptom of a disease or condition, e.g., FSD.
• Treatment is generally “effective” if one or more symptoms are reduced. That is, “treatment” includes the improvement of symptoms.
• Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s) and diminishment of extent of disease.
• treatment of FSD is considered effective if the number of satisfying sexual events (SSE) is increased from baseline in a sampled time (e.g., 4 weeks), in a significant manner.
• SSE sexual events
• Other established metrics to determine treatment efficacy for FSD include, for example, FSF1 (female sexual function index), SAL (Sexual Activity Log), SAR (Sexual Activity Record), FSDS (Female Sexual Distress Scale), and the FSDS-R (Female Sexual Distress Scale Revised).
• a therapeutic effect is seen when the difference from baseline is a "minimally important difference” or "MIN" defined in: DeRogatis, L. et. al, Journal of Sexual Medicine, 6:175-183 (2009), the contents of which are incorporated herein by reference. Such a change may be small but meaningful to patients.
• Efficacy of treatment for FSD and enhancement of sexual satisfaction can be determined by monitoring the number of satisfying sexual events (SSE) in a given experimental period.
• SSE sexual events
• a questionnaire may be administered by a clinician asking the number of SSEs a patient has experienced in a given four- week period.
• a treatment can thus be administered for another four-week period and the questionnaire can be re-assessed at the end of the treatment.
• An increase in SSE from baseline can then be evaluated, for example, in a statistically significantly large cohort. As but one example, an average increase from 6 to 6.7 SSEs would show efficacy of a treatment.
• secondary endpoints could include questionnaires assessing sexual satisfaction, e.g., change from baseline to end-of- study in arousal domain score, female sexual function index, satisfaction with arousal, desire domain from female sexual function index, satisfaction with desire, quality of relationship with partner, and a female sexual distress scale.
• Other established metrics to determine treatment efficacy for FSD can also be used, and they include, for example, FSFI (female sexual function index), SAL (Sexual Activity Log), SAR (Sexual Activity Record), FSDS (Female Sexual Distress Scale), and the FSDS-R (Female Sexual Distress Scale Revised).
• Other parameters to measure or quantify sexual arousal in females include arousal domain score from female sexual function index, satisfaction with arousal, desire domain from female sexual function index, satisfaction with desire as measured, quality of relationship with partner, and change in hormone levels such as oxytocin.
• a treatment is considered effective if any one or a combination of these parameters is increased as compared to a reference level that is measured in the absence of the treatment.
• compositions for use in the invention may be formulated using any suitable method.
• Formulation of cells with standard pharmaceutically acceptable carriers and/or excipients may be carried out using routine methods in the pharmaceutical art. The exact nature of a formulation will depend upon several factors including the cells to be administered and the desired route of administration. Suitable types of formulation are known in the art, many of which are fully described in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, Eastern Pennsylvania, USA.
• compositions may be prepared together with a physiologically acceptable carrier or diluent.
• a physiologically acceptable carrier or diluent typically, such compositions are prepared as liquid suspensions of cells.
• the cells may be mixed with an excipient which is pharmaceutically acceptable and compatible with the active ingredient.
• excipients include, for example, water, saline, dextrose, glycerol, of the like and combinations thereof.
• the pharmaceutical compositions of the invention may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and/or adjuvants which enhance effectiveness.
• the adjuvant comprises human serum albumin (HSA).
• HSA human serum albumin
• One suitable carrier or diluent is PlasmaLyte ATM. This is a sterile, nonpyrogenic isotonic solution for intravenous administration.
• Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (CeHnNaO?); 368 mg of Sodium Acetate Trihydrate, USP (C 2 H 3 Na0 2 3H 2 0); 37 mg of Potassium Chloride, USP (KC1); and 30 mg of Magnesium Chloride, USP (MgCl 2 6H 2 0). It contains no antimicrobial agents.
• the pH is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0).
• the mesenchymal stem cells are not genetically manipulated.
• the mesenchymal stem cells are cryopreserved.
• the mesenchymal stem cells can be suspended in cryoprotectant consisting of Hespan® (6% hetastarch in 0.9% sodium chloride) supplemented with 2% HSA and 5% DMSO and men aliquoted into cryopreservation containers for placement in vapor phase nitrogen freezers.
• the mesenchymal stem cells may be provided in PlasmaLyte ATM supplemented with 1% HSA.
• Allogeneic Human Mesenchymal Stem Cells in Patient with Aging FRAilTy via IntravenoL/S' Delivery (CRATUS) study is a phase ⁇ , randomized, double-blinded, placebo- controlled study of allogeneic human mesenchymal stem cells (allo-hMSCs) (100 or 200- million cell dose) versus placebo delivered intravenously (TV) in frail individuals to test the safety and efficacy- of allo-hMSCs in reducing markers of inflammation and improving markers of physical and mental functioning and quality of life. Screening and patient randomization are outlined in FIG. 1.
• Patient population and timeline [0062] Patient eligibility required diagnosis or symptomatology of frailty, defined by a frailty score between 4-7 as denoted by the Canadian Study on Health and Aging. Roller, K. et al, Cleve Clin. J. Med. «0 ⁇ : 168-174 (2013); McElhaney, J.E. et al, Curr. Opin. Immunol. 27 ⁇ :418-424 (2009). All patients were >60 and ⁇ 95 of age at the time of consent. Table 1 shows the baseline characteristics of the enrolled patients. Sixty percent of the patients were white males and the mean age was 75.5 ⁇ 7.3 years.
• Values are Mean ⁇ Std. Dev., N (%), or Median (interquartile range [IQR]).
• FEV1 Liters
• Hemoglobin grams/deciliter
• WBC cells/millimeters 3
• white blood cells AST (U/L), Aspartate Aminotransferase (units/liter).
• ALT Alanine Aminotransferase. 6 minute walk test distance (m, meters).
• Tumor Necrosis Factor-a pg/mL, picogram/milliliter).
• TE-SAE treatment emergent-serious adverse events
• the secondary endpoints assessed the efficacy of the therapy. Efficacy was demonstrated by differences in the rate of change of frailty markers as defined by: reduced activity (Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire), slowing of mobility (6 minute walk test (6MWT), 4-meter gait speed test (4MGST), and the short physical performance battery (SPPB) score, comprised of balance tests, gait speed tests, and chair stand tests), weight loss, diminished hand grip strength (dynamometry), exhaustion multidimensional fatigue inventory (MFl), quality of life assessments (Sexual Quality of Life-Female (SQOL-F) and International Index of Erectile Dysfunction (IIEF) Questionnaires), dobutamine-induced ejection fraction (EF) via echocardiography, C-reactive protein (CRP), IL-6, D-dimer, complete blood cell count (CBC) with differential, and TNF-a.
• CHAT Common Healthy Activities Model Program for Seniors
• SPPB short physical performance battery
• MFl exhaustion multidimensional

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