WO2005112911A2 - Compositions et procedes de traitement de troubles de deficience de la myeline - Google Patents

Compositions et procedes de traitement de troubles de deficience de la myeline Download PDF

Info

Publication number
WO2005112911A2
WO2005112911A2 PCT/US2005/019298 US2005019298W WO2005112911A2 WO 2005112911 A2 WO2005112911 A2 WO 2005112911A2 US 2005019298 W US2005019298 W US 2005019298W WO 2005112911 A2 WO2005112911 A2 WO 2005112911A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition
igf
ofthe
transferrin
polypeptide
Prior art date
Application number
PCT/US2005/019298
Other languages
English (en)
Other versions
WO2005112911A3 (fr
Inventor
Araceli M. Espinosa-Jeffrey
Jean S. Devellis
Original Assignee
The Regents Of The University Of California
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by The Regents Of The University Of California filed Critical The Regents Of The University Of California
Publication of WO2005112911A2 publication Critical patent/WO2005112911A2/fr
Publication of WO2005112911A3 publication Critical patent/WO2005112911A3/fr

Links

Classifications

    • 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
    • A61K31/202—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 having three or more double bonds, e.g. linolenic
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/215—IFN-beta
    • 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
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • 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
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins

Definitions

  • the present invention is in the field of demyelinating disorders.
  • Central nervous system (CNS) development is a multi-step spatial-temporal process in which a pool of uncommitted progenitors neural stem cells (NSCs) develops, giving rise to sequentially more restricted and specified phenotypes of NSC/progenitors for neurons during embryonic life, followed perinatally first by the generation of astrocytes and then a wave of oligodendrocytes (OL) between PI and PI 8.
  • NSCs neural stem cells
  • OL oligodendrocytes
  • Neural stem cells are identified by PSA-NCAM and nestin expression.
  • Nestin a class IV intermediate filament is expressed at the embryonic neurulation stage in neuroepithelial precursors. Subsequently, as nestin expression decreases, vimentin and GFAP are expressed in the astrocyte lineage, and neurofilament appears in immature neurons.
  • Neural precursors are committed to the OL fate when they express early OL markers such as transferrin, A 2 B 5 , and sulfatides. Later, these cells express myelin components that are also good OL markers, such as myelin basic protein (MBP) and proteolipid protein (PLP) among many others.
  • MBP myelin basic protein
  • PLP proteolipid protein
  • the OL myelinating glial cells ofthe CNS interact with axons forming an insulating compact membrane layer (myelin), to facilitate proper electrochemical signaling of neurons. OL also maintain myelin throughout the life ofthe organism.
  • md OL progenitors are able to express markers that are synthesized by more mature OL, even though the md OL progenitors did not express such markers in vivo.
  • IGF-1 Insulin-like growth factor one
  • IGF-1 is a polypeptide growth hormone homologous to insulin, well known to promote OL progenitor maturation. IGF-1 is widely distributed in the fetal and neonatal CNS, but is restricted in the adult. Similarly, IGF-1 receptor gene expression is heterogeneous within the CNS during early stages of development, but levels decline postnatally.
  • the present invention provides compositions, including pharmaceutical compositions, comprising transferrin and insulin-like growth factor-I (IGF-I); as well as containers, devices, and kits comprising the compositions.
  • the compositions are useful for treating myelin deficiency disorders.
  • the present invention further provides methods of treating myelin deficiency disorders, the methods generally involving administering to an individual in need thereof an effective amount of a subject composition.
  • Figures 1A and IB depict the number of cells expressing BrdU in the contralateral side vs. the ipsilateral side of wt ( Figure 1 A) and md ( Figure IB) rat brain treated with Tf + IGF-1.
  • Figure 2 provides an amino acid sequence of transferrin.
  • Figure 3 depicts cell-specific markers used to characterize the cell specification process of various cell lineages form neural stem cells to mature neurons, oligodendrocytes, and astrocytes.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease.
  • Treatment covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) increasing survival time; (b) decreasing the risk of death due to the disease; (c) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (d) inhibiting the disease, i.e., arresting its development (e.g., reducing the rate of disease progression); and (e) relieving the disease, i.e., causing regression ofthe disease.
  • treatment also includes improving the quality of life. In many embodiments, “treatment” includes recovery (whole or partial) of CNS function.
  • the terms "individual,” “host,” “subject,” and “patient,” used interchangeably herein, refer to a mammal, including primates, rodents (e.g., mice, rats), livestock, mammalian pets, horses, etc. In some embodiments, an individual is a human.
  • dosing event refers to administration of a therapeutic agent (e.g., a subject composition) to a patient in need thereof, which event may encompass one or more releases of agent from a drug dispensing device.
  • a therapeutic agent e.g., a subject composition
  • Continuous delivery as used herein (e.g. , in the context of “continuous delivery of a substance to a tissue”) is meant to refer to movement of drug to a delivery site, e.g., into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time.
  • Controlled release as used herein (e.g. , in the context of “controlled drug release”) is meant to encompass release of substance at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use. "Controlled release” thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).
  • controlled drug delivery device is meant to encompass any device wherein the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially influenced by the environment of use, or releasing at a rate that is reproducible within the environment of use.
  • substantially continuous as used in, for example, the context of “substantially continuous infusion” or “substantially continuous delivery” is meant to refer to delivery of drug in a manner that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected period never falls to zero.
  • substantially continuous drug delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery.
  • the present invention provides compositions, including pharmaceutical compositions, comprising transferrin and insulin-like growth factor-I (IGF-I); as well as containers, devices, and kits comprising the compositions.
  • the compositions are useful for treating myelin deficiency disorders.
  • the present invention further provides methods of treating myelin deficiency disorders, the methods generally involving administering to an individual in need thereof an effective amount of a subject composition.
  • compositions including pharmaceutical compositions, comprising transferrin and IGF-I.
  • the compositions are in many embodiments pharmaceutical compositions.
  • a subject composition is useful for treating myelin deficiency disorders.
  • a subject composition comprises an IGF-I polypeptide; a transferrin polypeptide; and pharmaceutically acceptable excipient(s).
  • Pharmaceutical compositions generally include therapeutically effective amounts of IGF-1 and transferrin, and a pharmaceutically acceptable carrier or excipient.
  • a carrier includes but is not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.
  • the carrier and composition are in many embodiments sterile. The formulation should suit the mode of administration.
  • Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxymethylcellulose, and polyvinyl pyrolidone.
  • salt solutions e.g., NaCl
  • alcohols e.g., gum arabic
  • vegetable oils e.g., benzyl alcohols
  • polyethylene glycols e.g., gelatin
  • carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxymethylcellulose, and polyvinyl pyrolidone.
  • the pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • the composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic to ease pain at the site ofthe injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the active agents can be formulated as neutral or salt forms.
  • Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • the effective amounts of IGF-1 and transferrin in a subject composition are synergistic amounts.
  • a "synergistic combination" or a “synergistic amount" of IGF-1 and transferrin is a combined dosage that is more effective in the therapeutic or prophylactic treatment of a demyelinating disorder than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of IGF-1 when administered at the same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit transferrin when administered at that same dosage as a monotherapy.
  • the IGF-I and transferrin polypeptides in a subject composition are purified.
  • Purified when used in reference to a given polypeptide, means that the substance is of 95% or greater (by weight) purity (e.g., 98%, 99%, or greater than 99% purity), e.g., that the polypeptide is substantially free of proteins, lipids, and carbohydrates with which it is naturally associated.
  • a subject composition comprises transferrin and IGF-1 in amounts that are effective for recruiting, and/or mobilizing, and/or increasing phenotype specification and/or proliferation of oligodendrocyte progenitors.
  • a subject composition comprises effective amounts of transferrin and IGF-1.
  • "effective amounts" of transferrin and IGF-1 are amounts that in combination are effective to induce or promote recruitment of stem/oligodendrocyte progenitors to a site of myelin deficiency or demyelination in the central nervous system (CNS) of a mammalian subject.
  • CNS central nervous system
  • "effective amounts" of transferrin and IGF-1 are amounts that in combination are effective to increase the number of myelin-producing cells (e.g., myelin- producing oligodendrocyte) by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, or more, compared to the number of myelin-producing cells in an untreated subject.
  • myelin-producing cells e.g., myelin- producing oligodendrocyte
  • "effective amounts" of transferrin and IGF-1 are amounts that in combination are effective to increase the number of myelin-producing cells at or near the site of myelin deficiency or demyelination in the CNS ofthe subject.
  • "effective amounts" of transferrin and IGF-1 are amounts that in combination are effective to increase the number of myelin-producing cells (e.g., myelin- producing oligodendrocyte) at or near a site of CNS demyelination by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, or more, compared to the number of myelin-producing cells at the site of CNS demyelination in an untreated subject.
  • myelin-producing cells e.g., myelin- producing oligodendrocyte
  • "effective amounts" of transferrin and IGF-1 are amounts that in combination are effective to induce differentiation and proliferation of stem/oligodendrocyte progenitors, such that the number of myelin-producing oligodendrocytes is increased.
  • Effective amounts" of transferrin and IGF-1 are in some embodiments amounts that induce mobilization of oligodendrocyte progenitors to a site of CNS demyelination, and that induce differentiation ofthe progenitors to myelin-producing oligodendrocytes.
  • "effective amounts" of transferrin and IGF-1 are amounts that in combination are effective to increase the degree or extent of myelination of a CNS axon by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, or more, compared to the degree or extent of myelination of a CNS axon in the absence of a combination of transferrin and IGF-1.
  • "effective amounts" of transferrin and IGF-1 are amounts that in combination are effective to decrease the degree or extent of demyelination of a CNS axon by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, compared the degree or extent of demyelination of a CNS axon in the absence of a combination of transferrin and IGF-1.
  • the molar ratio of IGF-I to transferrin in a subject composition ranges from about 0.01:1 to about 1 :0.01, e.g., the molar ratio of IGF-I to transferrin in a subject composition ranges from about 0.01:1 to about 0.05:1, from about 0.05:1 to about 0.1 :1, from about 0.1:1 to about 0.5:1, from about 0.5:1 to about 1:1, from about 1:1 to about 1 :0.5, from about 1 :0.5 to about 1 :0.1, from about 1 :0.1 to about 1 :0.5, or from about 1 :0.5 to about 1 :0.01.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of compounds ofthe present invention calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
  • the specifications for the unit dosage forms ofthe present invention depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.
  • the amount of IGF-I polypeptide in a given unit dosage form ranges from about 0.1 ⁇ g to about 100 mg, e.g., from about 0.1 ⁇ g to about 0.5 ⁇ g, from about 0.5 ⁇ g to about 1.0 ⁇ g, from about 1.0 ⁇ g to about 5.0 ⁇ g, from about 5.0 ⁇ g to about 25 ⁇ g, from about 25 ⁇ g to about 50 ⁇ g, from about 50 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 500 ⁇ g, from about 500 ⁇ g to about 1 mg, from about 1 mg to about 25 mg, from about 25 mg to about 50 mg, or from about 50 mg to about 100 mg.
  • the amount of transferrin polypeptide in a given unit dosage form ranges from about 0.05 mg to about 500 mg, e.g., from about 0.050 mg to about 0.075 mg, from about 0.075 mg to about 0.1 mg, from about 0.1 mg to about 0.2 mg, from about 0.2 mg to about 0.3 mg, from about 0.3 mg to about 0.4 mg, from about 0.4 mg to about 0.5 mg, from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 5 mg, from about 5 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 250 mg, or from about 250 mg to about 500 mg.
  • a subject composition comprises, as active agents, IGF-1 and transferrin.
  • the active agents e.g., IGF-I and transferrin
  • the active agents are in some embodiments formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • the active agents are formulated alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives, and flavoring agents.
  • conventional additives such as lactose, mannitol, corn starch or potato starch
  • binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins
  • disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose
  • lubricants such as talc or magnesium stearate
  • the active agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • the suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
  • Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount ofthe composition containing one or more active agents.
  • unit dosage forms for injection or intravenous administration may comprise the active agents in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
  • IGF-I polypeptides that are suitable for use in a subject composition include any IGF-I polypeptide, or variant, fragment, derivative, or analog thereof that retains at least about 25% ofthe biological activity of a naturally-occurring IGF-I, e.g., that binds to an IGF-I receptor and functions as an agonist ofthe IGF-I receptor.
  • amino acid sequences of IGF-I polypeptides from various species are known. For example, amino acid sequences of human IGF-I are found under GenBank Accession No. P05019; P01343; AAA52789; CAA40342; AAA96152; and IGHU1. Typically, the mature form, or a fragment, derivative, variant, or analog thereof, is used. The mature form is typically amino acids 49-118 ofthe precursor protein.
  • a suitable IGF-I has the following amino acid sequence: NH 2- PETLCGAELV DALQFVCGDR GFYFNKPTGY GSSSRRAPQ TGIVDECCFR SCDLRRLEMY CAPLKPAKSA -COOH (SEQ ID NO: 1). Also suitable for use are any of the IGF-I polypeptides disclosed under GenBank Accession Nos. CAA00835, CAA00281, and CAA01643.
  • an IGF-I variant can include an IGF-I polypeptide (a) in which an amino acid residue located at a single position selected from the group consisting of positions 4, 5, 7, 10, 14, 17, 23, 24, and 43 of a native-sequence human IGF-I (e.g., SEQ ID NO:l) is replaced with an alanine residue; or (b) in which both amino acid residues at positions 1 and 70 of a native-sequence human IGF-I (e.g., SEQ ID NO:l) are replaced with a serine residue and a valine residue, respectively; or (c) in which both amino acid residues at positions 1 and 70 of a native-sequence human IGF-I (e.g., SEQ ID NO:l) are replaced with a serine residue and a valine residue, respectively,
  • IGF-I includes modifications of any known IGF-I, e.g., where suitable modifications are readily identified by those skilled in the art, e.g., by identifying: (1) conservation of amino acid sequence among species; (2) presence of "conservative" amino acid substitutions among species (i.e., amino acids with similar shape, charge or other salient characteristics); (3) receptor shielding of tyrosine residues from radioiodination (Maly and Luthi, J. Biol. Chem.
  • IGF-I also includes fragments of IGF-I, especially fragments retaining at least about 25% ofthe biological activity of a naturally-occurring IGF-I polypeptide. Fragments include fragments of from about 25 contiguous amino acids to about 65 contiguous amino acids of a mature IGF-I polypeptide, e.g., fragments of from about 25 to about 30, from about 30 to about 40, from about 40 to about 50, or from about 50 to about 65 contiguous amino acids of a mature IGF-I polypeptide.
  • IGF-I fragments include: IGF-I (55-70) Arg Arg Leu Glu Met Tyr Cys Ala Pro Leu Lys Pro Ala Lys Ser Ala (SEQ ID NO:2); an IGF-I polypeptide comprising the sequence GPETL CGAEL VDALQ FVCGD RGFYF NKPTG YGSSS (SEQ ID NO:3); IGF-I (21-40) drgfyfnkpt gygsssrrap qlspkiklfg cpiprssasr gv (SEQ ID NO:4); and the like.
  • Suitable IGF-I polypeptides include cyclic peptides, which are cyclized fragments of IGF-I.
  • a cyclized IGF-I fragment is from about 5 amino acids to about 40 amino acid residues, e.g., from about 5 amino acids to about 25 amino acids in length, or from about 25 amino acids to about 40 amino acids in length.
  • Such peptides are generally modeled after the looped domains ofthe IGF molecules. Such loops may be a consequence of natural disulfide bond formation, while others are a consequence ofthe folding ofthe protein as it achieves a minimal energy conformation or a receptor-induced conformation to permit binding.
  • Cyclization can be effected by joining the amino and carboxyl ends of a linear peptide, either directly to form an amide (lactam) bond, or by disulfide bond formation employing terminal cysteine groups. Any internal cysteine groups present are typically selectively blocked before cyclization and may be unblocked afterward using well-established procedures. Alternatively, internal cysteines may be replaced by an amino acid which would be expected to have a minimal influence on peptide conformation, e.g. alanine, which is frequently used in scanning mutagenesis studies. Suitable cyclized IGF-I polypeptides, and methods of making same, are described in U.S. Patent No. 6,723,699.
  • any known IGF-I polypeptide may be altered in various ways known in the art to generate targeted changes in sequence.
  • a variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
  • the sequence changes may be substitutions, insertions or deletions.
  • Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
  • the IGF-I formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IGF-I.
  • IGF-I polypeptides can be produced by any known method. DNA sequences encoding IGF-I may be synthesized using standard methods. In many embodiments, IGF-I polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IGF-I is "recombinant IGF-I.” Where the host cell used to produce the IGF-I is a bacterial host cell, the IGF-I is modified to comprise an N-terminal methionine.
  • an IGF-I polypeptide suitable for use herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
  • Transferrin is fully discussed in Welch, S., Transferrin: The Iron Carrier, CRC Press, Boca Raton (1992) and the references cited therein, which are hereby incorporated by reference.
  • Transferrin is a glycoprotein which is needed for the transportation of iron in the blood of more complex organisms.
  • transferrin is a plasma glycoprotein with a molecular weight of approximately 80,000 daltons and is able to bind reversibly to two atoms of ferric iron in the presence of bicarbonate.
  • Related proteins have been found in all mammals, birds, reptiles, amphibians, bony fish, and cartilaginous fish.
  • Human transferrin is a glycoprotein with two N-linked oligosaccharide chains attached to asparagine residues 413 and 611 in both the C-lobe.
  • the structure of these sugar chains can vary greatly.
  • a variant polypeptide may be altered in various ways known in the art to generate targeted changes in sequence.
  • a variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
  • the sequence changes may be substitutions, insertions or deletions.
  • Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
  • transferrin polypeptide also includes active fragments of transferrin. Active fragments include fragments containing from about 50 to about 100, from about 100 to about 200, from about 200 to about 300, from about 300 to about 400, from about 400 to about 500, or from about 500 to about 600 contiguous amino acids of any naturally-occurring or synthetic transferrin polypeptide. Modifications
  • Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, carboxylation, glycosylation, PEGylation, etc.; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes.
  • sequences that have phosphorylated amino acid residues e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
  • depsi peptide analogs; and retro-inverso peptide analogs of an IGF-I and/or a transferrin polypeptide are also embraced.
  • an IGF-1 and or a transferrin polypeptide is a fusion protein comprising an IGF-1 polypeptide or a transferrin polypeptide and a heterologous polypeptide (e.g., a fusion partner).
  • Suitable fusion partners include peptides and polypeptides that confer enhanced stability in vivo (e.g., enhanced serum half-life); provide ease of purification, e.g., (His) n , e.g., 6His, and the like; provide for secretion ofthe fusion protein from a cell; provide an epitope tag, e.g., glutathione-S-transferase, hemagglutinin (HA; e.g., CYPYDVPDYA; SEQ ID NO:6), FLAG (e.g., DYKDDDDK; SEQ ID NO:7), c-myc (e.g., CEQKLISEEDL; SEQ ID NO:8), and the like; provide a detectable signal, e.g., an enzyme that generates a detectable product (e.g., ⁇ -galactosidase, luciferase), or a protein that is itself detectable, e.g.
  • a polypeptide e.g., an IGF-1 polypeptide, a transferrin polypeptide
  • a polypeptide is modified with one or more polyethylene glycol moieties, i.e., PEGylated.
  • the PEG molecule is conjugated to one or more amino acid side chains ofthe polypeptide.
  • a polypeptide e.g., an IGF-1 polypeptide, a transferrin polypeptide
  • a polypeptide (e.g., an IGF-1 polypeptide, a transferrin polypeptide) contains a PEG moiety on two or more amino acids, e.g., the polypeptide (e.g., an IGF-1 polypeptide, a transferrin polypeptide) contains a PEG moiety attached to two, three, four, five, six, seven, eight, nine, or ten different amino acid residues.
  • a polypeptide e.g., an IGF-1 polypeptide, a transferrin polypeptide
  • Polypeptides administered in methods ofthe invention may be chemically modified in such a way as to increase the transport ofthe polypeptide across the blood-brain barrier, e.g., by modifications ofthe polypeptide that increase lipophilicity, alter glycosylation, or increase net positive charge.
  • the transferrin and/or the IGF-I of a subject composition is conjugated with L-glutamic acid.
  • the transferrin and/or the IGF-I of a subject composition is conjugated to an oligomer, as described in U.S. Patent No. 6,703,381.
  • the transferrin and IGF-I are adsorbed onto polysorbate-80-coated nanoparticles (e.g., polybutylcyanoacrylate nanoparticles).
  • a retro-isomer of a peptide is defined by a reversal ofthe direction ofthe peptide bond while maintaining the side-chain topochemistry.
  • D-amino acids are substituted for L-amino acids to retain the overall conformation for biological response and receptor binding similar to the native peptides (Hayward et al., Peptides 1974: Proc. 13th Eur. Peptide Symp., ed. Y. Wolman, pp. 287-297; Goodman et al., Ace. Chem.Res. 12:1-7 (1979)). It has been shown that the retro-inverso peptides introduced well defined conformational constraints and showed limited biodegradation by endopeptidases. CONTAINERS, DEVICES, AND KITS
  • the present invention provides a container comprising a subject composition; and devices comprising the container(s).
  • the invention further provides a kit comprising a formulation comprising a unit dosage form of a subject composition in a container, and a label that provides instructions for use ofthe kit.
  • a subject device further comprises a catheter in fluid communication with the container (e.g., a reservoir), where the reservoir has an inlet and an outlet, and where the catheter is coupled to the outlet.
  • the device is implantable.
  • the catheter has a proximal end coupled to and in fluid communication with the outlet the reservoir; and a distal end from which the composition enters the body ofthe individual being treated.
  • the implantation site is distant from the delivery site.
  • the implantation site may be subcutaneous or intravenous; and the delivery site may be in the brain.
  • the device will in some embodiments include a fluid flow control means (e.g., a valve, a pump) for controlling the flow of a subject composition from the reservoir to the catheter, where the fluid control means may be situated at the outlet ofthe reservoir.
  • the fluid flow control means comprises a pump, e.g., a programmable flow rate pump, operably connected to the reservoir, which pump controls the rate of flow ofthe subject fluid composition from the reservoir through the catheter.
  • the pump allows the operator ofthe device to change fluid delivery parameters, such as flow rate, infusion period, ramp time, and bolus volume.
  • any of a variety of pumps known in the art can be used, including, e.g., an electromechanical pump, an electroosmotic pump, a hydrolytic pump, a piezoelectric pump, an elastomeric pump, a vapor pressure pump, and an electrolytic pump, xxx
  • Suitable containers include those adapted for administration by subcutaneous injection, including a syringe (for use with a needle), an injector pen, and the like.
  • a subject agonist is administered with a pen injector (e.g., a medication delivery pen), a number of which are known in the art.
  • exemplary devices which can be adapted for use in the present methods are any of a variety of pen injectors from Becton Dickinson, e.g., BDTM Pen, BDTM Pen II, BDTM Auto-Injector; a pen injector from Innoject, Inc.; any ofthe medication delivery pen devices discussed in U.S. Patent Nos.
  • the medication delivery pen can be disposable, or reusable and refillable. Also suitable for use is an Intraject® needle-free injection system (Aradigm Corp.).
  • Suitable containers also include those suitable for use with an implantable device.
  • a container is in some embodiments a reservoir for use with an implantable device.
  • containers suitable for use with an injection device e.g., a needle and syringe, e.g., suitable for stereotaxic intraspinal or intrathecal injection.
  • the present invention provides a device for delivery of a subject composition, where the device includes a container that includes a subject composition, operably connected to a catheter.
  • the container is a reservoir, e.g., an Ommaya reservoir.
  • kits for use in carrying out a subject method generally includes a device for administering an active agent(s) to an individual in need thereof, where the device includes a container comprising a unit dosage form of a subject composition.
  • the device will further include an additional container that comprises a second therapeutic agent, e.g., a steroid (e.g., dexamethasone, methylprednisolone, etc.); an interferon (IFN- ⁇ la, IFN- ⁇ lb); etc.
  • a second therapeutic agent e.g., a steroid (e.g., dexamethasone, methylprednisolone, etc.); an interferon (IFN- ⁇ la, IFN- ⁇ lb); etc.
  • a subject kit will further include instructions for practicing the subject methods or means for obtaining the same (e.g., a website URL directing the user to a webpage which provides the instructions), where these instructions are typically printed on a substrate, which substrate may be one or more of: a package insert, the packaging, reagent containers and the like.
  • the present invention provides methods of treating myelin deficiency disorders.
  • the methods generally involve administering to an individual in need thereof an effective amount of a subject composition.
  • the present invention features methods for recruiting/mobilizing and/or increasing proliferation of oligodendrocyte progenitors, as well as methods for recruiting/mobilizing and/or increasing proliferation ofthe progeny of such cells, by administration of a composition comprising effective amounts of transferrin and IGF-1.
  • the mobilized oligodendrocyte progenitors become committed to the oligodendrocyte lineage, mature into myelin-producing oligodendrocytes, and increase the degree or level of myelination of axons.
  • Myelin deficiency disorders and demyelinating disorders that can be treated with a subject method include Multiple Sclerosis (MS), optic neuritis, transverse neuritis and Guillain-Barre Syndrome (GBS), Pelizaeus-Merzbacher disease, leukodystrophies, extrapontine demyelination, intrapontine demyelination (also known as osmotic demyelination syndrome), and the like.
  • MS Multiple Sclerosis
  • GBS Guillain-Barre Syndrome
  • GBS Guillain-Barre Syndrome
  • Pelizaeus-Merzbacher disease leukodystrophies
  • extrapontine demyelination also known as osmotic demyelination syndrome
  • Demyelination resulting from head injury or spinal cord trauma can also be treated with a subject method.
  • the subject methods generally involve administering to an individual in need thereof an effective amount of a composition comprising transferrin and IGF-I.
  • an "effective amount" of a subject composition comprising transferrin and IGF-I is an amount that is effective to ameliorate a symptom of a demyelinating disorder by at least about 10%, at least about 20%, a at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to the degree or level ofthe symptom(s) in an untreated subject.
  • symptoms of demyelinating disorders are known in the art.
  • symptoms of MS include difficulty walking; numbness ("pins and needles") in the extremities; pain on moving the eyes; dim or blurred vision, double vision, or loss of central vision; tremors (shakiness); clumsiness; slurred speech; poor memory; reduced cognitive abilities; painful muscle spasms; etc.
  • the subject methods generally involve administering to an individual in need thereof an effective amount of a composition comprising transferrin and IGF-I.
  • an "effective amount" of a subject composition comprising transferrin and IGF-I is an amount that is effective to increase locomotor function by at least about 10%, at least about 20%, a at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to an untreated subject.
  • an "effective amount" of a subject composition is an amount that is effective to reduce the extent or degree of demyelination by at least about 10%, at least about 20%, a at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to the extent or degree of demyelination an untreated subject.
  • a subject composition can be administered twice daily, daily, every other day, once a week, twice a week, three times a week, every other week, three times per month, or once monthly, or substantially continuously or continuously.
  • a subject composition is administered in a single dose directly into the brain parenchyma.
  • a subject composition is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
  • a subject composition can be administered according to the appearance of symptoms, e.g., a subject composition is in some embodiments administered within a period of time of from about 5 minutes to about 24 hours following the appearance of symptoms of a demyelinating disorder, e.g., a subject composition is administered within from about 5 minutes to about 15 minutes, from about 15 minutes to about 30 minutes, from about 30 minutes to about 1 hour, from about 1 hour to about 4 hours, from about 4 hours to about 8 hours, from about 8 hours to about 12 hours, from about 12 hours to about 18 hours, or from about 18 hours to about 24 hours, ofthe appearance of a symptom of, or triggering of, a demyelinating disorder.
  • a subject method for treating a demyelinating disorder involves administering a subject composition, and at least a second therapeutic agent that treats a demyelinating disorder.
  • Suitable second therapeutic agents include, but are not limited to, IFN- ⁇ la (e.g., Avonex® IFN- ⁇ la; Rebif® IFN- ⁇ la; etc.); IFN- ⁇ lb (e.g., Betaseron® IFN- ⁇ lb); random copolymer of Ala, Lys, Glu, and Tyr (e.g., Copaxone® glatiramer acetate); a corticosteroid (e.g., methylprednisolone (e.g., Medrol®, Solu-Medrol®, etc.); prednisone (Deltasone®); prednisolone (Dalta-Cortel®); dexamethasone (Decadron®); etc.); antineoplastic agents (e.g., met
  • a subject method includes administration of a symptom management agent.
  • Symptom management agents that are suitable for use in a subject treatment method include agents that are effective for increasing or maintaining bladder control (e.g., DDAVP® desmopressin; Detrol® tolterodine tartrate; Debenzylin® phenoxybenzamine; Ditropan XL® oxybutynin chloride; Hytrin® terazosin hydrochloride; Pro-Banthine® propantheline; Tegretol® carbamazepine; etc.); agents that are effective for treating depression, such as tricyclic anti-depressants, selective serotonin re-uptake inhibitors, etc.
  • bladder control e.g., DDAVP® desmopressin; Detrol® tolterodine tartrate; Debenzylin® phenoxybenzamine; Ditropan XL® oxybutynin chloride; Hytrin® terazosin hydrochloride; Pro-Banthin
  • agents that are effective for treating fatigue e.g., Symmetrel® amantadine; Cylert® pemonline; Provigil® modafinil; and the like
  • agents effective for pain reduction e.g., Dilantin® phenytoin; Naprosyn; Neurontin® gabapentin); Tegretol® carbamazepine; etc.
  • agents that treat spasticity e.g., Clonidine® catapres-TTS; Dantrium® dantrolene; Lioresal® baclofen; Valium® diazepam; Zanaflex® tizanidine; etc.
  • agents that reduce tremors e.g., Klonopin® clonazepam; etc.
  • agents that treat vertigo and dizziness e.g., Anti
  • a subject composition and the second agent can be administered substantially simultaneously, or within about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 16 hours, about 24 hours, about 36 hours, about 72 hours, about 4 days, about 7 days, or about 2 weeks of one another.
  • the additional agent(s) is administered during the entire course of treatment with a subject composition, and the beginning and end ofthe treatment periods coincide. In other embodiments, the additional agent(s) is administered for a period of time that is overlapping with that of treatment with a subject composition, e.g., treatment with the additional therapeutic agent(s) begins before the treatment with a subject composition begins and ends before the treatment with a subject composition ends; treatment with the additional therapeutic agent(s) begins after the treatment with a subject composition begins and ends after the treatment with a subject composition ends; treatment with the additional therapeutic agent(s) begins after the treatment with a subject composition begins and ends before the treatment with a subject composition ends; or treatment with the additional therapeutic agent(s) begins before the treatment with a subject composition begins and ends after the treatment with a subject composition ends.
  • Dosages of second therapeutic agents for treating a demyelinating disorder such as MS are well known in the art.
  • Avonex® is typically administered by intramuscular injection once per week at a dose of 30 ⁇ g per injection
  • Betaseron® is typically administered by subcutaneous injection every other day at a dose of 250 ⁇ g per injection
  • Copaxone® is typically administered by subcutaneous injection 3 times per week at a dose of 44 ⁇ g per injection
  • Novantrone® is typically administered once every three months by intravenous infusion at a dose of 12 ⁇ g/m 2 .
  • Dosages for other therapeutic agents are well known in the art. Determining efficacy of treatment
  • Whether a subject treatment regimen is effective to treat a demyelinating disorder can be readily determined by standard methods that are well known in the art. For example, efficacy in treating MS is determined, e.g., by magnetic resonance imaging (e.g., to detect gaps in the myelin sheath on the spinal cord or brain; to evaluate the degree or extent of demyelination); evaluation of locomotor movement (e.g., gait, etc.); lumbar puncture (e.g., to obtain a sample of cerebrospinal fluid (CSF) for evaluating the number of autoreactive T lymphocytes in the CSF, for evaluating the presence of autoantibodies in the CSF, etc); evoked potential testing (e.g., to measure electrical signals in the brain in response to stimulation, which allows an evaluation ofthe degree or extent of demyelination); and neuropsychological tests (e.g., to evaluate cognitive abilities, etc.).
  • magnetic resonance imaging e.g., to detect gaps in the myelin
  • An active agent e.g., IGF-I polypeptide; transferrin; etc.
  • a drug e.g., IGF-I polypeptide; transferrin; etc.
  • a therapeutic agent e.g., a "therapeutic agent” or an “active agent”
  • an active agent is administered to individuals in a formulation with a pharmaceutically acceptable excipient(s).
  • a pharmaceutically acceptable excipient(s) are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20 th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C.
  • compositions such as vehicles, adjuvants, carriers or diluents
  • pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
  • an active agent e.g., IGF-I polypeptide; transferrin; etc.
  • an active agent e.g., IGF-I polypeptide; transferrin; etc.
  • an active agent can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.
  • administration of an active agent(s) can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intrathecal, intraspinal, intracistemal, intracapsular, subcutaneous, intravenous, intramuscular, transdermal, intratracheal, etc., administration.
  • two different routes of administration are used.
  • the active agent typically comprises part of an aqueous or physiologically compatible fluid suspension or solution.
  • a liquid is in some embodiments the dosage form that is used for intravenous, intrathecal, intraspinal, intraventricular, or intramedullary administration of an active agent for use in a subject method.
  • solvents can be used, as exemplified by purified water, physiological saline, alcohols such as ethanol, propylene glycol, glycerin and polyethylene glycol, and triacetin.
  • the thus prepared liquids may be used as dilutions with a lactated Ringer's solution, a maintaining solution, a postoperative recovery fluid, a solution for supplying water to compensate for dehydration, physiological saline for use in dripping.
  • the preparations may further be admixed with adjuvants such as antiseptics, moistening agents, emulsifiers, dispersing agents and stabilizers.
  • Suspensions are another exemplary dosage form to be administered.
  • active agent e.g., IGF-I polypeptide; transferrin; etc.
  • intrathecally including, e.g., administration into a cerebral ventricle, administration into the lumbar area, and administration into the cisterna magna; or by an intraspinal route.
  • active agent e.g., IGF-I polypeptide; transferrin; etc.
  • the term "intrathecal administration” includes delivering an active agent directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebroventricular injection through a burrhole or cistemal or lumbar puncture or the like (e.g., as described in Lazorthes et al. Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1 : 169-179, the contents of which are inco ⁇ orated herein by reference).
  • the term "lumbar region” includes the area between the third and fourth lumbar (lower back) vertebrae.
  • cisterna magna includes the area where the skull ends and the spinal cord begins at the back ofthe head.
  • Cerebral ventricle includes the cavities in the brain that are continuous with the central canal ofthe spinal cord.
  • Administration of an active agent to any ofthe above mentioned sites can be achieved by direct injection ofthe active agent or by the use of infusion pumps.
  • the active agent can be formulated in liquid solutions, e.g., in physiologically compatible buffers such as Hank's solution or Ringer's solution.
  • the active agent may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms are also included.
  • the injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) ofthe active agent.
  • Subcutaneous administration of active agent e.g., IGF-I polypeptide; transferrin; etc.
  • active agent e.g., IGF-I polypeptide; transferrin; etc.
  • standard methods and devices e.g., needle and syringe, a subcutaneous injection port delivery system, and the like. See, e.g., U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017,328.
  • a combination of a subcutaneous injection port and a device for administration of an active agent to a patient through the port is referred to herein as "a subcutaneous injection port delivery system.”
  • subcutaneous administration is achieved by a combination of devices, e.g., bolus delivery by needle and syringe, followed by delivery using a continuous delivery system.
  • active agent e.g., IGF-I polypeptide; transferrin; etc.
  • continuous delivery system controlled delivery system
  • controlled drug delivery device are used interchangeably to refer to controlled drug delivery devices, and encompass pumps in combination with catheters, injection devices, and the like, a wide variety of which are known in the art.
  • Mechanical or electromechanical infusion pumps can also be suitable for use with the present invention.
  • Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; 5,820,589; 5,643,207; 6,198,966; and the like.
  • the present methods of drug delivery can be accomplished using any of a variety of refillable, pump systems. Pumps provide consistent, controlled release over time.
  • the agent is in a liquid formulation in a drug-impermeable reservoir, and is delivered in a continuous fashion to the individual.
  • the drug delivery system is an at least partially implantable device.
  • the implantable device can be implanted at any suitable implantation site using methods and devices well known in the art.
  • An implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned.
  • Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are generally preferred because of convenience in implantation and removal ofthe drug delivery device.
  • Drug release devices suitable for use in the invention may be based on any of a variety of modes of operation.
  • the drug release device can be based upon a diffusive system, a convective system, or an erodible system (e.g., an erosion-based system).
  • the drug release device can be an electrochemical pump, osmotic pump, an electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e.g., where the drug is inco ⁇ orated into a polymer and the polymer provides for release of drug formulation concomitant with degradation of a drug-impregnated polymeric material (e.g., a biodegradable, dmg-impregnated polymeric material).
  • the d g release device is based upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc.
  • Dmg release devices based upon a mechanical or electromechanical infusion pump can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852, and the like.
  • the present methods of dmg delivery can be accomplished using any of a variety of refillable, non-exchangeable pump systems. Pumps and other convective systems are generally preferred due to their generally more consistent, controlled release over time. Osmotic pumps are particularly preferred due to their combined advantages of more consistent controlled release and relatively small size (see, e.g., PCT published application no. WO 97/27840 and U.S.
  • Exemplary osmotically-driven devices suitable for use in the invention include, but are not necessarily limited to, those described in U.S. Pat. Nos. 3,760,984; 3,845,770; 3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like.
  • the dmg delivery device is an implantable device.
  • the dmg delivery device can be implanted at any suitable implantation site using methods and devices well known in the art.
  • an implantation site is a site within the body of a subject at which a dmg delivery device is introduced and positioned.
  • Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, intraspinal, or other suitable site within a subject's body.
  • a therapeutic agent is delivered using an implantable dmg delivery system, e.g., a system that is programmable to provide for administration of a therapeutic agent.
  • implantable dmg delivery system e.g., a system that is programmable to provide for administration of a therapeutic agent.
  • exemplary programmable, implantable systems include implantable infusion pumps.
  • Exemplary implantable infusion pumps, or devices useful in connection with such pumps, are described in, for example, U.S. Pat. Nos. 4,350,155; 5,443,450; 5,814,019; 5,976,109; 6,017,328; 6,171,276; 6,241,704; 6,464,687; 6,475,180; and 6,512,954.
  • a further exemplary device that can be adapted for the present invention is the SynchroMed® infusion pump (Medtronic).
  • active agent e.g., IGF-I polypeptide; transferrin; etc.
  • active agent may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds.
  • the following methods and excipients are merely exemplary and are in no way limiting.
  • An active agent e.g., IGF-I polypeptide; transferrin; etc.
  • an active agent can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • an aqueous or nonaqueous solvent such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol
  • solubilizers such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • an active agent e.g., IGF-I polypeptide; transferrin; etc.
  • an active agent e.g., IGF-I polypeptide; transferrin; etc.
  • conventional additives such as lactose, mannitol, com starch or potato starch
  • binders such as crystalline cellulose, cellulose derivatives, acacia, com starch or gelatins
  • disintegrators such as com starch, potato starch or sodium carboxymethylcellulose
  • lubricants such as talc or magnesium stearate
  • diluents buffering agents, moistening agents, preservatives, and flavoring agents.
  • an active agent can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • An active agent can be administered rectally via a suppository.
  • the suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
  • Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount ofthe composition containing one or more active agents.
  • unit dosage forms for injection or intravenous administration may comprise the agent(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
  • Subjects suitable for treatment with a subject method include individuals who have been diagnosed as having a demyelinating disorder or a myelin deficiency disorder, e.g., Multiple Sclerosis (MS), optic neuritis, transverse neuritis and Guillain-Barre Syndrome (GBS), or Pelizaeus-Merzbacher disease. Also suitable are individuals who have suffered traumatic head and/or spinal cord injury; and individuals who have suffered osmotic striatal extra- or intra-pontine demyelination.
  • Subjects suitable for treatment with a subject method include individuals having benign MS, relapsing/remitting MS, secondary/progressive MS, primary/progressive MS, or progressive/relapsing MS.
  • Subjects suitable for treatment with a subject method include individuals who have been treated with a therapeutic agent for the treatment of a demyelinating disorder, and who are refractory to such treatment (e.g., treatment failure patients).
  • Subjects suitable for treatment with a subject method include individuals who have been treated with a therapeutic agent for the treatment of a demyelinating disorder, and who can for any reason no longer tolerate treatment with the agent.
  • Subjects suitable for treatment with a subject method include individuals who have been treated with a therapeutic agent for the treatment of a demyelinating disorder, who were in remission, but who subsequently relapsed.
  • Standard abbreviations may be used, e.g., bp, base ⁇ air(s); kb, kilobase(s); pi, picoliter(s); s or sec, second(s); min, minute(s); h or hr, hour(s); aa, amino acid(s); kb, kilobase(s); bp, base pair(s); nt, nucleotide(s); i.m., intramuscular(ly); i.p., intraperitoneal(ly); s.c, subcutaneous(ly); and the like.
  • Example 1 Treatment with transferrin and IGF-1 promotes recruitment of stem oligodentrocyte progenitors in the normal and myelin-deficient postnatal brain.
  • Materials and Methods Animals and Growth factors administration [00120] The myelin deficient rat mutants (+md/Y), the littermate controls (++/Y), and the wild type (Wt) Wistar rats were bred at UCLA in a restricted access, temperature-controlled vivarium on a 12: 12 h cycle, and free access to food and water.
  • Tissues were embedded in OCT compound to prepare and 20 ⁇ m frozen sections as described (Espinosa et al, (1999) supra; Espinosa et al. (2002) Rat.Dev. Neurosci. 24:227-241). Evaluation of growth factors ' treatment
  • Double immunofluorescence for PSA-NCAM from the Hybridoma Bank (Pharmacia 556309), nestin and Tf Nordic Immunology, 2693) detection was performed as previously described by Espinosa et al, (1999) supra).
  • An IgG anti-mouse FITC (Sigma, F-9006) and IgG anti- rabbit Texas red (Jackson Immuno Research Laboratories Inc. Cat. # 112 075 075) were used to visualize these markers.
  • GFAP glial fibrillary acidic protein antibody
  • the Zeiss LSM 510 Meta confocal microscope and Adobe Photoshop software, were respectively used to acquire and record the images depicting the effects ofthe trophic factors.
  • mice were injected with 10 uM BrdU, (lml/lOOg body weight BrdU Kit II, 1299 964, Roche Molecular Biochemicals), and left 24 hours.
  • animals were given a second injection and 2h after the second injection they were perfused as previously described (Espinosa et al., (2002) supra), brains harvested and left in 30% sucrose for cryoprotection.
  • the day ofthe immunocytochemistry sections were immersed in 70% ethanol in 50mM glycine buffer pH2.0 at -20°C for 20 min, and rehydrated in PBS.
  • Tf positive/nestin negative cells of enlarged cell bodies were located along the wall ofthe lateral ventricle. However, these enlarged cells were not seen in the SVZ or the parenchyma.
  • the untreated md brain did not show any significant expression of either marker, only very few short and isolated nestin positive sprout-like fibers.
  • the mutant 13 days after the injection no longer had nestin in the ventricular wall and only a thin stream of nestin positive/Tf positive small bipolar cells was observed.
  • nestin expression remained localized to the ependymal canal that had thickened and the hair-like processes had displaced farther into the parenchyma. After treatment the nestin labeled ependymal canal had also thickened and hair-like staining had appeared in unaffected pups. The nestin expression pattern resembled the md untreated brain. Neither the ependymal canal nor the adjacent parenchyma expressed Tf, whether animals were unaffected or mutants nor in response to the injection of Tf+IGF-1. Older untreated animals PI 8/19 days no longer expressed nestin in these regions.
  • the unaffected littermates without treatment showed a reduced GFAP staining when compared to the untreated md mutant. Moreover, no nestin positive cells or fibers were present. However, Wt animals responded to the treatment by displaying numerous radial like processes extending pe ⁇ endicularly from the subventricular region into the brain parenchyma, these fibers were GFAP negative. Thus, the two factors induced nestin expression in regions of neurogenesis yet not in GFAP expressing cells neither in the unaffected nor in the md animal. Neither unaffected nor mutants displayed colocalization of GFAP with nestin. Expression of Nestin and Neurofilaments
  • both the ipsilateral and contralateral hemispheres displayed a gradient of BrdU positive cells along the CC.
  • BrdU inco ⁇ oration increased from the mid line peaking around the injection site.
  • the points closest to the midline in both hemispheres had the lowest and equivalent number of BrdU positive cells.
  • the ipsilateral CC had twice as many BRDU positive cells when compared to the corresponding regions ofthe CC in the contralateral side and equivalent to the non treated animal.
  • the combined factors had a greater impact on cell proliferation in the md brain when compared with their wild type counte ⁇ arts.
  • Fig. 1A and IB depict the number of cells expressing BrdU in the contralateral side vs. the ipsilateral side of wt ( Figure 1A) and md (Figure IB) rat brain treated with Tf + IGF-1.
  • Figures 1A and IB show the results of examination of BRDU inco ⁇ oration on coronal brain sections two days after injection. Bars represent the number of BRDU+ cells per area in different regions ofthe CC.
  • Both the ipsilateral and contralateral hemispheres displayed a BRDU gradient of positive cells along the co ⁇ us callosum (CC). In the ipsilateral hemisphere BRDU inco ⁇ oration increased from the mid line peaking around the injection site.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Endocrinology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention se rapporte à des compositions, y compris des compositions pharmaceutiques, comprenant un facteur I de croissance de type transferrine et insuline (IGF-I); ainsi qu'à des contenants, des dispositifs et des kits contenant ces compositions. L'invention porte aussi sur des procédés de traitement de troubles de déficience de la myéline, lesdits procédés consistant généralement à administrer à une personne qui en a besoin une quantité efficace de la composition.
PCT/US2005/019298 2004-05-21 2005-05-19 Compositions et procedes de traitement de troubles de deficience de la myeline WO2005112911A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US57316604P 2004-05-21 2004-05-21
US60/573,166 2004-05-21

Publications (2)

Publication Number Publication Date
WO2005112911A2 true WO2005112911A2 (fr) 2005-12-01
WO2005112911A3 WO2005112911A3 (fr) 2006-10-26

Family

ID=35428826

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/019298 WO2005112911A2 (fr) 2004-05-21 2005-05-19 Compositions et procedes de traitement de troubles de deficience de la myeline

Country Status (1)

Country Link
WO (1) WO2005112911A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008086813A2 (fr) * 2007-01-19 2008-07-24 Kobenhavns Universitet Peptides dérivés de protéines de la superfamille de l'insuline
WO2012004416A3 (fr) * 2010-07-09 2012-04-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Traitement d'une maladie associée à un trouble dégénératif de la rétine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3849550A (en) * 1971-04-21 1974-11-19 Yeda Res & Dev Therapeutic copolymer
SU1171036A1 (ru) * 1983-05-10 1985-08-07 Ленинградский Государственный Ордена Ленина Институт Усовершенствования Врачей Им.С.М.Кирова Способ лечени рассе нного склероза
US6410046B1 (en) * 1996-11-19 2002-06-25 Intrabrain International Nv Administering pharmaceuticals to the mammalian central nervous system
US20030021765A1 (en) * 1998-10-16 2003-01-30 Blake Pepinsky Polymer conjugates of interferon beta-1a and uses
US20030027755A1 (en) * 2000-12-08 2003-02-06 Jian Guan Compositions and methods for the rescue of white matter

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3849550A (en) * 1971-04-21 1974-11-19 Yeda Res & Dev Therapeutic copolymer
SU1171036A1 (ru) * 1983-05-10 1985-08-07 Ленинградский Государственный Ордена Ленина Институт Усовершенствования Врачей Им.С.М.Кирова Способ лечени рассе нного склероза
US6410046B1 (en) * 1996-11-19 2002-06-25 Intrabrain International Nv Administering pharmaceuticals to the mammalian central nervous system
US20030021765A1 (en) * 1998-10-16 2003-01-30 Blake Pepinsky Polymer conjugates of interferon beta-1a and uses
US20030027755A1 (en) * 2000-12-08 2003-02-06 Jian Guan Compositions and methods for the rescue of white matter

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ESPINOSA J. ET AL.: 'Transferrin regulates transcription of the MBP gene and its action synergizes with IGF-1 to enhance myelinogenesis in the md rat' DEVELOP. NEUROSCI. vol. 24, no. 2-3, 2002, pages 227 - 241, XP008071171 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008086813A2 (fr) * 2007-01-19 2008-07-24 Kobenhavns Universitet Peptides dérivés de protéines de la superfamille de l'insuline
WO2008086813A3 (fr) * 2007-01-19 2008-12-04 Uinv Kobenhavns Peptides dérivés de protéines de la superfamille de l'insuline
WO2012004416A3 (fr) * 2010-07-09 2012-04-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Traitement d'une maladie associée à un trouble dégénératif de la rétine

Also Published As

Publication number Publication date
WO2005112911A3 (fr) 2006-10-26

Similar Documents

Publication Publication Date Title
CA2114251C (fr) Igf-1 permettant d'ameliorer l'etat du systeme nerveux
EP1364655B1 (fr) Procédé pour favoriser la récupération fonctionnelle de la coordination motrice, de la parole ou de la perception sensorielle à la suite d'une ischemie ou d'un traumatisme du système nerveux central
AU2007229301B2 (en) Continuous dosing regimens for neural stem cell proliferating agents and neural stem cell differentiating agents
PT2019683T (pt) Administração de fatores de crescimento para o tratamento de distúrbios do snc
US20050176627A1 (en) Long acting erythropoietins that maintain tissue protective activity of endogenous erythropoietin
JP6403062B2 (ja) 組織修復活性組成物及びその利用
JP2002523518A (ja) 環状プロサポシン由来のペプチドおよびその使用
WO1997032895A1 (fr) Methodes de soulagement de la douleur nevropathique a l'aide de peptides derives de prosaposine
JPH09503999A (ja) 治療剤としてのプロサポシンおよびサイトカイン由来ペプチド
US8361965B2 (en) Recombinant chimeric protein of neutrophil inhibitory factor and hirugen, and pharmaceutical composition thereof
KR20200003889A (ko) C-말단 cdnf 및 manf 단편, 이를 포함하는 약학적 조성물 및 그 용도
WO1996009064A1 (fr) Procede et preparation pharmaceutique pour la prevention et le traitement des lesions cerebrales
EP1622636A2 (fr) Methode de traitement de la maladie de parkinson chez l'homme par administration par voie intraputaminale du facteur neurotrophique derive d'une lignee de cellules gliales
JP2012197290A (ja) Ｉｇｆの構造的アナログを投与することによる中枢神経系の治療方法
US20030027755A1 (en) Compositions and methods for the rescue of white matter
WO2005112911A2 (fr) Compositions et procedes de traitement de troubles de deficience de la myeline
CN109106943B (zh) 抗癫痫的毒素Martentoxin及其应用
CA2497960A1 (fr) Erythropoietines a action longue qui maintiennent l'activite protectrice du tissu d'une erythropoietine endogene
JP2002543096A (ja) ＴＧＦ−αポリペプチド、機能性断片およびそれらの利用法
US20040121958A1 (en) Methods of alleviating neuropathic pain
KR20040008177A (ko) 신경 사 단백질 세그먼트를 사용하여 세포 사멸을억제하는 방법
JPH10504320A (ja) 稀突起膠芽細胞の再生のための治療剤の調製方法
WO2013021196A2 (fr) Différenciation d'oligodendrocytes
US20170137483A1 (en) Use of epo-derived peptide fragments for the treatment of inflammatory diseases
WO1997003689A1 (fr) Procede de traitement de l'epilepsie au moyen du facteur neurotrophique derive du cerveau

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase