Classifications

• • 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
  • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
• • 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
  • A61K35/50—Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells

Definitions

• the present invention broadly relates to methods of harvesting mammalian feto-placental proteins and in particular, chaperone proteins, for use in compositions and medical therapies for the 5 treatment of disease or aging in mammals, and in particular, to humans.
• Aging which is both chronological and determined by cellular processes, is associated with an increase in disease and pathological processes.
• the causes of aging are unknown, but recent reviews correlate aging in humans with the instability of mitochondria leading to an increase in intra-cellular reactive oxygen species (ROS), potential shortening of the telomere, protein o dysfunction and/or cellular death.
• ROS reactive oxygen species
• the increase in ROS in turn appears to adversely affect DNA, mRNA, and protein synthesis, folding, transport and degradation.
• the culmination of these events in turn leads to apoptosis, i.e., cellular "suicide", followed by necrosis, i.e., cellular death.
• chaperone proteins which include pharmacological chaperones, pharmacoperones, and pharma-cochaperones, are defined as target-specific, small molecules that bind to their target proteins to facilitate biogenesis0 and/or prevent and/or correct protein misfolding.
• Chaperone protein targets include enzymes, receptors, transporters, and ion channels. Id. Chaperone proteins prevent the accumulation of misfolded proteins by promoting their refolding, degeneration and/or exocytosis. Keep your heart in shape: molecular chaperone networks for treating heart disease,Tarone Guido,
• Chaperone proteins also play a role in intracellular signaling by controlling conformational changes required for the activation and 5 deactivation of signaling proteins and assembly in signalosome complexes. Id.
• chaperone proteins are not readily available for medical research and possible medical therapies, however. Thus, there is a need for methods of harvesting, processing and storing chaperone proteins. In addition, there is a need to develop compositions and medical therapies which make use of chaperone proteins in the treatment of disease or aging, and in particular, l o disease related to protein dysfunction.
• the invention provides a method of harvesting, processing and storing a plurality of proteins from a mammalian feto-placental unit.
• the method includes dissecting a mammalian uterus to harvest at least one component of the mammalian feto-placental unit; blast freezing the component; and storing the blast frozen component; wherein the blast frozen component includes the plurality of mammalian feto-placental unit proteins.
• the method includes lyophilizing the blast frozen component to remove at least some water from the blast frozen component thereby creating a freeze-dried form; and storing the lyophilized component; wherein the lyophilized component includes the mammalian feto-placental unit proteins.
• the mammalian feto-placental unit proteins include at least one essential fragment of at least one of the mammalian feto-placental unit proteins. In a further additional embodiment, the mammalian feto-placental unit proteins include a plurality of chaperone proteins.
• the mammalian feto-placental unit proteins are selected from the group consisting of Serum albumin, Actin, cytoplasmic 1, 1 alpha globin, Hemoglobin fetal subunit beta, Vimentin, Beta globin chain, TPMl, Annexin A2, Protein disulfide isomerase family A member 3, Alpha-2-HS -glycoprotein, Fatty acid binding protein 5, Cofilin-1, 78 kDa glucose- regulated protein, Gelsolin isoform b, Beta-A globin chain, Glyceraldehyde-3 -phosphate dehydrogenase, Heat shock protein alpha, Heat shock protein 70, Peptidylprolyl isomerase A, 14-3- 3 protein zeta/delta, Histone H3, Peroxiredoxin 2, Cathepsin D, Uterine milk protein, Tubulin beta chain, Myosin light chain 6, Endoplasmic reticulum protein 29, Tubulin alpha chain, Solute carrier
• the method includes using at least a portion of the mammalian fetoplacental unit proteins for medicinal purposes.
• the step of using at least a portion of the mammalian feto-placental unit proteins for medicinal purposes includes treating for cellular repair in a mammalian subject.
• the step of using at least a portion of the mammalian feto-placental unit proteins for medicinal purposes includes treating for a disease or aging in a mammalian subject.
• the treating step includes administering the portion of the mammalian feto-placental unit proteins to the mammalian subject with at least one of a sublingual procedure, an intra-ocular procedure, an intra-rectal procedure, and an intra-gastro-intestinal procedure.
• the treating step includes reconstituting the portion of the mammalian feto-placental unit proteins of the lyophilized component with a fluid; and administering the reconstituted portion of the mammalian feto-placental unit proteins to the mammalian subject.
• the fluid is an oil.
• the administering step includes administering the reconstituted portion of the mammalian fetoplacental unit proteins to the mammalian subject through a procedure selected from the group consisting of an oral administration, a rectal administration, a cutaneous administration, a subcutaneous administration, an intravenous injection, and an intramuscular injection.
• the administering procedure is a cutaneous administration
• the component is selected from the group consisting of a placenta- cord fetal component, a liver component, a spleen component, a whole brain component, an ocular component, a gastro-intestinal component, a female specific component, and a male specific component.
• the invention provides a composition.
• the composition includes a plurality of mammalian feto-placental unit proteins from at least one lyophilized, blast frozen component of a harvested mammalian feto-placental unit.
• the mammalian feto-placental unit proteins include at least one essential fragment of at least one of the mammalian feto-placental unit proteins.
• the mammalian feto-placental unit proteins include a plurality of chaperone proteins.
• the lyophilized, blast frozen component is selected from the group consisting of a placenta-cord fetal component, a liver component, a spleen component, a whole brain component, an ocular component, a gastrointestinal component, a female specific component, and a male specific component.
• the invention provides a method of treatment of a disease or aging in a mammalian subject including administering to the mammalian subject a plurality of mammalian feto-placental unit proteins from at least one blast frozen component harvested from a mammalian feto-placental unit; and reducing an accumulation of at least one intracellular protein in the mammalian subject.
• the mammalian feto-placental unit proteins include at least one essential fragment of at least one of the mammalian feto-placental unit proteins.
• the mammalian feto-placental unit proteins include a plurality of chaperone proteins.
• the step of reducing the accumulation of the intracellular protein comprises at least one of folding at least a portion of the intracellular protein, refolding at least a portion of the intracellular protein, degrading at least a portion of the intracellular protein and transferring at least a portion of the intracellular protein across a cellular membrane.
• FIG. 1 shows the steps of the method according to an embodiment of the invention
• FIG. 2 shows the steps of the method according to an embodiment of the invention
• FIG. 3 shows the steps of the method according to an embodiment of the invention
• FIG. 4 shows the steps of the method according to an embodiment of the invention
• FIG. 5 shows schematically the mis-folding and refolding of a protein, as described in the prior art
• FIG. 6 shows schematically the degradation of a protein by a chaperone protein, as described in the prior art
• FIG. 7 shows schematically cell apoptosis, as described in the prior art.
• FIG. 8 shows the steps of the method according to an embodiment of the invention.
• the present invention relates to methods for harvesting proteins or essential fragments thereof, and in particular chaperone proteins, from the mammalian feto-placental unit, and the use of such mammalian feto-placental unit proteins in compositions and medical therapies for the treatment of disease and aging.
• the "essential fragment" of a protein of a mammalian feto-placental unit is defined as the portion of the protein which is capable of at least one of the reversal of cell apoptosis, the repair of cells, the regeneration of cells, and the regulation of protein folding, re-folding, transportation and degradation, through for example, the Ubiquitin Protease Pathway (UPP).
• UPB Ubiquitin Protease Pathway
• the invention provides a method 10 of harvesting and processing proteins from a mammalian feto-placental unit, as shown in FIG. 1.
• the method includes the steps of dissecting a mammalian uterus to harvest at least one component of the mammalian feto-placental unit, as shown in step 12; and blast freezing the component, as shown in step 14; wherein the component includes the proteins.
• the method includes storing the blast frozen component, as shown in step 16.
• the method includes lyophilizing the blast frozen component to remove at least some water from the frozen component thereby creating a freeze-dried form, as shown in step 18; and storing the lyophilized component, as shown in step 19.
• the invention provides the method 20 shown in FIG 2.
• a female pregnant mammal such as, for example, a pregnant ewe
• a registered veterinarian conducts a pre-mortem and postmortem examination of the selected first donor mammal to ensure that the donor is healthy and free of any visible disease.
• the veterinarian inspects for muscular wasting which in an ovine could indicate parasitism or Johnes disease.
• the registered veterinarian also inspects for normal motor-function to rule out any central nervous system disease, such as, for example, aberrant larval migration, spinal cord and/or brain infection including infection in the middle and inner ear.
• the registered veterinarian also conducts a post-mortem examination of the selected first donor mammal to confirm the health and absence of disease in the donor mammal.
• the veterinarian can inspect for, for example, enlarged kidneys and nephrosis which could indicate a clostridial type infection.
• Core samples are taken from the liver and/or spleen of the first donor mammal for bacterial and viral isolation. For purposes of the present invention, only tissue negative to bacterial and viral isolation are harvested.
• the uterus is harvested and inspected by the registered veterinarian to confirm the absence of lesions and/or other defects in the uterus, as shown in step 24.
• the uterus is dissected and the placenta with cotyledons and umbilical cord are separated from the remaining fetal mass and washed in a sterile non-pyrogenic solution containing no antimicrobial agents such as, for example, Lactated Ringers Solution (LRS), as shown in step 26.
• LPS Lactated Ringers Solution
• placenta-cord fetal component or components refer to the fetal placenta with cotyledons and umbilical cord which are harvested from the remaining fetal mass for a particular donor mammal while the term “feto-placental unit” includes the dissected placenta-cord fetal component plus the remaining dissected fetal mass.
• the harvested placenta-cord fetal components are inspected for damage such as, for example, tissue bruising or tearing which may have occurred during harvesting and dissection. Samples of the undamaged harvested placenta-cord fetal components are analyzed for infection using bacterial and/or viral cultures.
• Undamaged, confirmed non-infected harvested placenta-cord fetal components are weighed and placed in a labeled sterile sample container, as shown in step 28.
• the sterile sample container holding the placenta-cord fetal components is then transferred into a first clipped, that is, securely closed, sterile container, as shown in step 29 of FIG. 2. Damaged and/or infected dissected placenta-cord components are discarded. Further embodiments including the steps of method 30 are illustrated in FIG. 3.
• the remaining fetal mass not including the placenta-cord fetal components is also washed in a sterile non-pyrogenic solution containing no antimicrobial agents such as, for example, LRS, and transferred to a dissection table, as shown in step 32.
• the sterilized remaining fetal mass is dissected into relevant specialized fetal components such as, for example, a liver component, a spleen component, a whole brain component, an ocular component, a gastrointestinal component, a female specific component which includes accessory sexual glands, and a male specific component which includes male penile tissue, testicular tissue and accessory sexual glands.
• relevant specialized fetal components such as, for example, a liver component, a spleen component, a whole brain component, an ocular component, a gastrointestinal component, a female specific component which includes accessory sexual glands, and a male specific component which includes male penile tissue, testicular tissue and accessory sexual glands.
• the harvested specialized fetal components are
• Samples of undamaged harvested specialized fetal components are analyzed for infection using bacterial and/or viral cultures. Damaged and/or infected dissected specialized fetal components are discarded. Non-damaged, non-infected harvested specialized fetal components are again washed in a similar sterile, non-pyrogenic solution, such as, for example, LRS. Each re-sterilized harvested specialized fetal component is weighed and placed in its own sterile labeled container per component, as shown in step 34.
• the labeled containers holding the harvested specialized fetal components corresponding to the same first donor mammal are then transferred into the first clipped sterile container along with the placenta-cord fetal components for the same first donor mammal, as shown in step 36.
• the first sterile clipped container is closed, sealed and labeled with identification information including weight and any notes regarding the dissection as shown in step 38.
• identification information including weight and any notes regarding the dissection as shown in step 38.
• the prior multiple inspections of the entire feto-placental unit ensures that normal fetal growth has occurred and that there is no sign of infection and concomitant disease.
• the first sterile clipped container is directly submitted to a process for freezing the harvested components, as shown in step 39.
• the freezing and storage processes 40 of the invention are shown in FIG. 4.
• the freezing process is accomplished using a fast or rapid freezing otherwise known as a blast freezing, as shown in step 42.
• the blast freezing lowers the temperature of the components to at least -6 °C, and preferably to at least -10°C, and more preferably to at least -20 °C, in eight hours, and preferably in six hours, and more preferably in four hours and most preferably in two hours.
• the components can be stored in a freezer in medium term storage, as shown in step 44, for up to twelve months, and preferably for up to six months, and more preferably for up to three months, and most preferably for up to two months.
• medium term storage the temperature of the components is maintained between -20 °C and -100 °C, and preferably between -40 °C and -90 °C, and more preferably -60 °C and -80 °C, and most preferably between -65 °C and -75 °C.
• the components can be further lyophilized or freeze dried to remove water from the components, as shown in step 46, using methods known to those of ordinary skill in the art. A freeze dried form of the component is thereby formed. Lyophilization is conducted on a batch basis by weight and according to type of component. Thus, the placenta-cord fetal component and the specialized liver, spleen, brain, ocular, gastro-intestinal, and female and male specific fetal components are lyophilized by weight according to component type to satisfy minimum weight requirements. Components are lyophilized to weigh a minimum of 10 grams of specific tissue, and preferably a minimum of 8 grams of specific tissue, and more preferably a minimum of 6 grams of specific tissue, and most preferably a minimum of 4 grams of specific tissue.
• the components can then be stored for long term storage in their lyophilized, that is, freeze- dried form, as shown in step 48.
• the temperature of long term storage is maintained between 5 °C and 30 °C, and preferably between 10 °C and 25 °C, and more preferably between 15 °C and 20 °C, and most preferably at 20 °C.
• the duration of long term storage can equal as much as 100 years, and preferably a maximum of 50 years, and more preferably a maximum of 10 years, and even more preferably a maximum of 2 years, and most preferably a maximum of 1 year.
• the harvested and processed mammalian fetal unit components include a plurality of proteins or essential fragments thereof.
• the mammalian feto-placental unit protein or essential fragments include chaperone proteins.
• the chaperone proteins can have the ability to re-fold wrongly folded proteins as shown in FIG. 5.
• the chaperone proteins can degrade otherwise not fully metabolized proteins.
• FIG. 6 demonstrates this mechanism, where UB identifies ubiquitors, CP identifies chaperone proteins, and RP identifies residual proteins.
• the chaperone proteins can reverse cellular apoptosis, as shown in FIG. 7.
• the shutdown mechanisms take various forms but in essence lead to intracellular protein accumulation mainly through a lack of protein transport out of the cell.
• the protein accumulation in turn leads to osmotic imbalance, cell membrane disruption and cell membrane disintegration.
• Chaperone proteins can work intracellularly to fold, refold, transport or degrade accumulated proteins.
• the reverse of toxic protein accumulation ameliorates osmotic imbalance thereby preventing cellular membrane disruption. As a result, the cellular death spiral is reversed.
• the chaperone proteins can affect intracellular signaling by controlling conformational changes required for activation or deactivation of signaling proteins, and their assembly in specific signalosome complexes. See Tarone at abstract. Accordingly, m embodiments of the method of the invention, the proteins of the components of the mammalian feto-placental unit can be used for medicinal purposes in the treatment of disease and/or aging in mammalian subjects including, for example, humans. Most disease and aging is characterized by some form of cellular dysfunction including the slowing of cellular mechanisms and the buildup of dysfunctional proteins within the cell. This cellular dysfunction leads to cellular under performance and clinical manifestation of disease and/or aging. The proteins of the components of the mammalian placental unit including essential fragments and chaperone proteins can be administered to promote folding, refolding, transport or degradation of accumulated proteins within cells.
• An example of a disease mechanism which can be targeted by the method of the invention is the manifestation of type 2 diabetes.
• this disease can have multi-centric etiologies and manifestations
• the cellular basis of the disease relates to the compromised ability of the cell to make insulin receptors and/or to respond to insulin/insulin receptor interaction because of the accumulation of proteins.
• the compromised cellular abilities lead to a lack of systemic glucose regulation which in turn leads to a cascade of multi-compartmental manifestations of clinical symptoms, but most specifically to an interference with arteriole circulation.
• the arteriole circulation interference leads to a decrease in blood circulation, vascular constriction, rise in blood pressure, and a decrease in vascular support for organs and cells. Ischemia, cellular apoptosis and eventually cell death result.
• the method of the present invention including the administration of mammalian fetoplacental unit proteins to a mammalian subject such as a human can counteract and at least partially reverse this cascade of events.
• the chaperone proteins administered to the human subject are from an exogenous biologic source of mammalian feto-placental tissue.
• the mammalian feto-placental unit proteins including chaperone proteins can work intracellularly to fold, refold, transport, and/or degrade accumulated proteins. These mechanisms at least partially reverse the toxic accumulation proteins.
• the cellular death spiral is reversed at least partially leading to the return of cellular function related to the response of the insulin/insulin receptor complex, the relaxation of arterioles, the decrease in blood pressure, the re oxygenation of tissue, the reverse of ischemia and the return to normal cell function and organ function.
• At least portions of the tissues including the proteins can be extracted from the blast frozen components of the mammalian feto-placental unit, thawed and directly administered to the mammalian subject using different procedures employing, for example, a spatula, a sponge, a gel, and encapsulation.
• Non-limiting procedures for protein administration to a mammalian subject include a sublingual procedure, an intra-ocular procedure, an intra-rectal procedure and an intra- gastro-intestinal procedure.
• tissues including the proteins can be extracted from the lyophilized components of the mammalian feto-placental unit and reconstituted with a fluid, such as, for example, sterilized water or saline.
• a fluid such as, for example, sterilized water or saline.
• the reconstituted proteins can be administered to the mammalian subject using various procedures such as, for non-limiting examples, an oral administration, a rectal administration, a cutaneous administration, a subcutaneous administration, an intravenous injection, and an intramuscular injection.
• the proteins including the essential fragments thereof harvested from the mammalian fetoplacental unit, processed and stored according to a method of the invention are included in the list provided in Table 1. All versions of the database: the uniprot-_20130128_5wcYYr database are included for the purposes of the specification.
• Examples of various diseases and/or symptoms characteristic of aging which can be treated by the proteins including the essential fragments thereof harvested from the mammalian fetoplacental unit, and processed according to a method of the invention include, for example, type 2 diabetes, type 1 diabetes, cardiomyopathy, prostate cancer, renal dysfunction, and intra- and extracellular storage disease, Alzeimer disease, Parkinson disease, sexual dysfunction including female dysfunction (e.g., fluid reduction) and male dysfunction (e.g., erectile dysfunction), hormonal imbalance including hormonal imbalance around the cessation of mensus or menopause, musculoskeletal disorder, and neoplasia.
• intra- and extracellular storage disease refers to conditions where the body makes proteins but does not have the mechanism such as, for example, the enzymes, to break down the proteins, and the accumulation of such proteins becomes harmful for the subject.
• Selected proteins are known to those of ordinary skill in the art to ammeliorate selected specific diseases as discussed in, for example, Growth chartsor patients with Hunter syndrome, Patel P, Suzuki Y, Maeda M, Yasuda E, Shimada T, Orii KE, Orii T, Tomatsu S., Mol Genet Metab Rep. 2014;1 :5-18, PMID: 24955330, [PubMed], and other articles identified in
• mammalian feto-placental unit proteins are administered to a mammalian subject for the treatment of extracellular storage diseases involving the toxic accumulation of extracellular proteins.
• the mammalian feto-placental proteins act to reduce the toxic accumulation of extra-cellular proteins by degrading, folding, refolding and/or transferring the toxic proteins across cellular membranes.
• mammalian fetoplacental unit proteins are administered to a mammalian subject for the treatment of intra- and extra-cellular storage diseases involving the toxic accumulation of mucopolysaccharides.
• Mucopolysaccharides also known as glycosaminoglycans, consist of long chains of sugar molecules.
• enzymes are produced to break down the mucopolysaccharides into simpler molecules which the body can then utilize.
• individuals suffering from mucopolysaccharide storage diseases either the individuals do not produce sufficient quantities of the necessary enzymes to break down the mucopolysaccharides into smaller molecules for use by the body, or the individual produces enzymes which are defective and unable to break down the mucopolysaccharides into the necessary smaller molecules.
• mucopolysaccharides can accumulate in cells, connective tissue and/or the blood stream and lead to severe disease and death. Such individuals are traditionally treated with exogenous enzymatic therapies for breaking down the mucopolysaccharides.
• mammalian feto-placental protecins can be administered to the mammalian subject, and the mammalian feto-placental proteins can break down the mucopolysaccharides into smaller molecules thereby reducing the toxic accumulation of such long chain sugars.
• the invention provides a composition including proteins originating from at least one blast frozen, lyophilized component of a harvested mammalian feto-placental unit.
• the proteins include at least one essential fragment of at least one of the proteins.
• the proteins include chaperone proteins.
• the component is selected from the group consisting of at least one of a placenta-cord fetal component, a liver component, a spleen component, a whole brain component, an ocular component, a gastrointestinal component, a female specific component, and a male specific component.
• FIG. 8 An additional aspect of the invention is shown by method 50 in FIG. 8 which provides for the treatment of a disease or aging in a mammalian subject.
• the method includes administering to the mammalian subject a plurality of proteins from at least one blast frozen component harvested from a mammalian feto-placental unit, as shown in step 52; and reducing an accumulation of at least one intracellular protein in the mammalian subject, as shown in step 54.
• the step of reducing the accumulation of the intracellular protein includes at least one of folding, refolding, transfer, and degradation of the intracellular protein.
• a donor sheep certified according to New Zealand Protocol was selected. Placenta-cord, liver, gastro-intestinal and specific male fetal components were dissected, harvested, and processed including inspection, sterilization, blast freezing followed by lyophilization. The lyophilized components were stored for at least of two years. Tissue samples were then extracted from the lyophilized components periodically according to the patient treatment protocol and reconstituted with sterilized saline to form 6 ml injection samples including 1 gram of reconstituted lyophilized component per each sample.
• Patient X was in his early 90 's and had concomitant prostatic cancer which exhibited as an enlargement of the prostate gland coupled with a prostate specific antigen (PSA) score of over 20.
• PSA prostate specific antigen
• the patient had experienced baldness for approximately 40 years.
• the patient suffered from clinical stiffness and exhibited stooped posture due to osteoporosis.
• the patient reported experiencing erectile dysfunction and low libido.
• the injection samples including the lyophilized components reconstituted with sterilized saline were injected subcutaneously into Patient X once per month for 6 months and once per 3 months thereafter for 5 years.
• the patient's clinical physician observed a PSA of 15 and a decrease in prostatic gland size to 30% of the pre-treatment size. Subsequently, the patient's PSA dropped to less than 5 and remained less than 5 thereafter. New hair growth was observed on top of the patient's head. The patient no longer suffered from pre-treatment clinical stiffness and maintained an erect posture. The patient reported return of libido and erectile function.

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• 2014
  • 2014-11-24 WO PCT/IB2014/003107 patent/WO2016009246A1/en active Application Filing
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