WO2025230830A1 - Compositions de fractions de plasma sanguin et leur utilisation dans le traitement de l'amyotrophie spinale (sma) - Google Patents

Compositions de fractions de plasma sanguin et leur utilisation dans le traitement de l'amyotrophie spinale (sma)

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Publication number
WO2025230830A1
WO2025230830A1 PCT/US2025/026412 US2025026412W WO2025230830A1 WO 2025230830 A1 WO2025230830 A1 WO 2025230830A1 US 2025026412 W US2025026412 W US 2025026412W WO 2025230830 A1 WO2025230830 A1 WO 2025230830A1
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plasma
fraction
subfraction
sma
blood
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Benson LU
Annette Tennstaedt
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Alkahest Inc
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Alkahest Inc
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    • 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
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases

Definitions

  • This invention pertains to the prevention and treatment of disease.
  • the invention relates to the use of blood plasma fractions to treat and/or prevent conditions associated with genetic -related degenerative disease including spinal muscular atrophy (SMA).
  • SMA spinal muscular atrophy
  • SMA Spinal muscular atrophy
  • SMA is a genetic -related degenerative disease. It is a progressive neuromuscular disorder and is associated with continuous motor function loss and complications including scoliosis and contractures (Ribero VA, et al., Neurology, 101:e2103-e2113 (2023)). SMA is an autosomal recessive disease that is the cause of the most genetic infant mortalities (1 in 10,000 live births). Id. SMA not only affects infants and children, but adults as well. It is commonly classified into five types (SMA Types 0 through 4), which is based on the age of symptom onset.
  • nusinersen brand name Spinraza
  • nusinersen brand name Spinraza
  • This invention pertains to the prevention and treatment of disease including diseases associated with genetic-related degeneration affecting the central nervous system, peripheral nervous system, and skeletal muscle function.
  • Disease prevention and treatment is achieved through the administration of blood plasma fractions derived from blood plasma fractionation processes.
  • SMA spinal muscular atrophy
  • motor neurons These are the nerves that control voluntary (skeletal) muscle movement. As the disease progresses, the degeneration of the motor neurons makes it difficult for them to signal the muscles to contract, resulting in atrophy due to reduced activity. SMA patients often struggle with simple movements like standing or sitting up.
  • the invention provides such therapeutic interventions in the form of fractions of blood plasma obtained through the plasma fractionation process.
  • fractions have been described before (see U.S. Patent No. 11,439,687 which is incorporated by reference herein), and include by way of example and not limitation, plasma protein fractions (PPF), human albumin solution (HAS), Fraction IV- 1 (effluent and paste) and Fraction IV-4 (effluent and paste), which may be administered through various means to the subject.
  • Figure 1 shows a study design used to treat SMN A7 mice, a mouse model for spinal muscular atrophy (SMA). Mice were administered standard of care daily, risdiplam, for the entire study (58 days). From days 21 through 28, mice received intravenous PF1 or vehicle control.
  • SMA spinal muscular atrophy
  • Figure 2A shows that the weights of mouse gastrocnemius muscle from SMN A7 mice treated in the study from Figure 1 trended towards an increase with PF1 administration compared to vehicle control.
  • Figure 2B shows that the weights of mouse tibialis anterior muscle from SMN A7 mice treated in the study from Figure 1 trended towards an increase with PF1 administration compared to vehicle control.
  • Figure 3 shows that in mice treated with PF1 from the study in Figure 1 showed an increase in probability of survival compared to those treated with vehicle control.
  • FIG 4A shows that serum levels of TNFa in mice treated with PF1 from the study in Figure 1 showed a dramatic decrease in protein concentration compared to those treated with vehicle control.
  • TNFa is known to be a biomarker for SMA due to its elevated levels in SMA patients.
  • FIG 4B shows that serum levels of CCL2 in mice treated with PF1 from the study in Figure 1 showed a dramatic decrease in protein concentration compared to those treated with vehicle control.
  • CCL2 is known to be a biomarker for SMA due to its elevated levels in SMA patients.
  • FIG 5A shows that mRNA for a receptor (Fnl4) for the Tweak protein is upregulated in the gastrocnemius muscle of mice treated with PF1 as described in Figure 1, compared to vehicle control-treated mice.
  • the Tweak/Fnl4 signaling pathway has been shown to promote SMA survival and muscle function.
  • Figure 5B shows that mRNA for a receptor (Fnl4) for the Tweak trimeric cytokine is upregulated in the tibialis anterior muscle of mice treated with PF1 as described in Figure 1, compared to vehicle control-treated mice.
  • the Tweak/Fnl4 signaling pathway has been shown to promote SMA survival and muscle function.
  • Figure 6 reports that the SMA beneficial protein factor, Tweak, is present in PF1, and to a relatively lesser extent, in HAS1.
  • Figure 7 shows a study design used to treat SMN A7 mice, a mouse model for spinal muscular atrophy (SMA). Mice are administered standard of care daily, risdiplam for the entire study (84 days). From days 21 through 42 (20 days), mice receive intravenous PF1 or vehicle control. Wild type (WT) control mice are used as comparative healthy controls to SMN A7 mice for all readouts.
  • SMA spinal muscular atrophy
  • Nucleic acid sequences may be provided as DNA, as RNA, or a combination of DNA and RNA (e.g., a chimeric nucleic acid) and may contain non-natural nucleotides and/or bases. Unless otherwise stated, protein sequences described herein are given, when read from left to right, in the N-terminal to C-terminal direction. Protein sequences may contain non-natural amino acids and may contain chemical modifications at specified locations within the sequence and with various degrees of modification.
  • the term "about,” as applied to one or more values of interest, refers to a value that falls within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of a stated reference value, unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • a range includes each individual member.
  • a group having 1-3 articles refers to groups having 1, 2, or 3 articles.
  • a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.
  • the present invention relates to the treatment of disorders or diseases of muscle caused by genetic -related degeneration such as spinal muscular atrophy (SMA).
  • Plasma fractions including products of blood plasma fractionation of the invention have marked activity in improving symptoms of SMA. For example, muscle weights in animal models for SMA are increased with plasma fraction treatment. Additionally in these models, biomarkers for SMA are decreased by treatment with plasma fractions, and receptor gene expression for a ligand shown to rescue SMA muscle phenotype was up regulated upon treatment with plasma fractions. Notably, plasma fractions exhibit trends in increasing survival in SMA models.
  • plasma fractions have exhibited unexpected improvement in efficacy compared to unfractionated young plasma in certain analyses (see, e.g., U.S. Patent Application No. 15/499,694 and U.S. Patent Application No. 16/432,114; and which are both incorporated by reference herein in their entirety).
  • predicting efficacy from whole plasma serum to products of plasma fractionation is not subject to reasonable predictability.
  • the invention provides a method of treating a subject with a genetic- related degenerative disease such as SMA with blood plasma fractions
  • the invention also contemplates coadministration with current standard of care treatments.
  • plasma fractions may be co-administered with one or more of the SMN1 and 2 gene-based therapeutics such as one or more of onathioene abeparvovec, risdiplam, and nusinersen.
  • the terms “host”, “subject”, “individual” and “patient” are used interchangeably and refer to any mammal in need of such treatment according to the disclosed methods.
  • Such mammals include, e.g., humans, ovines, bovines, equines, porcines, canines, felines, non-human primate, mice, and rats.
  • the subject is a non-human mammal.
  • the subject is a farm animal.
  • the subject is a pet.
  • the subject is mammalian. In certain instances, the subject is human.
  • subjects can include domestic pets (e.g., dogs and cats), livestock (e.g., cows, pigs, goats, horses, and the like), rodents (e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease), as well as non-human primates (e.g., chimpanzees, and monkeys).
  • subjects of the invention include but are not limited to mammals, e.g., humans and other primates, such as chimpanzees and other apes and monkey species; and the like, where in certain embodiments the subject are humans.
  • the term subject is also meant to include a person or organism of any age, weight or other physical characteristic, where the subjects may be an adult, a child, an infant or a newborn.
  • a “young” or “young individual” it is meant an individual that is of chronological age of 40 years old or younger, e.g., 35 years old or younger, including 30 years old or younger, e.g., 25 years old or younger or 22 years old or younger.
  • the individual that serves as the source of the young plasma-comprising blood product is one that is 10 years old or younger, e.g., 5 years old or younger, including 1- year-old or younger.
  • the subject is a newborn and the source of the plasma product is the umbilical cord, where the plasma product is harvested from the umbilical cord of the newborn.
  • “young” and “young individual” may refer to a subject that is between the ages of 0 and 40, e.g., 0, 1, 5, 10, 15, 20, 25, 30, 35, or 40 year’s old.
  • “young” and “young individual” may refer to a biological (as opposed to chronological) age such as an individual who has not exhibited the levels of inflammatory cytokines in the plasma exhibited in comparatively older individuals.
  • these “young” and “young individual” may refer to a biological (as opposed to chronological) age such as an individual who exhibits greater levels of anti-inflammatory cytokines in the plasma compared to levels in comparatively older individuals.
  • the inflammatory cytokine is Eotaxin
  • the fold difference between a young subject or young individual and older individuals is at least 1.5-fold.
  • the fold difference between older and younger individuals in other inflammatory cytokines may be used to refer to a biological age. See U.S. Pat. Application No. 13/575,437 which is herein incorporated by reference).
  • the individual is healthy, e.g., the individual has no hematological malignancy or autoimmune disease at the time of harvest.
  • treatment refers to any of (i) the prevention of the disease or disorder, or
  • Treatment may be effected prophylactically (prior to the onset of disease) or therapeutically (following the onset of the disease).
  • 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 effect attributable to the disease.
  • treatment covers any treatment of a condition associated with genetic-related degenerative disease (such as, by way of example and not limitation, spinal muscular atrophy (SMA)), cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination- associated disease in a mammal, and includes: (a) preventing the condition from occurring in a subject; (b) inhibiting the condition, i.e., arresting its occurrence; or (c) relieving the condition, i.e., causing regression of the condition.
  • SMA spinal muscular atrophy
  • Treatment may result in a variety of different physical manifestations, e.g., modulation in gene expression, rejuvenation of tissue or organs, decreasing inflammation, etc.
  • the therapeutic agent may be administered before, during or after the onset of the condition.
  • the subject therapy may be administered during the symptomatic stage of the condition, and in some cases after the symptomatic stage of the condition.
  • a blood product comprising plasma components is administered to an individual in need thereof, e.g., an individual suffering from one or more of the following conditions: genetic -related degenerative disease (such as, by way of example and not limitation, spinal muscular atrophy (SMA)), cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease.
  • genetic -related degenerative disease such as, by way of example and not limitation, spinal muscular atrophy (SMA)
  • cognitive disorders such as, by way of example and not limitation, spinal muscular atrophy (SMA)
  • cognitive disorders motor disorders, inflammation and neuroinflammation
  • cardiovascular disease e.g., cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease.
  • methods according to embodiments of the invention include administering a blood product comprising plasma components from an individual (the "donor individual”, or “donor”) to an individual suffering from one or more of the following conditions: genetic-related degenerative disease (such as, by way of example and not limitation, spinal muscular atrophy (SMA)), cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease (the "recipient individual” or “recipient”).
  • a blood product comprising plasma components it is meant any product derived from blood that comprises plasma (e.g.
  • plasma is used in its conventional sense to refer to the straw- colored/pale- yellow liquid component of blood composed of about 92% water, 7% proteins such as albumin, gamma globulin, anti-hemophilic factor, and other clotting factors, and 1 % mineral salts, sugars, fats, hormones and vitamins.
  • Non-limiting examples of plasma-comprising blood products suitable for use in the subject methods include whole blood treated with anti-coagulant (e.g., EDTA, citrate, oxalate, heparin, etc.), blood products produced by filtering whole blood to remove white blood cells ("leukoreduction"), blood products consisting of plasmapheretically-derived or a pheretically-derived plasma, fresh-frozen plasma, blood products consisting essentially of purified plasma, and blood products consisting essentially of plasma fractions.
  • anti-coagulant e.g., EDTA, citrate, oxalate, heparin, etc.
  • blood products produced by filtering whole blood to remove white blood cells (“leukoreduction")
  • blood products consisting of plasmapheretically-derived or a pheretically-derived plasma fresh-frozen plasma
  • blood products consisting essentially of purified plasma and blood products consisting essentially of plasma fractions.
  • plasma product that is employed is a non-whole blood plasma product, by which is meant that the product is not whole blood, such that it lacks one or more components found in whole blood, such as erythrocytes, leukocytes, etc., at least to the extent that these components are present in whole blood.
  • the plasma product is substantially, if not completely, acellular, where in such instances the cellular content may be 5% by volume or less, such as 1 % or less, including 0.5% or less, where in some instances acellular plasma fractions are those compositions that completely lack cells, i.e., they include no cells.
  • Collection of blood products comprising plasma components Embodiments of the methods described herein include administration of blood products comprising plasma components which can be derived from donors, including human volunteers.
  • the term, “human- derived” can refer to such products.
  • Methods of collection of plasma comprising blood products from donors are well-known in the art. (See, e.g., AABB TECHNICAL MANUAL, (Mark A. Fung, et al., eds., 18th ed. 2014), herein incorporated by reference).
  • donations are obtained by venipuncture.
  • the venipuncture is only a single venipuncture.
  • no saline volume replacement is employed.
  • the process of plasmapheresis is used to obtain the plasma comprising blood products.
  • Plasmapheresis can comprise the removal of a weight- adjusted volume of plasma with the return of cellular components to the donor.
  • sodium citrate is used during plasmapheresis in order to prevent cell clotting.
  • the volume of plasma collected from a donor is preferably between 690 to 880 mL after citrate administration, and preferably coordinates with the donor’s weight.
  • An embodiment of the methods described herein includes the administration of plasma fractions to a subject. Fractionation is the process by which certain protein subsets are separated from plasma. Fractionation technology is known in the ail and relies on steps developed by Cohn et al. during the 1940s. (E. Cohn, Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. 68 J Am Chem Soc 459 (1946), herein incorporated by reference). Several steps are involved in this process, each step involving specific ethanol concentrations as well as pH, temperature, and osmolality shifts which result in selective protein precipitation. Precipitates are also separated via centrifugation or precipitation.
  • each fraction, filtrate (or effluent or waste streams from a prior separation step) contains or potentially contains therapeutically useful protein fractions.
  • Blood plasma fractionation can also be ammonium sulfate based.
  • ammonium sulfate-based fractionation has been employed to reduce abundant proteins from plasma. (Saha S, et al., J. Proteomics Bioinform, 5(8) (2012), herein incorporated by reference).
  • blood plasma is fractionated in an industrial setting. Frozen plasma is thawed at 1°C to 4°C. Continuous refrigerated centrifugation is applied to the thawed plasma and cryoprecipitate isolated. Recovered cryoprecipitate is frozen at -30°C or lower and stored. The cryoprecipitate-poor (“cryo-poor”) plasma is immediately processed for capture (via, for example, primary chromatography) of labile coagulation factors such as factor IX complex and its components as well as protease inhibitors such as antithrombin and Cl esterase inhibitor. Serial centrifugation and precipitate isolation can be applied in subsequent steps.
  • the plasma fraction may comprise a plasma fraction containing a substantial concentration of albumin.
  • the plasma fraction may comprise a plasma fraction containing a substantial concentration of IgG or intravenous immune globulin (IGIV) (e.g. Gamunex-C®).
  • IGIV intravenous immune globulin
  • the plasma fraction may comprise an IGIV plasma fraction, such as Gamunex-C® which has been substantially depleted of immune globulin (IgG) by methods well-known by one of ordinary skill in the art, such as for example, Protein A-mediated depletion.
  • IgG immune globulin
  • the blood plasma fraction may be one in which substantially all the clotting factors are removed in order to retain the efficacy of the fraction with reduced risk of thromboses.
  • the plasma fraction may be a plasma fraction as described in United States Patent App. No. 62/376,529 filed on August 18, 2016; the disclosure of which is incorporated by reference in its entirety herein.
  • PPF Plasma protein fraction
  • HAS human albumin solution
  • PPF is derived from a process with a higher yield than HAS but has a lower minimum albumin purity than HAS (>83% for PPF and > 95% for HAS).
  • human albumin solution a continually developing colloid, P. Matejtschuk et al., British J. of Anaesthesia 85(6): 887-95, at 888 (2000)).
  • PPF has albumin purity of between 83% and 95% or alternatively 83% and 96%.
  • the albumin purity can be determined by electrophoresis or other quantifying assays such as, for example, by mass spectrometry.
  • PPF has a disadvantage because of the presence of protein “contaminants” such as PKA. Id.
  • PPF preparations have lost popularity as Albumin Plasma Products, and have even been delisted from certain countries’ Pharmacopoeias. Id. Contrary to these concerns, the invention makes beneficial use of these “contaminants.”
  • the methods of the invention utilize additional proteins or other factors within the “contaminants” that promote processes such as, by way of example and not limitation, muscle regeneration, muscle cell survival, improved motor function and muscle strength, and decreased inflammation.
  • HAS Preparations include AlbuminarTM (CSL Behring), AlbuRxTM (CSL Behring), AlbuteinTM (Grifols, Clayton, NC), BuminateTM (Baxatla, Inc., Bannockburn, IL), FlexbuminTM (Baxatla, Inc., Bannockburn, IL), and PlasbuminTM (Grifols, Clayton, NC).
  • AlbuminarTM CSL Behring
  • AlbuRxTM CSL Behring
  • AlbuteinTM Grifols, Clayton, NC
  • BuminateTM Baxatla, Inc., Bannockburn, IL
  • FlexbuminTM Baxatla, Inc., Bannockburn, IL
  • PlasbuminTM Grifols, Clayton, NC.
  • PPF Protein Fraction (Human), is the proper name of the product defined as “a sterile solution of protein composed of albumin and globulin, derived from human plasma.”
  • CFR Code of Federal Regulations “CFR” 21 CFR 640.90 which is herein incorporated by reference.
  • PPF source material is plasma recovered from Whole Blood prepared as prescribed in 21 CFR 640.1 - 640.5 (incorporated by reference herein), or Source Plasma prepared as prescribed in 21 CFR 640.60 - 640.76 (incorporated by reference herein).
  • the final product shall be a 5.0 +/- 0.30 percent solution of protein
  • the total protein in the final product shall consist of at least 83 percent albumin, and no more than 17 percent globulins. No more than 1 percent of the total protein shall be gamma globulin.
  • the protein composition is determined by a method that has been approved for each manufacturer by the Director, Center for Biologies Evaluation and Research, Food and Drug Administration.
  • PPF Protein Fraction
  • Hink, J.H., Jr., et al., Preparation and Properties of a Heat-Treated Human Plasma Protein Fraction, VOX SANGUINIS 2(174) (1957) can also refer to a solid form, which when suspended in solvent, has similar composition.
  • the total globulin fraction can be determined through subtracting the albumin from the total protein. (Busher, J., Serum Albumin and Globulin, CLINICAL METHODS: THE HISTORY, PHYSICAL, AND LABORATORY EXAMINATIONS, Chapter 0, Walker HK, Hall WD, Hurst JD, eds. (1990)).
  • albumin (Human) also referred to herein as “HAS” is the proper name of the product defined as “sterile solution of the albumin derived from human plasma.”
  • CFR Code of Federal Regulations “CFR” 21 CFR 640.80 which is herein incorporated by reference.
  • the source material for Albumin (Human) is plasma recovered from Whole Blood prepared as prescribed in 21 CFR 640.1-640.5 (incorporated by reference herein), or Source Plasma prepared as prescribed in 21 CFR 640.60-640.76 (incorporated by reference herein).
  • Other requirements for Albumin (Human) are listed in 21 CFR 640.80 - 640.84 (incorporated by reference herein).
  • albumin Human
  • HAS refers to a to a sterile solution of protein composed of albumin and globulin, derived from human plasma, with an albumin content of at least 95%, with no more than 5% globulins (including al, a2, p, and y globulins) and other plasma proteins.
  • HAS can also refer to a solid form, which when suspended in solvent, has similar composition. The total globulin fraction can be determined through subtracting the albumin from the total protein.
  • PPF and HAS fractions can also be freeze-dried or in other solid form.
  • Such preparations can be used to make tablets, powders, granules, or capsules, for example.
  • the solid form can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or non-aqueous 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 blood product can be derived from a young donor or pool of young donors and can be rendered devoid of IgM in order to provide a young blood product that is ABO compatible.
  • IgM appears to be responsible for transfusion reactions when patients are given plasma that is not ABO matched. Removal of IgM from blood products or fractions helps eliminate transfusion reactions in subjects who are administered the blood products and blood plasma fractions of the invention.
  • the invention is directed to a method of treating a subject suffering from an unwanted condition associated with any of the following: cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease.
  • the method comprises: administering to the subject a blood product or blood fraction derived from whole blood from an individual or pool of individuals, wherein the blood product or blood fraction is substantially devoid of (a) at least one clotting factor and/or (b) IgM.
  • the individual(s) from whom the blood product or blood fraction is derived are young individuals.
  • the blood product is substantially devoid of at least one clotting factor and IgM. In certain embodiments, the blood product is substantially devoid of fibrinogen (Factor I). In additional embodiments, the blood product substantially lacks erythrocytes and/or leukocytes. In further embodiments, the blood product is substantially acellular. In other embodiments, the blood product is derived from plasma. Such embodiments of the invention are further supported by U.S. Patent No. 10,525,107 which is incorporated by reference in its entirety herein.
  • Additional embodiments of the invention use plasma fractions with reduced albumin concentration compared to PPF, but with increased amounts of globulins and other plasma proteins (what have been referred to by some as “contaminants”).
  • the embodiments as with PPF, HAS, Fraction I (effluent and paste), Fraction II/III (effluent and paste), Fraction IV- 1 (effluent and paste), Fraction IV-4 (effluent and paste), and Fraction V (effluent and paste) are all effectively devoid of clotting factors.
  • protein-enriched plasma protein products Such plasma fractions are hereinafter referred to as “protein-enriched plasma protein products.”
  • an embodiment of the invention may use a protein-enriched plasma protein product comprised of 82% albumin and 18% a, p, and y globulins and/or other plasma proteins.
  • Another embodiment of the invention may use a protein-enriched plasma protein product comprised of 81% albumin and 19% of a, P, and y globulins and/or other plasma proteins.
  • Another embodiment of the invention may use a protein-enriched plasma protein product comprised of 80% albumin and 20% of a, P, and y globulins and/or other plasma proteins.
  • Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 70-79% albumin and a corresponding 21- 30% of a, P, and y globulins and/or other plasma proteins. Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 60-69% albumin and a corresponding 31-40% of a, p, and y globulins and/or other plasma proteins. Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 50-59% albumin and a corresponding 41-50% of a, , and y globulins and/or other plasma proteins.
  • Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 40- 49% albumin and a corresponding 51-60% of a, P, and y globulins and/or other plasma proteins. Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 30-39% albumin and a corresponding 61-70% of a, P, and y globulins and/or other plasma proteins. Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 20-29% albumin and a corresponding 71-80% of a, P, and y globulins and/or other plasma proteins.
  • Additional embodiments of the invention may use protein- enriched plasma protein products comprised of 10-19% albumin and a corresponding 81-90% of a, P, and y globulins and/or other plasma proteins. Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 1-9% albumin and a corresponding 91- 99% of a, p, and y globulins and/or other plasma proteins. A further embodiment of the invention may use protein-enriched plasma protein products comprised of 0% albumin and 100% of a, P, and y globulins and/or other plasma proteins.
  • Embodiments of the invention described above may also have total gamma globulin concentrations of 1-5%.
  • the specific concentrations of proteins in a plasma fraction may be determined using techniques well-known to a person having ordinary skill in the relevant art.
  • such techniques include electrophoresis, mass spectrometry, ELISA analysis, and Western blot analysis.
  • An embodiment of the invention allows for blood used in the preparation of human plasma protein fraction to be collected in flasks with citrate or anticoagulant citrate dextrose solution (or other anticoagulant) for inhibition of coagulation, with further separation of Fractions I, II + III, IV, and PPF as per the method disclosed in Hink et al. (See Hink, J.H., Jr., et al., Preparation and Properties of a Heat- Treated Human Plasma Protein Fraction, VOX SANGUINIS 2(174) (1957), herein incorporated by reference.)
  • the mixture can be collected to 2 - 8 °C.
  • the plasma can then subsequently be separated by centrifugation at 7°C, removed, and stored at -20°C.
  • the plasma can then be thawed at 37°C and fractionated, preferably within eight hours after removal from -20°C storage.
  • Plasma can be separated from Fraction I using 8% ethanol at pH 7.2 and a temperature at
  • Fraction I can be separated and removed from the effluent (Effluent I) through ultracentrifugation. Fibrinogen can be obtained from Fraction I as per methods well-known to those having ordinary skill in the art.
  • Fraction II + III can be separated from Effluent I through adjustment of the effluent to 21 percent ethanol at pH 6.8, temperature at -6°C, with protein concentration of 4.3 percent.
  • Cold 95 percent ethanol (176 mL/L of Effluent I) with 10 M acetic acid used for pH adjustment can be added using jets at a rate, for example, of 500 mL/minute during the lowering of the temperature of Effluent I to -6°C.
  • the resulting precipitate (Fraction II + III) can be removed by centrifugation at -6°C.
  • Gamma globulin can be obtained from Fraction II + III using methods well-known to those having ordinary skill in the art.
  • Fraction IV- 1 can be separated from Effluent II + III (“Effluent II/III”) through adjustment of the effluent to 19 percent ethanol at pH 5.2, temperature at -6°C, and protein concentration of 3 percent. H2O and 10 M acetic acid used for pH adjustment can be added using jets while maintaining Effluent II/III at -6°C for 6 hours. Precipitated Fraction IV- 1 can be settled at -6°C for 6 hours and subsequently separated from the effluent by centrifugation at the same temperature. Stable plasma protein fraction can be recovered from Effluent IV- 1 through adjustment of the ethanol concentration to 30 percent at pH 4.65, temperature -7°C and protein concentration of 2.5 percent. This can be accomplished by adjusting the pH of Effluent IV- 1 with cold acid-alcohol (two parts 2 M acetic acid and one-part 95 percent ethanol). While maintaining a temperature of
  • the recovered proteins can be dried (e.g. by freeze drying) to remove alcohol and H2O.
  • the resulting dried powder can be dissolved in sterile distilled water, for example using 15 liters of water/kg of powder, with the solution adjusted to pH 7.0 with 1 M NaOH.
  • a final concentration of 5 per cent protein can be achieved by adding sterile distilled water containing sodium acetyl tryptophanate, sodium caprylate, and NaCl, adjusting to final concentrations of 0.004 M acetyl tryptophanate, 0.004 M caprylate, and 0.112 M sodium.
  • the solution can be filtered at 10°C to obtain a clear solution and subsequently heat-treated for inactivation of pathogens at 60°C for at least 10 hours.
  • each of the different fractions and effluents described above could be used with the methods of the invention to treat conditions such as cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease.
  • Effluents I or Effluent II/III may be utilized to treat conditions such as cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease, and are embodiments of the invention.
  • plasma fractions and plasma protein fraction are only exemplary and involve merely embodiments of the invention.
  • pH, temperature, and ethanol concentration among other things can be adjusted to produce different variations of plasma fractions and plasma protein fraction in the different embodiments and methods of the invention.
  • additional embodiments of the invention contemplate the use of nanofiltration for the removal/inactivation of pathogens from plasma fractions and plasma protein fraction.
  • An additional embodiment of the invention contemplates methods and composition using and/or comprising additional plasma fractions.
  • the invention contemplates that specific concentrations of albumin are not critical for treating conditions associated with cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease.
  • fractions with reduced albumin concentration such as those fractions having below 83% albumin, are contemplated by the invention.
  • aspects of the methods of the inventions described herein include treatment of a subject with a plasma comprising blood product, such as a blood plasma fraction, e.g., as described above.
  • An embodiment includes treatment of a human subject with a plasma comprising blood product.
  • One of skill in the art would recognize that methods of treatment of subjects with plasma comprising blood products are recognized in the art.
  • one embodiment of the methods of the inventions described herein is comprised of administering fresh frozen plasma to a subject for treatment of conditions such as cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination- associated disease.
  • conditions such as cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination- associated disease.
  • the plasma comprising blood product is administered immediately, e.g., within about 12-48 hours of collection from a donor, to the individual suffering from a condition associated with cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination- associated disease.
  • the product may be stored under refrigeration, e.g., 0-10°C.
  • fresh frozen plasma is one that has been stored frozen (cryopreserved) at
  • the fresh frozen plasma Prior to administration, the fresh frozen plasma is thawed and once thawed, administered to a subject 60-75 minutes after the thawing process has begun.
  • Each subject preferably receives a single unit of fresh frozen plasma (200-250 mL), the fresh frozen plasma preferably derived from donors of a pre-determined age range.
  • the fresh frozen plasma is donated by (derived from) young individuals.
  • the fresh frozen plasma is donated by (derived from) donors of the same gender.
  • the fresh frozen plasma is donated by (derived from) donors of the age range between 18-22 years old.
  • the plasma comprising blood products are screened after donation by blood type.
  • the plasma comprising blood products are screened for infectious disease agents such as HIV I & II, HBV, HCV, HTLV I & II, anti-HBc per the requirements of 21 CFR 640.33 and recommendations contained in FDA guidance documents.
  • the subject is treated with a Plasma Fraction.
  • the plasma fraction is a PPF, HAS, Fraction IV-1 (including effluent or paste), Fraction IV-4 (including effluent or paste).
  • the plasma fraction is one of the Commercial PPF Preparations of the Commercial HAS Preparations.
  • the plasma fraction is a PPF, HAS, Fraction IV-1 or Fraction IV-4 derived from a pool of individuals of a specific age range, such as young individuals, or is a modified PPF, HAS, Fraction IV-1 or Fraction IV-4 fraction which has been subjected to additional fractionation or processing (e.g.
  • the plasma fraction is an IGIV plasma fraction which has been substantially depleted of immune globulin (IgG).
  • IgG immune globulin
  • Additional embodiments encompass where the subject is treated with subtractions of plasma fractions such as those described previously in U.S. Patent Application No. 63/470,325, including by way of example and not limitation, subtraction 1 , subtraction 2, subtraction 3, subtraction 4, subtraction 5, subtraction 6, subtraction 7, subtraction 8, subtraction 9, subtraction 10, subtraction 11 .subtraction 12, and subtraction 13 described in U.S. Patent Application No. 63/470,325 , which is herein incorporated by reference in its entirety.
  • aspects of the methods of the inventions described herein include treatment of a subject with a plasma comprising blood product, such as a blood plasma or Plasma Fraction, e.g., as described above.
  • a plasma comprising blood product such as a blood plasma or Plasma Fraction, e.g., as described above.
  • An embodiment includes treatment of a human subject with a plasma comprising blood product.
  • One of skill in the ait would recognize that methods of treatment of subjects with plasma comprising blood products are recognized in the art.
  • one embodiment of the methods of the inventions described herein is comprised of administering fresh frozen plasma to a subject for treatment of conditions such as genetic-related degenerative disease including spinal muscular atrophy (SMA), cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease.
  • SMA spinal muscular atrophy
  • cognitive disorders including motor disorders, inflammation and neuroinflammation
  • cardiovascular disease cancer
  • impaired mobility muscle recovery dysfunction
  • loss of muscle stem cell differentiation capacity muscle injury
  • peripheral nerve injury chronic nerve injury
  • impaired nerve injury recovery due to aging and demyelination-associated disease is a subject for treatment of conditions such as genetic-related degenerative disease including spinal muscular atrophy (SMA), cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury
  • the plasma comprising blood product is administered immediately, e.g., within about 12-48 hours of collection from a donor, to the individual suffering from an unwanted condition such as cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination- associated disease.
  • the product may be stored under refrigeration, e.g., 0-10°C.
  • fresh frozen plasma is one that has been stored frozen (cryopreserved) at
  • the fresh frozen plasma Prior to administration, the fresh frozen plasma is thawed and once thawed, administered to a subject 60-75 minutes after the thawing process has begun.
  • Each subject preferably receives a single unit of fresh frozen plasma (200-250 mL), the fresh frozen plasma preferably derived from donors of a pre-determined age range.
  • the fresh frozen plasma is donated by (derived from) young individuals.
  • the fresh frozen plasma is donated by (derived from) donors of the same gender.
  • the fresh frozen plasma is donated by (derived from) donors of the age range between 18-22 years old.
  • the plasma comprising blood products are screened after donation by blood type.
  • the plasma comprising blood products are screened for infectious disease agents such as HIV I & II, HBV, HCV, HTLV I & II, anti-HBc per the requirements of 21 CFR 640.33 and recommendations contained in FDA guidance documents.
  • the subject is treated with a Plasma Fraction.
  • the plasma fraction is PPF or HAS.
  • the plasma fraction is one of the Commercial PPF Preparations or the Commercial HAS Preparations.
  • the plasma fraction is a PPF or HAS derived from a pool of individuals of a specific age range, such as young individuals, or is a modified PPF or HAS fraction which has been subjected to additional fractionation or processing (e.g. PPF or HAS with one or more specific proteins partially or substantially removed).
  • the plasma fraction is an IGIV plasma fraction which has been substantially depleted of immune globulin (IgG).
  • a blood fraction which is “substantially depleted” or which has specific proteins “substantially removed,” such as IgG, refers to a blood fraction containing less than about 50% of the amount that occurs in the reference product or whole blood plasma, such as less than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 5%, 4%, 3%, 2%, 1%, 0.5%, .25%, .1%, undetectable levels, or any integer between these values, as measured using standard assays well known in the ail.
  • the plasma fraction is Fraction IV-1 (including effluent or paste), Fraction IV-4 (including effluent or paste) or plasma subfractions such as those described previously in U.S. Patent Application No. 63/470,325, which is herein incorporated by reference in its entirety.
  • An embodiment of the invention includes treating a subject suffering from a condition such as such as genetic-related degenerative disease including spinal muscular atrophy (SMA), cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease by administering to the subject an effective amount of blood plasma or Plasma Fraction.
  • Another embodiment of the invention includes administering the effective amount of blood plasma or Plasma Fraction and subsequently monitoring the subject for improved function, wound healing, the presence of markers, decreased pain, or decreased inflammation.
  • Another embodiment of the invention includes treating a subject suffering from a condition associated such as such as genetic -related degenerative disease including spinal muscular atrophy (SMA), cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease by administering to the subject an effective amount of blood plasma or Plasma Fraction wherein the blood plasma or Plasma Fraction is administered in a manner resulting in improved function wound healing, muscle functioning and/or strengthening, the presence of markers, decreased pain, or decreased inflammation after the mean or median half-life of the blood plasma proteins or Plasma Fraction proteins been reached, relative to the most recent administered dose (referred to as “Pulsed Dosing” or “Pulse Dosed” herein) (See U.S.
  • SMA spinal muscular atrophy
  • cognitive disorders including motor disorders, inflammation and neuroinflammation
  • cardiovascular disease cancer
  • impaired mobility muscle recovery dysfunction
  • Another embodiment of the invention includes administering the blood plasma or Plasma Fraction via a dosing regimen of at least two consecutive days and monitoring the subject for improved function or HSC marker levels at least 3 days after the date of last administration.
  • a further embodiment of the invention includes administering the blood plasma or Plasma Fraction via a dosing regimen of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days and monitoring the subject for improved function, wound healing, the presence of markers, decreased pain, or decreased inflammation at least 3 days after the date of last administration.
  • Yet another embodiment of the invention includes administering the blood plasma or Plasma Fraction via a dosing regimen of at least 2 consecutive days and after the date of last administration, monitoring for functional improvement, wound healing, the presence of markers, decreased pain, or decreased inflammation beyond when the average half-life of the proteins in the blood plasma or Plasma Fraction has been reached.
  • Another embodiment of the invention includes administering the blood plasma or Plasma Fraction via a dosing regimen of 2 to 14 non- consecutive days wherein each gap between doses may be between 0-3 days each.
  • Pulsed Dosing in accordance with the invention includes administration of a first set of doses, e.g., as described above, followed by a period of no dosing, e.g., a "dosing- free period", which in turn is followed by administration of another dose or set of doses.
  • the duration of this "dosing-free" period may vary, but in some embodiments, is 7 days or longer, such as 10 days or longer, including 14 days or longer, wherein some instances the dosing-free period ranges from 15 to 365 days, such as 30 to 90 days and including 30 to 60 days.
  • embodiments of the methods include nonchronic (i.c., non-continuous) dosing, e.g., non-chronic administration of a blood plasma product.
  • the pattern of Pulsed Dosing followed by a dosing-free period is repeated for a number of times, as desired, where in some instances this pattern is continued for 1 year or longer, such as 2 years or longer, up to and including the life of the subject.
  • Another embodiment of the invention includes administering the blood plasma or Plasma Fraction via a dosing regimen of 5 consecutive days, with a dosing-free period of 2-3 days, followed by administration for 2-14 consecutive days.
  • the subject suffering from the disease or disorder as described supra is treated using a therapeutic plasma exchange method to administer the plasma fraction.
  • a therapeutic plasma exchange method to administer the plasma fraction.
  • Such methods have been described before for HAS and may be applied similarly to other plasma fractions (see, e.g., U.S. Patent No. 7,851,446; U.S. Patent Publication Nos. US20220047680; US20180280603; US20240115665; and PCT Patent Publication No. WO2022229705A1).
  • an “effective amount” or “effective dose” of active agent is meant an amount of active agent that will inhibit, antagonize, decrease, reduce, or suppress by about 20% or more, e.g., by 30% or more, by 40% or more, or by 50% or more, in some instances by 60% or more, by 70% or more, by 80% or more, or by 90% or more, in some cases by about 100%, i.e., to negligible amounts, and in some instances, reverse unwanted conditions such as such as symptoms of genetic-related degenerative disease including spinal muscular atrophy (SMA), cognitive disorders, motor disorders, inflammation and neuroinflammation, cardiovascular disease, cancer, impaired mobility, muscle recovery dysfunction, loss of muscle stem cell differentiation capacity, muscle injury, peripheral nerve injury, chronic nerve injury, impaired nerve injury recovery due to aging and demyelination-associated disease.
  • SMA spinal muscular atrophy
  • an “effective amount” or “effective dose” of an active agent can be determined by the amount of active agent that will produce positive readouts of, for example, growth of tissue, strengthening of tissue such as muscle, increased nerve conductance, improved performance by the treated subject in tests that measure or diagnose the degree of a disorder or disease, or an increase in one or more biomarkers that indicate reversal of negative symptoms of a disease/disorder indication,
  • a plasma fraction is administered to the subject.
  • the plasma fraction is plasma protein fraction (PPF).
  • PPF plasma protein fraction
  • the PPF is selected from the Commercial PPF Preparations.
  • the PPF is comprised of 88% normal human albumin, 12% alpha and beta globulins and not more than 1% gamma globulin as determined by electrophoresis.
  • Further embodiments of this embodiment used in practicing methods of the invention include, for example, the embodiment as a 5% solution of PPF buffered with sodium carbonate and stabilized with 0.004 M sodium caprylate and 0.004 M acetyltryptophan. Additional formulations, including those modifying the percentage of PPF (e.g. about 1% to about 10%, about 10% to about 20%, about 20% to 25%, about 25% to 30%) in solution as well as the concentrations of solvent and stabilizers may be utilized in practicing methods of the invention.
  • Additional embodiments of the invention include administering a plasma protein fraction derived from the plasma of individuals of certain age ranges.
  • An embodiment includes administering PPF or HAS which have been derived from the plasma of young individuals.
  • the young individuals are of a single specific age or a specific age range.
  • the average age of the donors is less than that of the subject or less than the average age of the subjects being treated.
  • Certain embodiments of the invention include pooling blood or blood plasma from individuals of specific age ranges and fractionating the blood plasma as described above to attain a plasma protein fraction product such as PPF or HAS.
  • a plasma protein fraction product such as PPF or HAS.
  • the plasma protein fraction or specific plasma protein fraction is attained from specific individuals fitting a specified age range.
  • An embodiment of the invention is using plasma fractions and products of blood plasma fractionation to administer to a subject diagnosed with a disease or disorder such as genetic -related degeneration that could benefit from improved muscle regeneration.
  • a further embodiment of the invention includes when said disease or disorder is spinal muscular atrophy (SMA).
  • SMA spinal muscular atrophy
  • Common symptoms of SMA include muscle weakness and decreased muscle tone, limited mobility, breathing difficulties, difficulties in eating and swallowing, delayed gross motor skills, spontaneous tongue movements, scoliosis (curvature of the spine), floppy arms and legs, difficulties sitting up, crawling, or walking, twitching or shaking muscles (tremors), bone and joint problems.
  • An embodiment of the invention includes administering a plasma fraction to the subject diagnosed with SMA and monitoring said subject for improvement in symptoms of SMA.
  • Type 0 is very rare and severe. Symptoms start prior to birth and present as decreased fetal movement prior to delivery. The infant has severe weakness with difficulty breathing and eating and commonly had joint contractures and problems with its heart.
  • SMA Type 1 commonly referred to as Werdnig-Hoffmann disease, is the predominant form of spinal muscular atrophy, accounting for 60% of cases. It is identified as the most severe variant and is typically diagnosed within the first six months of an infant's life. Infants affected by SMA Type 1 encounter numerous physical difficulties such as muscle weakness and problems with breathing, coughing, and swallowing. Traditionally, they have required support with breathing and feeding tubes. Without treatment, this condition can lead to early mortality.
  • SMA Type 2 is typically identified between six months and two years of age. The initial indication of this condition is frequently either a delay in achieving motor milestones or a complete inability to meet them. Those with SMA Type 2 usually have the ability to sit independently, although they often need help to get into a sitting position. Traditionally, individuals with this type of SMA are unable to walk and depend on a wheelchair for mobility.
  • SMA Type 3 also known as Kugelberg-Welander disease or juvenile SMA, is commonly diagnosed between 18 months and three years of age, though it can sometimes be identified as late as the teenage years. Those with SMA Type 3 typically have the ability to walk initially. Over time, their mobility tends to decrease progressively, and many eventually require the use of a wheelchair as they grow older.
  • SMA Type 4 is exceptionally uncommon, accounting for less than 1% of all cases. It typically manifests in adulthood and results in mild motor impairment. Symptoms can start as early as 18 years old, but they more frequently commence after the age of 35.
  • SMA spinal muscular atrophy with lower extremity predominant and dominant inheritance
  • SBMA spinal and bulbar muscular atrophy
  • Kennedy Kennedy’s Disease
  • reagents, devices, and kits thereof for practicing one or more of the above-described methods.
  • the subject reagents, devices, and kits thereof may vary greatly.
  • Reagents and devices of interest include those mentioned above with respect to the methods of preparing plasma-comprising blood product for transfusion into a subject in need hereof, for example, anti-coagulants, cryopreservatives, buffers, isotonic solutions, etc.
  • Kits may also comprise blood collection bags, tubing, needles, centrifugation tubes, and the like.
  • kits as described herein include two or more containers of blood plasma product such as plasma protein fraction, such as three or more, four or more, five or more, including six or more containers of blood plasma product.
  • the number of distinct containers of blood plasma product in the kit may be 9 or more, 12 or more, 15 or more, 18 or more, 21 or more, 24 or more 30 or more, including 36 or more, e.g., 48 or more.
  • Each container may have associated therewith identifying information which includes various data about the blood plasma product contained therein, which identifying information may include one or more of the age of the donor of the blood plasma product, processing details regarding the blood plasma product, e.g., whether the plasma product was processed to remove proteins above an average molecule weight (such as described above), blood type details, etc.
  • each container in the kit includes identifying information about the blood plasma contained therein, and the identifying information includes information about the donor age of the blood plasma product, e.g., the identifying information provides confirming age- related data of the blood plasma product donor (where such identifying information may be the age of the donor at the time of harvest).
  • each container of the kit contains a blood plasma product from a donor of substantially the same age, i.e., all of the containers include product from donors that are substantially the same, if not the same, age.
  • substantially the same age is meant that the various donors from which the blood plasma products of the kits are obtained differ in each, in some instances, by 5 years or less, such as 4 years or less, e.g., 3 years or less, including 2 years or less, such as 1 year or less, e.g., 9 months or less, 6 months or less, 3 months or less, including 1 month or less.
  • the identifying information can be present on any convenient component of the container, such as a label, an RFID chip, etc.
  • the identifying information may be human readable, computer readable, etc., as desired.
  • the containers may have any convenient configuration. While the volume of the containers may vary, in some instances the volumes range from 10 ml to 5000 mL, such as 25 mL to 2500 mL, e.g., 50 ml to 1000 mL, including 100 mL to 500 mL.
  • the containers may be rigid or flexible, and may be fabricated from any convenient material, e.g., polymeric materials, including medical grade plastic materials. In some instances, the containers have a bag or pouch configuration.
  • such kits may further include administration devices, e.g., as described above.
  • the components of such kits may be provided in any suitable packaging, e.g., a box or analogous structure, configured to hold the containers and other kit components.
  • the subject kits will further include instructions for practicing the subject methods. These instructions may be present in the subject kits in a variety of forms, one or more of which may be present in the kit.
  • One form in which these instructions may be present is as printed information on a suitable medium or substrate, e.g., a piece or pieces of paper on which the information is printed, in the packaging of the kit, in a package insert, etc.
  • Yet another means would be a computer readable medium, e.g., diskette, CD, portable flash drive, etc., on which the information has been recorded.
  • Yet another means that may be present is a website address which may be used via the internet to access the information at a removed site. Any convenient means may be present in the kits.
  • Figure 1 shows a study design used to treat SMN A7 mice, which is a mouse model for spinal muscular atrophy (SMA).
  • SMA spinal muscular atrophy
  • SMN A7 mice were treated daily with risdiplam for the entirely of the study (i.e., 56 days).
  • Mice received 3 mg/kg of risdiplam interperitoneally (i.p.) from postnatal days (PND) 1 through 21. From PND 21 through 56, the mice were administered 9 mg/kg of risdiplam orally (p.o.).
  • mice received intravenous (i.v.) injections of either vehicle or PF1 for 7 consecutive days.
  • tissues were harvested for analysis.
  • Figure 2A shows a bar graph of the weights of the mouse gastrocnemius muscle in vehicle and PFl-treated groups. Weight was normalized as grams per millimeters of length of the limb (limb length or LL). In the PFl-treated group, there was a trend in improvement in muscle weight in the gastrocnemius muscle. Welch’s t-test was applied, and error bars show standard error of the mean (SEM).
  • Figure 2B shows a bar graph of the weights of the mouse tibialis anterior muscle in vehicle and PFl-treated groups. Weight was normalized as grams per millimeters of length of the limb (limb length or LL). In the PFl-treated group, there was a trend in improvement in muscle weight in the tibialis anterior muscle. Welch’s t-test was applied and error bars show standard error of the mean (SEM).
  • FIG 4A shows serum levels of TNFa in the SMN A7 mice treated with either vehicle or PF1 in this study.
  • TNFa is known to be elevated in the cerebrospinal fluid (CSF) and SMA patients.
  • CSF cerebrospinal fluid
  • SMA SMA biomarker
  • Detection of TNFa was via a Luminex bead-based multiplex assay.
  • An ordinary one-way ANOVA was applied to the data with *p ⁇ 0.05, **p ⁇ 0.005, **** ⁇ 0.0001. Error bars show standard error of the mean (SEM).
  • FIG 4B shows serum levels of CCL2 in the SMN A7 mice treated with either vehicle or PF1 in this study.
  • CCL2 is known to be elevated in the cerebrospinal fluid (CSF) and SMA patients.
  • CSF cerebrospinal fluid
  • SMA SMA biomarker
  • Detection of CCL2 was via a Luminex bead-based multiplex assay.
  • An ordinary one-way ANOVA was applied to the data with *p ⁇ 0.05, **p ⁇ 0.005, **** ⁇ 0.0001. Error bars show standard error of the mean (SEM).
  • FIG 5A shows that a receptor for Tweak, (Fnl4), is upregulated in the gastrocnemius muscle of SMN A7 mice treated with PF1 compared to vehicle control in the mouse gastrocnemius muscle.
  • Tweak is responsible for signaling to the Fnl4 receptor to activate Fnl4 expression which results in the promotion of muscle survival in SMN A7 mice (see Meijboom KE et al., Skeletal Muscle, 12(18) (2022)).
  • Upregulation of the Tweak/Fnl4 signaling pathway has also been shown to promote SMA survival and muscle functions.
  • Gene expression level of the Fnl4 receptor was quantified by qPCR and Welch’s T-test applied to the results. (*p ⁇ 0.05).
  • FIG. 5B shows that a receptor for Tweak, (Fnl4), is upregulated in the tibialis anterior muscle of SMN A7 mice treated with PF1 compared to vehicle control in the mouse gastrocnemius muscle.
  • Tweak is responsible for signaling to the Fnl4 receptor to activate Fnl4 expression which results in the promotion of muscle survival in SMN A7 mice (see Meijboom KE el al., Skeletal Muscle, 12(18) (2022)).
  • Upregulation of the Tweak/Fnl4 signaling pathway has also been shown to promote SMA survival and muscle functions.
  • Gene expression level of the Fnl4 receptor was quantified by qPCR and Welch’s T-test applied to the results. (*p ⁇ 0.05).
  • FIG. 6 reports that PF1 contains the SMA beneficial cytokine, Tweak, which improves the SMA phenotype. Protein levels were determined by affinity-based detection (SomaLogic, Boulder, CO) of Tweak in PF1 and HASE Tweak was detected in PF1 at a higher concentration than in HASE The dashed line shows the limit of detection.
  • FIG. 7 is a depiction of a 20 consecutive day study where either PF1 or vehicle control is administered to SMN A7 mice. The mice are treated daily with standard of care (risdiplam) from birth and throughout the study. On postnatal day (PND) 21, the mice are randomized into 2 groups receiving i.v. injections of either vehicle control or PF1 for 20 consecutive days. Sex- and age-matched wildtype mice are used as healthy control for all readouts. Automatic locomotor activities (Blackbox behavior, shown in red circles) and muscle torque measurements (yellow circle) are performed at indicated time points.
  • Muscle, liver, and serum is analyzed for muscle fiber cross-sectional area (CSA), gene expression, serum cytokine profiling, liver histology, and total liver triglyceride (TG) content. Additionally, spinal cords, dorsal root ganglia (DRG), and brains are collected to assess neuroinflammation with immunohistochemistry (1HC) and quantitative PCR (qPCR).
  • CSA muscle fiber cross-sectional area
  • cytokine profiling serum cytokine profiling
  • liver histology liver histology
  • TG total liver triglyceride
  • TG total liver triglyceride
  • spinal cords, dorsal root ganglia (DRG), and brains are collected to assess neuroinflammation with immunohistochemistry (1HC) and quantitative PCR (qPCR).

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Abstract

L'invention concerne des méthodes et des compositions pour le traitement et/ou la prévention d'une maladie. Les compositions utilisées dans les procédés comprennent des fractions de plasma sanguin issues de donneurs, ayant une efficacité dans le traitement et/ou la prévention de maladies comprenant une maladie dégénérative d'origine génétique affectant les muscles, comprenant l'amyotrophie spinale (SMA).
PCT/US2025/026412 2024-04-29 2025-04-25 Compositions de fractions de plasma sanguin et leur utilisation dans le traitement de l'amyotrophie spinale (sma) Pending WO2025230830A1 (fr)

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