Peptides for treating neurological disorders

Abstract

Disclosed herein are peptides, derivatives thereof, and salts thereof, as well as pharmaceutical compositions containing them, useful alone or in combination with other therapies for treating multifactorial neurological and other diseases. The pharmaceutical compositions may include the peptides, derivatives thereof, or salts thereof, where the peptides may include at least five consecutive amino acids having the general formula: EFGHI, or derivatives thereof, and the multifactorial neurological diseases may include Lewy body variant of Alzheimer's disease (LBVAD) or vascular dementia.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Application No. 63 / 443,497, filed February 6, 2023, and U.S. Provisional Application No. 63 / 603,774, filed November 29, 2023, the disclosures of which are hereby incorporated by reference in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ST.26 xml format, which is hereby incorporated by reference in its entirety. The xml copy, created on January 30, 2024, is named 199260-717601_SL.xml and is 30,001 bytes in size.

[0003] STATEMENT REGARDING GOVERNMENT-SPONSORED RESEARCH This invention was made with Government support under Contract Nos. 1R43AG074715 and 1R43AG071064 awarded by the Department of Health and Human Services. The Government has certain rights in this invention.

[0004] Incorporation by Reference All publications, patents, and patent applications herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event of a conflict between a term in this specification and a term in an incorporated reference, the term in this specification shall control. Summary of the Invention [Means for solving the problem]

[0005] Abstract Disclosed herein are methods of treating a multifactorial neurological disease in a subject in need thereof. In some embodiments, the method may include administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the multifactorial neurological disease. In some embodiments, the pharmaceutical composition may include a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five consecutive amino acids or derivatives thereof having the general formula: EFGHI, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these. In some embodiments, the multifactorial neurological disease may include Lewy Body variant of Alzheimer's Disease (LBVAD) or vascular dementia.In some embodiments, the peptide, derivative, or salt thereof may comprise at least 8 consecutive amino acids or derivatives thereof comprising the general formula ABCEFGHI, wherein A is D-Ala, or a derivative thereof; B is D-Ser or D-Thr, or a derivative of any of these; C is D-Ser or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these. In some embodiments, the peptide or salt thereof may be D-Thr, D-Thr, D-Asn, D-Tyr, or D-Thr, or a salt thereof. In some embodiments, the derivative of I may be esterified, glycosylated, or amidated at the C-terminus. In some embodiments, the multifactorial neurological disease may be vascular dementia. In some embodiments, the administering step is daily. In some embodiments, the multifactorial neurological disease may be LBVAD. In some embodiments, the vascular dementia may include subcortical vascular dementia or multi-infarct dementia. In some embodiments, the pharmaceutical composition may be in unit dose form. In some embodiments, the pharmaceutical composition may further comprise an excipient, a diluent, a carrier, or a combination thereof. In some embodiments, the pharmaceutical composition may further comprise an excipient. In some embodiments, the pharmaceutical composition may further comprise a carrier. In some embodiments, the administering step may be weekly or monthly. In some embodiments, the administering step may be once, twice, three times, or four times daily.In some embodiments, the pharmaceutical composition can be administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong. In some embodiments, the pharmaceutical composition can comprise the peptide, its derivative, or a salt thereof in an amount of about 0.005 mg to about 1000 mg. In some embodiments, the pharmaceutical composition can be administered by oral, injection, sublingual, buccal, rectal, vaginal, ocular, aural, nasal, intranasal, inhalation, dermal, subcutaneous, intramuscular, intravenous, systemic, topical, transdermal, or any combination thereof. In some embodiments, the pharmaceutical composition may be formulated for oral administration. In some embodiments, the pharmaceutical composition may be in pill or liquid form. In some embodiments, a second treatment may be administered concurrently or sequentially. In some embodiments, the second treatment may include carbidopa, levodopa, a cholinesterase inhibitor, an N-methyl D-aspartate antagonist, a catechol O-methyltransferase (COMT) inhibitor, an MAO-B inhibitor, aducanumab, lecanemab, remternetug, a hypertension medication, a high cholesterol medication, an anticoagulant medication, a diabetes medication, a salt of any of these, or any combination thereof. In some embodiments, the pharmaceutical composition may further include a second treatment. In some embodiments, the subject may be diagnosed with a multifactorial neurological disease prior to administration. In some embodiments, the diagnosis may include in vitro testing, a physical examination, an imaging diagnostic method, or a combination thereof. In some embodiments, the subject may be a mammal. In some embodiments, the mammal may be a human.

[0006] Also disclosed herein is a method for treating a disease in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the disease. In some embodiments, the pharmaceutical composition may comprise a peptide, a derivative thereof, or a salt thereof. In some embodiments, the peptide may comprise at least five consecutive amino acids or derivatives thereof comprising the general formula: EFGHI, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, D-Leu, or a derivative thereof; F is D-Ser, D-Thr, D-Asp, D-Asn, or a derivative thereof; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, D-Trp, or a derivative thereof; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, Gly, or a derivative thereof. In some embodiments, the disease may be selected from the group consisting of postural instability, gait disorders, balance problems, post-traumatic stress disorder (PTSD), urinary incontinence, and any combination thereof. In some embodiments, the peptide, derivative thereof, or salt thereof may comprise at least 8 consecutive amino acids comprising the general formula ABCEFGHI, or a derivative thereof. In some embodiments, A is D-Ala, or a derivative thereof; B is D-Ser or D-Thr, or a derivative of any of these; C is D-Ser or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these.In some embodiments, the peptide or its salt may be D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr, or a salt thereof. In some embodiments, the derivative of I may be esterified, glycosylated, or amidated at the C-terminus. In some embodiments, the disease may be postural instability. In some embodiments, the disease may be gait disorder. In some embodiments, the disease may be balance problems. In some embodiments, the disease may be PTSD. In some embodiments, the disease may be urinary incontinence. In some embodiments, the pharmaceutical composition may be in unit dose form. In some embodiments, the pharmaceutical composition may further comprise an excipient, a diluent, a carrier, or a combination thereof.

[0007] Also disclosed herein are methods for treating a disease in a subject in need thereof. In some embodiments, the method may include administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the disease. In some embodiments, the pharmaceutical composition comprises a peptide, a derivative thereof, or a salt thereof. In some embodiments, the peptide may include: i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2 (SEQ ID NO: 1) or a derivative thereof, wherein the first amino acid is a D stereoisomer, the remaining amino acids are L stereoisomers, and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 2) or a derivative thereof, wherein the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof. In some embodiments, the disease may be selected from the group consisting of postural instability, gait disturbances, balance problems, post-traumatic stress disorder (PTSD), urinary incontinence, Alzheimer's disease with Lewy bodies (LBVAD), Alzheimer's disease-related dementia (ADRD), vascular dementia, and any combination thereof.

[0008] Also disclosed herein is a method for treating mild cognitive impairment or mild dementia in a subject in need thereof. In some embodiments, the method may include administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat mild cognitive impairment or mild dementia. In some embodiments, the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five consecutive amino acids or derivatives thereof comprising the general formula: EFGHI, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and II) lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these. In some embodiments, the peptide, derivative, or salt thereof may comprise at least 8 consecutive amino acids or derivatives thereof comprising the general formula ABCEFGHI, wherein A is D-Ala, or a derivative thereof; B is D-Ser or D-Thr, or a derivative of any of these; C is D-Ser or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these.In some embodiments, the peptide or salt thereof may be D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr, or a salt thereof. In some embodiments, I may be esterified, glycosylated, or amidated at the C-terminus. In some embodiments, the mild cognitive impairment or mild dementia may be a disease involving amyloid beta (Aβ). In some embodiments, the mild cognitive impairment or mild dementia may be Alzheimer's disease. In some embodiments, the mild cognitive impairment or mild dementia may be mixed dementia. In some embodiments, the mild cognitive impairment or mild dementia may be vascular dementia. In some embodiments, the pharmaceutical composition may be in unit dose form. In some embodiments, the pharmaceutical composition may further comprise an excipient, a diluent, a carrier, or a combination thereof. In some embodiments, the mild cognitive impairment or mild dementia may include deposition of alpha-synuclein, tau, or both in the brain. In some embodiments, the administering step may be daily, weekly, or monthly. In some embodiments, the administering step may be once, twice, three times, or four times daily. In some embodiments, the pharmaceutical composition can be administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong. In some embodiments, the pharmaceutical composition can comprise the peptide, its derivative, or a salt thereof in an amount of about 0.005 mg to about 1000 mg. In some embodiments, the pharmaceutical composition can be administered orally, by injection, sublingually, buccally, rectally, vaginally, ocularly, aurally, nasally, internasally, inhalationally, cutaneously, subcutaneously, intramuscularly, intravenously, systemically, topically, transdermally, or any combination thereof. In some embodiments, the pharmaceutical composition may be formulated for oral administration or intravenous administration. In some embodiments, the pharmaceutical composition may be in pill or liquid form. In some embodiments, the pharmaceutical composition may be in liquid form.In some embodiments, the subject may be diagnosed with mild cognitive impairment or mild dementia before administration. In some embodiments, the diagnosis may include in vitro testing, physical examination, imaging diagnostic methods, or a combination thereof. In some embodiments, the subject may be a mammal. In some embodiments, the mammal may be a human.

[0009] Also disclosed herein are methods for treating a disease in a subject in need thereof. In some embodiments, the method may include administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the disease. In some embodiments, the pharmaceutical composition may include a peptide, a derivative thereof, or a salt thereof, wherein the peptide includes: i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2 (SEQ ID NO: 1) or a derivative thereof, wherein the first amino acid is a D stereoisomer, the remaining amino acids are L stereoisomers, and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 2) or a derivative thereof, wherein the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof; and lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these. In some embodiments, the disease may be mild cognitive impairment or mild dementia.

[0010] Pharmaceutical compositions are also disclosed herein. In some embodiments, the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five consecutive amino acids comprising the general formula: EFGHI, or a derivative thereof, and E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and II) lecanemab, aducanumab, lemternetag, a derivative of any of these, a biosimilar of any of these, or a salt of any of these. In some embodiments, the peptide, derivative, or salt thereof comprises at least 8 consecutive amino acids or derivatives thereof comprising the general formula ABCEFGHI, wherein A is D-Ala or a derivative thereof; B is D-Ser or D-Thr, or a derivative of any of these; C is D-Ser or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these. In some embodiments, the peptide or salt thereof can be D-Thr, D-Thr, D-Asn, D-Tyr and D-Thr, or a salt thereof.In some embodiments, I may be esterified, glycosylated, or amidated at the C-terminus. In some embodiments, the pharmaceutical composition may further comprise an excipient, diluent, carrier, or a combination thereof. In some embodiments, the pharmaceutical composition may comprise lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these. In some embodiments, the pharmaceutical composition may comprise aducanumab, a derivative thereof, a biosimilar thereof, or a salt of any of these. In some embodiments, the pharmaceutical composition may comprise lemternetag, a derivative thereof, a biosimilar thereof, or a salt of any of these. In some embodiments, the pharmaceutical composition may be in unit dose form. In some embodiments, the pharmaceutical composition may comprise the peptide, a derivative thereof, or a salt thereof in an amount of about 0.005 mg to about 1000 mg. In some embodiments, the pharmaceutical composition may comprise lecanemab, aducanumab, lemternetag, a derivative thereof, a biosimilar thereof, or a salt of any of these in an amount of about 1 mg to about 500 mg. In some embodiments, the pharmaceutical composition may comprise lecanemab, aducanumab, lemternetag, a derivative thereof, a biosimilar thereof, or a salt of any of these in an amount of about 10 mg / kg. In some embodiments, the pharmaceutical composition may be formulated for intravenous or oral delivery. In some embodiments, the pharmaceutical composition may be in the form of a pill or liquid.

[0011] Pharmaceutical compositions are also disclosed herein. In some embodiments, the pharmaceutical composition may include a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises: i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2 (SEQ ID NO: 1) or a derivative thereof, wherein the first amino acid is a D stereoisomer, the remaining amino acids are L stereoisomers, and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 2) or a derivative thereof, wherein the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof; and lecanemab, aducanumab, lemternetag, any derivative thereof, any biosimilar thereof, or any salt thereof, and optionally an excipient, diluent, carrier, or any combination thereof.

[0012] Also disclosed herein is a kit comprising the pharmaceutical composition disclosed herein and a container. In some embodiments, the kit may include I) a peptide, a derivative thereof, or a salt thereof. In some embodiments, the peptide in the first container may include at least five consecutive amino acids or derivatives thereof comprising the general formula: EFGHI (wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these); and II) one or more of lecanemab, aducanumab, lemternetag, a derivative of any of these, a biosimilar of any of these, or a salt of any of these in the second container.

[0013] Also disclosed herein is a method for treating dementia in a subject in need thereof. In some embodiments, the method may include administering to the subject a therapeutically effective amount of I) a peptide, a derivative thereof, or a salt thereof. In some embodiments, for treating dementia, the peptide may include at least 5 consecutive amino acids or derivatives thereof comprising the general formula: EFGHI, where E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these; and II) lecanemab, a derivative, a biosimilar, or a salt of any of these.

[0014] In some embodiments, the peptide, derivative, or salt thereof may comprise at least 8 consecutive amino acids or derivatives thereof comprising the general formula ABCEFGHI, wherein A is D-Ala, or a derivative thereof; B is D-Ser or D-Thr, or a derivative of any of these; C is D-Ser or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these. In some embodiments, the peptide, its derivative, or a salt thereof may be in unit dose form. In some embodiments, lecanemab, its derivative, its biosimilar, or a salt of any of these may be in unit dose form. In some embodiments, the pharmaceutical composition may be administered by oral, injection, sublingual, buccal, rectal, vaginal, ocular, aural, nasal, internasal, inhalation, dermal, subcutaneous, intramuscular, intravenous, systemic, topical, transdermal, or any combination thereof. In some embodiments, the pharmaceutical composition may be formulated for intravenous or oral administration. In some embodiments, lecanemab, its derivative, its biosimilar, or a salt of any of these may be in pill or liquid form, and the peptide, its derivative, or a salt thereof may be in pill or liquid form. In some embodiments, lecanemab, its derivative, its biosimilar, or a salt of any of these may be administered concurrently or sequentially with the peptide, its derivative, or a salt thereof. In some embodiments, the peptide, derivative thereof, or salt thereof may be in an amount of about 0.005 mg to about 1000 mg.In some embodiments, lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these may be administered in an amount of about 1 mg to about 500 mg. In some embodiments, lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these may be administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or for life. In some embodiments, the peptide, its derivative, or its salt may be administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong. In some embodiments, the peptide, its derivative, or its salt may be administered daily, weekly, or monthly. In some embodiments, the lecanemab, its derivative, its biosimilar, or a salt of any of these may be administered daily, weekly, or monthly. [Brief explanation of the drawings]

[0015] [Figure 1] Figures 1A-B show graphs of the pharmacokinetic properties of RAP-103 (R103). Figure 1A shows the pharmacokinetic properties of RAP-103, which has rapid brain entry following oral and intravenous administration in rats and guinea pigs. Figure 1B shows the plasma levels of RAP-103 over several hours in non-human primates (monkeys).

[0016] [Figure 2] Figure 2 shows an exemplary peptide manufacturing process for RAP-103. The figure discloses SEQ ID NO:3.

[0017] [Figure 3A]Figures 3A-3E show that RAP-103 prevents Aβ oligomer-induced spine loss in rodent neurons. A neurite map was acquired of a 23-DIV mouse hippocampal neuron immunolabeled for MAP2, PSD95, and VGLUT. Figure 3A shows that the MAP2 channel in this overexposed image shows weakly labeled dendrites (see arrows). Figure 3B shows the inverse deconvolved neurite map of MAP2 (light gray) overlaid with PSD95 (dark gray spots). While some MAP2-positive dendrites (see arrows in Figure 3A) are too faint to be visible on the deconvolved overlay, most PSD95 spots coincide with dendrites. Figure 3C shows a magnified boxed area from Figure 3B. While many spines are MAP2-positive, PSD95 spots along dendrites can be present in spines without MAP2. Figure 3D shows that quantitative analysis of spines (PSD95 puncta) normalized to MAP2 area from multiple fields of view on multiple coverslips indicates that Aβd / t reduces spines, but this reduction is inhibited by RAP-103. *p<0.05. Figure 3E shows the number of synapses per 20 μm dendrite. Synapses were quantified per 20 μm segment of five secondary dendrites per field (205–230 segments) from approximately 50 fields from each of four coverslips per treatment. [Figure 3B] Same as above. [Figure 3C] Same as above. [Figure 3D] Same as above. [Figure 3E] Same as above.

[0018] [Figure 4A]Figures 4A-4B show that RAP-103 prevents Aβ oligomer-induced synapse and spine loss in human neurons. Figure 4A shows a confocal image of a sample of a human neuron at day 55. The inset of immunolabeling for vGlut (dark gray) and PSD95 (light gray) shows several synapses where the immunolabeling for the markers touch or overlap. Treatment with Aβ d / t ± RAP-103 (1 nM) was for 5 days. Normalized to total dendritic area per field (MAP2 immunolabeling), the significant reduction in synapses or spines due to Aβ d / t (shown in Figure 4B) is eliminated by RAP-103 but not by the control peptide 3, which did not block rods. [Figure 4B] Same as above.

[0019] [Figure 5A] Figures 5A-5B show that RAP-103 reverses Aβ-induced cofilin rod formation in hippocampal neurons. Hippocampal neurons were treated with Aβ (1 nM) to induce rods. After overnight incubation, rods (shown in white boxes) were tracked by fluorescence microscopy at 4-minute intervals upon treatment with 0.1 nM RAP-103 or 50 nM AMD3100. Figure 5A shows selected images of fluorescent rods from RAP-103-treated cells over a time course. Figure 5B shows the time course of rod area over a 150-minute treatment period. The Y-axis represents the percent of initial rod area, and the X-axis represents time in minutes. RAP-103 prevents rod formation and reverses existing rods with a T1 / 2 of approximately 30 minutes, as shown herein. [Figure 5B] Same as above.

[0020] [Figure 6A]Figures 6A-6D show that RAP-103 prevents memory impairment in the Morris Water Maze (MWM) test in Thy1-aSyn mice. Figure 6A shows that the total swimming distance was the same in alpha-synuclein compared to WT mice, and RAP-103 had no adverse or stimulatory effect on swimming. Figures 6B-D show that RAP-103-treated alpha-synuclein mice maintained their ability to remember the location of the platform across three assessments; Figure 6B shows the distance spent in the target; Figure 6C shows the time spent in the target; and Figure 6D shows target crossing. In contrast, untreated mice did not remember the location of the platform and swam around all four quadrants. *P<0.05, **P<0.01. [Figure 6B] Same as above. [Figure 6C] Same as above. [Figure 6D] Same as above.

[0021] [Figure 7A] Figures 7A-7B show the effects of peptides on rods induced by other initiators. Figure 7A shows that glutamate-induced rod formation is not inhibited by RAP-310 at a concentration that completely inhibits Aβd / t-induced rods. Treatment of 6 DIV rat hippocampal neurons with glutamate (150 μM for 1 hour) induced rods in >70% of neurons, whereas overnight treatment with Aβd / t induced rods in a 25% or less subpopulation. 0.1 nM RAP-310 added together with rod inducers inhibited Aβd / t-induced rod formation but not glutamate-induced rod formation. ****p<0.0001. ns=not significant. Figure 7B shows that rods induced in 55-day-old human neurons treated with IL-6 on DIV54 were inhibited in a dose-dependent manner by RAP-103 with an EC50 of approximately 0.1 pM. **p<0.01. This data indicates that the peptides herein can be used to treat IL-6-associated diseases, such as multifactorial neurological diseases. [Figure 7B] Same as above.

[0022] [Figure 8] Figure 8 shows quantification of the percentage of rod-bearing neurons (fold change compared to control) after 7 days of in vitro growth (DIV7). Hippocampal neurons were pretreated for 24 hours with control (PBS) or 1 μg / ml alpha-synuclein preformed fibrils (PFF), and with control (HO) or 50 pM RAP-103. Data represent mean ± SEM (≥100 neurons / sample, n = 6 independent samples / condition). *p < 0.05, **p < 0.01 by one-way ANOVA with Tukey's multiple comparison test. Additionally, Figure 8 shows quantification of rod index (expressed as the fold change in rod number compared to control) after 14 days of in vitro growth (DIV14) of hippocampal neurons pretreated for 24 hours with control (PBS) or 1 μg / ml alpha-synuclein PFFs, and with control (HO) or 50 pM RAP-103. Data represent mean ± SEM (≥100 neurons / sample, n=6 independent samples / condition). *p<0.05, **p<0.01.

[0023] [Figure 9A] Figures 9A-9D show that RAP-103 and RAP-310 inhibited Aβd / t-induced rod formation in both rodent and human neurons in a dose-dependent manner. Rod quantification in DIV6 mouse hippocampal neurons is shown in Figures 9A and 9B. Rod quantification in day 55 human neurons is shown in Figures 9C and 9D. Cells were treated with Aβd / t for 24 hours along with the indicated concentrations of RAP-103 (Figures 9A and 9C) or RAP-310 (Figures 9B and 9D). EC50 values ​​for inhibition of Aβd / t-induced rods were estimated from semilogarithmic plots of these data to be approximately 1 pM in mouse hippocampal neurons and approximately 0.1 pM in human neurons. Error bars represent SD. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001; ns=not significantly different. [Figure 9B] Same as above. [Figure 9C] Same as above. [Figure 9D] Same as above.

[0024] [Figure 10A] Figures 10A-10B show the effect of RAP on rods induced by other initiators. Figure 10A shows rod formation induced by adenovirus-mediated overexpression of PrP in rat hippocampal neurons infected with AdPrP ​​and treated with RAP-103 [50 pM] either simultaneously (day 4) or at DIV5 (day 1). Figure 10B shows that rods induced in human neurons treated with gp120 are inhibited from forming by RAP-103 [10 pM]. (n=1) Error bars are SD. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001; ns=not significantly different. [Figure 10B] Same as above.

[0025] [Figure 11] Figure 11 shows the inhibition of TNF-alpha release by Aβ and alpha-synuclein preformed fibrils (PFFs) by RAP-103 (1 nM). The Y-axis shows the level of TNF-alpha release by cultured THP.1 human monocytes. The X-axis shows different treatments (e.g., Aβ (Abeta), aSyn (alpha-synuclein), Aβ and aSyn) in two conditions: medium only (left bar) or medium plus RAP-103 (right bar). DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description definition Unless otherwise defined, all terms, notations, and other technical and scientific terms or technical and scientific terminology of the art used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as indicating a substantial difference beyond that commonly understood in the art.

[0027] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Thus, the description of a range should be considered to specifically disclose all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range, e.g., 1 to 6, should be considered to specifically disclose subranges, e.g., 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numerical values ​​within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0028] As used herein, the term "about" a number may refer to a number plus or minus 10% of that number. The term "about" a range may refer to a range from minus 10% of its lowest value to plus 10% of its highest value.

[0029] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a sample" includes multiple samples, including mixtures thereof.

[0030] The terms "determining," "measuring," "evaluating," "assessing," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement, including determining whether an element may be present (e.g., detecting). These terms can include quantitative determinations, qualitative or quantitative determinations, and qualitative determinations. Alternatively, the assessing can be relative or absolute. "Detecting the presence of" includes determining the amount of something present, as well as determining whether it may or may not be present.

[0031] The terms "subject," "individual," or "patient" are often used interchangeably herein. A "subject" can be a biological entity. The biological entity can be a plant, an animal, or a microorganism, including, for example, bacteria, viruses, fungi, and protozoa. A subject can be tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro. A subject can be a mammal. A mammal can be a human. A subject can be diagnosed or suspected of being at high risk for a disease. In some cases, a subject may not necessarily be diagnosed or suspected of being at high risk for a disease.

[0032] The term "at least partially" can refer to a qualitative term that indicates a partial extent or degree of a feature or characteristic of interest. For example, at least partially reducing postural instability in a subject can include a reduction in postural instability of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% compared to an untreated subject.

[0033] The term "in vivo" can be used to describe events that take place in the body of a subject.

[0034] The term "ex vivo" may be used to describe events that occur outside of a subject's body. An "ex vivo" assay does not have to be performed on a subject. Rather, it may be performed on a sample separate from the subject. An example of an "ex vivo" assay performed on a sample would be an "in vitro" assay.

[0035] The term "in vitro" can be used to describe events that occur when a material is contained in a container that holds laboratory reagents so that it can be separated from the living biological source organism from which it can be obtained. In vitro assays can include cell-based assays in which live or dead cells are used. In vitro assays can also include cell-free assays in which intact cells are not used.

[0036] As used herein, the term "treatment" or "treating" is used in reference to a pharmaceutical or other intervention regimen to obtain a beneficial or desired result in a recipient, for example, to prevent the symptoms of a multifactorial neurological disease. Beneficial or desired results include, but are not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit can refer to the eradication or amelioration of symptoms or the underlying disorder being treated. Therapeutic benefit can also be achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement can be observed in a subject, even though the subject may still be suffering from the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease or reporting one or more physiological symptoms of a disease can receive treatment even if the disease has not been diagnosed.

[0037] As used herein, a "dose" may refer to a measured amount of a therapeutic agent taken at one time.

[0038] As used herein, the terms "unit dose" or "dosage form" may be used interchangeably and may refer to a pharmaceutical drug product in the form in which it is sold for use, with a specific mixture of active ingredients and inactive ingredients or excipients in a specific configuration and dispensed into a specific dose to be delivered. The term "unit dose" may sometimes also include non-reusable packaging. More than one unit dose may refer to separate pharmaceutical drug products packaged together, or a single pharmaceutical drug product containing multiple drugs and / or doses. The term "unit dose" may also sometimes refer to particles comprising pharmaceutical compositions, and any mixtures involved. The type of unit dose may vary depending on the route of administration for drug delivery and the substance(s) to be delivered. A solid unit dose may be a solid form of a dose of a pharmaceutically acceptable drug or chemical compound used as a drug therapy intended for administration or ingestion.

[0039] As used herein, "pharmaceutically acceptable salts" refers to pharmaceutical drug molecules that can be formed as weak acids or bases and chemically converted into their salt forms, most often as hydrochloride, sodium salts, or sulfate salts. Drug products synthesized as salts can enhance drug dissolution, boost absorption into the bloodstream, promote therapeutic effects, and increase their efficacy. Pharmaceutically acceptable salts can also facilitate the development of controlled-release dosage forms, improve drug stability, extend shelf life, enhance targeted drug delivery, and improve drug efficacy.

[0040] The phrase "pharmaceutically acceptable excipient," as used herein, may refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, carrier, solvent, or encapsulating material.

[0041] As used herein, "drug" or "biologically active agent" can refer to a biological, pharmaceutical, or chemical compound or any salt thereof. Non-limiting examples can include simple or complex organic or inorganic molecules, peptides, proteins, nucleotides, such as engineered RNA, engineered DNA, alternative nucleic acids, proteins, carbohydrates, toxins, or chemotherapeutic compounds. Various compounds, such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides), or synthetic organic compounds based on various core structures can be synthesized. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts.

[0042] As used herein, the term "effective amount" or "therapeutically effective amount" of a drug used to treat a disease can be an amount that can reduce the severity of the disease, reduce the severity of one or more symptoms associated with the disease or its treatment, or delay the onset of more severe symptoms or more severe diseases that may occur with a certain frequency after the treated condition. "Effective amount" can be determined experimentally and in a conventional manner for the stated purpose.

[0043] As used herein, "time to peak plasma concentration" may refer to the time required for a drug to reach a peak concentration in plasma. The peak concentration in plasma may be defined as the plasma concentration achieved by a drug in a specified compartment or test area of ​​the body after the drug is administered and before the administration of a second dose.

[0044] The terms "substantially" or "essentially" can refer to the qualitative term indicating the entire or most of the total extent or degree of a feature or characteristic of interest. In some cases, substantially refers to the total extent or degree of a feature or characteristic of interest, plus or minus: about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, %,approximately 21%,approximately 22%,approximately 23%,approximately 24%,approximately 25%,approximately 26%,approximately 27%,approximately 28%,approximately 29%,approximately 30%,approximately 31%,approximately 32%,approximately 33%,approximately 34%,approximately 35%,approximately 36%,approximately 37%,approximately 38%,approximately 39%,approximately 40%,approximately 41%,approximately 42%,approximately 43%,approximately 44%,approximately 45%,approximately 46%,approximately 47%, Approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately %, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%. In some cases, substantially can refer to at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% of the total extent or degree of the feature or characteristic of interest.

[0045] As used herein, "HPLC" may refer to high performance liquid chromatography (formerly called high pressure liquid chromatography), a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. HPLC may be a common technique used in pharmaceutical development, as it may be a method to ensure product purity.

[0046] The terms peptide and polypeptide may be used interchangeably herein.

[0047] The term "fragment," as used herein, can refer to a portion of a sequence, a subset that may be shorter than the full-length sequence. A fragment can be a portion of a gene. A fragment can be a portion of a peptide or protein. A fragment can be a portion of an amino acid sequence. A fragment can be a portion of an oligonucleotide sequence. A fragment can be less than about 20, 30, 40, or 50 amino acids in length. A fragment can be about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, or 70% of the total length of the amino acid or nucleotide sequence. A fragment can be less than about 20, 30, 40, or 50 oligonucleotides in length.

[0048] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Overview

[0049] Disclosed herein are compositions (e.g., pharmaceutical preparations), methods for treating diseases, diagnostic methods for detecting diseases, or kits containing pharmaceutical preparations. The compositions and preparations herein can be used to treat subjects with multifactorial neurological diseases. In some cases, the compositions and preparations herein can be used to treat Alzheimer's disease with Lewy bodies (LBVAD). In some cases, the compositions and preparations herein can be used to treat Alzheimer's disease-related dementia (ADRD). In some cases, the compositions and preparations herein can be used to treat vascular dementia. In some cases, the compositions and preparations herein can be used to treat frontotemporal dementia.

[0050] In some embodiments, Aβ and α-syn may act synergistically, promoting each other's aggregation and accumulation as well as neurofibrillary tangles (NFTs), creating a more severe pathology in dementia that is not merely additive. Treatments addressing the causes and effects of mixed proteinopathies are needed because they more accurately define dementia patient populations than clinical impressions. Unexpectedly, RAP-103 and other peptides disclosed herein can block the combined effects of amyloid-beta and alpha-synuclein on TNFα secretion by monocytes. The results herein demonstrate that when both amyloid-beta and alpha-synuclein are present, as in mixed dementia, synergistic release of neurotoxic TNFα secretion by human monocytes occurs. Without being bound by any theory, this may occur due to the formation of novel combined oligomeric toxic species formed from the interaction of both oligomers. These results indicate that RAP-103 has unexpected effects on neurotoxic processes (e.g., reducing TNFα secretion) occurring in patients with mixed proteinopathies that contribute to accelerated cognitive decline. The peptides herein can be used to treat subjects with mixed proteinopathies.

[0051] Similarly, the peptides herein can directly block the individual direct effects of amyloid-beta and alpha-synuclein on neuronal synaptogenesis, and, without being bound by any theory, the peptides herein can directly block the combined effects of amyloid-beta and alpha-synuclein on neuronal synaptogenesis.

[0052] In other embodiments, the compositions and formulations herein may be used to treat other diseases and / or conditions, such as postural instability, gait disorders, balance problems, loss of bladder control, urinary incontinence, or any combination thereof.

[0053] In certain instances, the compositions herein can be used to treat postural instability. In some cases, postural instability can be described as the inability to maintain balance under dynamic and static conditions, such as preparation for movement, perturbation, and static posture.

[0054] There is strong evidence of coexisting pathologies (amyloid beta, tau and alpha-synuclein, infarction, ischemia) in Alzheimer's disease-related dementia (ADRD). These factors are typically assumed to act independently and without specific interactions with each other. However, the combination of these pathologies influences the clinical picture in unexpected ways and is a better predictor of dementia than the severity of any single pathology. Treating multifactorial neurological diseases has additional benefits in other dementias, including Lewy body dementia (LBD) and Alzheimer's disease with Lewy bodies (LBVAD), which account for up to 25% of all dementias in patients older than 65 years. Multifactorial neurological diseases cause novel and difficult-to-treat synergistic contributions to neurodegeneration affecting different regions of the brain compared to pure Alzheimer's disease or Parkinson's disease, which occur in a subset of patients and cause unexpected clinical presentations in a subset of patients.

[0055] These multifactorial patients show more severe and rapid dementia progression compared to single-factor dementia, such as Alzheimer's disease, whose approved treatments only target amyloid beta, or Parkinson's disease, which is mainly related to the formation of alpha-synuclein.For example, the accumulation of Abeta in Parkinson's disease patients causes a pathological process that is separate from that occurring in Alzheimer's disease.As a result, multifactorial pathologies are synergistic and interact with each other, rather than simply combining individual pathologies (amyloid beta and alpha-synuclein, or amyloid beta and tau), so that patients with mixed pathologies show more heterogeneous, faster and more severe clinical phenotypes, with faster death.Successful treatment of multifactorial pathologies is needed to overcome the limitations of single-target therapy and treat neurological diseases in a subset of patients.

[0056] In some embodiments, the peptides herein can reduce neurodegenerative cytokines, including IL-1, IL-6, IL-8, and TNF-alpha, compared to cytokine levels before treatment. In some cases, the peptides herein can block microglia, astrocyte activation, and immune cell infiltration into the CNS. In some cases, the peptides herein can antagonize chemokine receptor clusters to promote spine and synaptic nerve regeneration. In some cases, the peptides herein can reduce the synergistic effect of amyloid beta (Aβ) and alpha synuclein (α-Syn). For example, the peptides herein may reduce cytokine (e.g., TNF-alpha) release in monocytes exposed to Aβ and α-Syn by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% compared to monocytes not exposed to Aβ and α-Syn. In some cases, the peptides herein may reduce cytokine (e.g., TNF-alpha) release in monocytes exposed to Aβ and α-Syn by about 5% to about 100%, about 5% to about 25%, about 10% to about 30%, about 40% to about 60%, about 30% to about 70%, about 45% to about 75%, about 50% to about 80%, about 60% to about 75%, about 60% to about 70%, about 65% to about 80%, about 70% to about 80%, about 80% to about 90%, about 85% to about 95%, or about 90% to about 100% compared to monocytes not exposed to Aβ and α-Syn.

[0057] In some examples, the peptides herein may comprise up to 8 or more consecutive amino acids or derivatives thereof, including the general formula ABCEFGHI, wherein A is D-Ala or a derivative thereof; B is D-Ser or D-Thr, or a derivative of any of these; C is D-Ser or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof, and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these. In some cases, the peptides herein may comprise at least five consecutive amino acids or derivatives thereof comprising the general formula: EFGHI, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these.

[0058] In some embodiments, the peptides in the compositions may be used to reverse synapse and / or dendritic spine loss. In some embodiments, the peptides in the compositions may be used to induce synapse growth. In some cases, the peptides in the compositions may be used to induce dendritic spine growth. In some cases, the peptides in the compositions may be used to induce neuronal growth cone growth. In some cases, the peptides in the compositions may be used to prevent and / or reverse actin rod formation. In some cases, the peptides in the compositions may be used to prevent and / or reverse cofilin rod formation. In some cases, the peptides in the compositions may be used to prevent actin and cofilin rod formation. In some cases, the peptides in the compositions may be used to reverse actin and cofilin rod formation. In some cases, the RAP peptide can inhibit rod formation by targeting PrP C-lipid raft expansion and / or NOX recruitment mediated by binding of Aβd / t and / or other rod-inducing factors. In some cases, the peptides herein can inhibit rod formation by targeting PrP-lipid raft expansion and / or NOX recruitment mediated by binding of Aβd / t and / or other rod-inducing factors.

[0059] The multi-chemokine receptor antagonist peptide RAP-103 (an all-D peptide - Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 3)) has been developed to provide treatment for multifactorial neurological and other diseases. Treatment with the peptide disclosed herein surprisingly and unexpectedly resulted in improvements in cognitive function and improved postural stability in subjects with advanced dementia and postural instability. In some cases, RAP-103 and other peptides disclosed herein can be used to treat multifactorial neurological and / or other diseases. peptide

[0060] As used herein, amino acids may be referred to by their one-letter or three-letter codes, as shown in Table 1. [Table 1]

[0061] Amino acids can be D or L, depending on the configuration at the alpha carbon, except for glycine, which does not contain four non-identical substituents on its alpha carbon atom. The designations D and L are not to be confused with the single-letter amino acid codes. In some embodiments, D amino acids are designated by a D before the amino acid (e.g., D-Ser, dA). If an amino acid has four non-identical substituents on its alpha carbon atom and the amino acid is not designated with a D before the amino acid, the amino acid may be of the L configuration. The amino acid glycine, which lacks four non-identical substituents on its alpha carbon atom, may be neither D nor L.

[0062] The peptides herein may include those in Table 2. [Table 2]

[0063] Here, peptides TTNYT (SEQ ID NO:3) (RAP-103), SSTYR (SEQ ID NO:4), STNYT (SEQ ID NO:5), and ASTTTNYT (SEQ ID NO:8) (RAP-310) are all-D peptides, such that each amino acid in the peptide is in the D configuration. Here, in peptide NTSYG (SEQ ID NO:6), each amino acid, except for glycine, is in the D configuration. Here, in peptide ETWYS (SEQ ID NO:9), each amino acid is in the D configuration. Here, in table, the alanine of dASTTTNYT (SEQ ID NO:2) is in the D configuration, and all other amino acids in peptide 5 are in the L configuration. And here, in table, the alanine of dASTTTNYT-NH2 (SEQ ID NO:1) is in the D configuration, and all other amino acids in peptide 5 are in the L configuration. In some cases, a peptide, such as TTNYT (SEQ ID NO:3), can include an N-terminal methyl group (e.g., N-methyl-TTNYT (SEQ ID NO:10)). In some cases, a peptide can include an amide. For example, ASTTTNYT (SEQ ID NO: 8) can be ASTTTNYT-amide (SEQ ID NO: 7). Peptide Composition

[0064] In some examples, a composition is provided comprising a peptide, wherein the peptide comprises at least five consecutive amino acids or derivatives thereof comprising the general formula: EFGHI, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these.

[0065] In some examples, E can be D-Thr. In some examples, F can be D-Thr. In some examples, E can be D-Thr and F can be D-Thr. In some examples, G can be D-Asn. In some examples, F can be D-Thr and G can be D-Asn. In some examples, E can be D-Thr, F can be D-Thr, and G can be D-Asn. In some examples, H can be D-Tyr. In some examples, E can be D-Thr and H can be D-Tyr. In some examples, G can be D-Asn and H can be D-Tyr. In some examples, I can be D-Thr. In some examples, E can be D-Thr, F can be D-Thr, G can be D-Asn, H can be D-Tyr, and I can be D-Thr.

[0066] In some examples, the peptide may comprise at least 8 consecutive amino acids or derivatives thereof comprising the general formula ABCEFGHI, wherein A is D-Ala or a derivative thereof; B is D-Ser or D-Thr, or a derivative of any of these; C is D-Ser or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys or D-Trp, or a derivative of any of these; H is D-Tyr or a derivative thereof, and I is D-Thr, D-Ser, D-Arg, or a derivative of any of these.

[0067] In some cases, A can be D-Ala. In some cases, B can be D-Ser. In some cases, B can be D-Thr. In some cases, A can be D-Ala and B can be D-Ser. In some cases, A can be D-Ala and B can be D-Thr. In some cases, C can be D-Ser. In some cases, C can be D-Thr. In some cases, B can be D-Ser and C can be D-Ser. In some cases, B can be D-Thr and C can be D-Ser. In some cases, B can be D-Thr and C can be D-Thr. In some cases, E can be D-Thr. In some cases, F can be D-Thr. In some cases, E can be D-Thr and F can be D-Thr. In some cases, G can be D-Asn. In some cases, F can be D-Thr and G can be D-Asn. In some examples, E can be D-Thr, F can be D-Thr, and G can be D-Asn. In some examples, H can be D-Tyr. In some examples, E can be D-Thr, and H can be D-Tyr. In some examples, G can be D-Asn, and H can be D-Tyr. In some examples, I can be D-Thr. In some examples, E can be D-Thr, F can be D-Thr, G can be D-Asn, H can be D-Tyr, and I can be D-Thr.

[0068] In some embodiments, the C-terminal peptide may be esterified, glycosylated, or amidated at the C-terminus. In some cases, I or a derivative thereof may be esterified, glycosylated, or amidated at the C-terminus.

[0069] In some examples, the peptide sequence may include the sequence ASTTTNYT (SEQ ID NO: 11), in which each amino acid may individually be of the L-configuration or the D-configuration; in some examples, all of the amino acids in the sequence ASTTTNYT (SEQ ID NO: 12) may be of the L-configuration; in some examples, all of the amino acids in the sequence ASTTTNYT (SEQ ID NO: 8) may be of the D-configuration.

[0070] In some examples, the peptide sequence may include the sequence SSTYR (SEQ ID NO: 13), in which each amino acid may individually be of the L-configuration or the D-configuration; in some examples, all of the amino acids in the sequence SSTYR (SEQ ID NO: 14) may be of the L-configuration; in some examples, all of the amino acids in the sequence SSTYR (SEQ ID NO: 4) may be of the D-configuration.

[0071] In some examples, the peptide sequence may include the sequence STNYT (SEQ ID NO: 15), in which each amino acid may individually be of the L-configuration or the D-configuration; in some examples, all of the amino acids in the sequence STNYT (SEQ ID NO: 16) may be of the L-configuration; in some examples, all of the amino acids in the sequence STNYT (SEQ ID NO: 5) may be of the D-configuration.

[0072] In some examples, the peptide sequence may include the sequence of NTSYG (SEQ ID NO: 17), in which each amino acid may individually be of the L-configuration or the D-configuration; in some examples, all of the amino acids in the sequence NTSYG (SEQ ID NO: 18) may be of the L-configuration; in some examples, all of the amino acids in the sequence NTSYG (SEQ ID NO: 19) may be of the D-configuration.

[0073] In some examples, the peptide sequence may include the sequence of TTNYT (SEQ ID NO: 20), in which each amino acid may be individually of the L- or D-configuration; in some examples, all of the amino acids in the sequence TTNYT (SEQ ID NO: 21) may be of the L-configuration; in some examples, all of the amino acids in the sequence TTNYT (SEQ ID NO: 3) may be of the D-configuration. In some cases, all of the amino acids in the sequence TTNTY (SEQ ID NO: 22) may be of the D-configuration. ASTTTNYT-NH2 (SEQ ID NO: 23), in which each amino acid may be individually of the L- or D-configuration; in some examples, all of the amino acids in the sequence ASTTTNYT-NH2 (SEQ ID NO: 24) may be of the L-configuration; in some examples, all of the amino acids in the sequence ASTTTNYT-NH2 (SEQ ID NO: 7) may be of the D-configuration. In some examples, the A in the sequence ASTTTNYT-NH2 (SEQ ID NO: 1) may be of the D-configuration, and all other amino acids in this sequence may be of the L-configuration. In the sequence, -NH2 specifies that the amino acid threonine at the C-terminus of the sequence has an amide as opposed to a carboxylic acid.

[0074] In some examples, the peptide sequence is the multi-chemokine receptor antagonist RAP-103 (R103) (an all-D peptide - Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 3)), as shown in Figures 1 and 2.

[0075] In some examples, the peptides described herein may be in the form of a pharmaceutically acceptable salt, for example, an acetate salt. Pharmaceutical Composition An active pharmaceutical ingredient can be any substance or mixture of substances intended for use in the manufacture of a drug (medicinal) product, which, when used in the production of a drug, becomes the active ingredient of the drug product. Such substances can be intended to impart pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body. In some embodiments, the compositions herein comprise a peptide as an active pharmaceutical ingredient. In some cases, the compositions herein comprise pharmaceutical compositions.

[0076] In some embodiments, the peptides described herein have a pH of 10 by HPLC when stored in a sealed container placed in a room at about 5°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, or about 40°C, and in a room atmosphere having a relative humidity of about 40 percent, about 45 percent, about 50 percent, about 55 percent, about 60 percent, or about 75 percent. The peptides may be measured to retain at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% of the active ingredient or salt thereof after about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, or about 24 months. In some cases, the peptides may be formulated as pills. In some embodiments, the peptides described herein formulated as a liquid exhibit a HPLC stability when stored in a sealed container placed in a room at about 5°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, or about 40°C, and in a room atmosphere having a relative humidity of about 40 percent, about 45 percent, about 50 percent, about 55 percent, about 60 percent, or about 75 percent. C retains at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% of the active ingredient or salt thereof after about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, or about 24 months.

[0077] In some embodiments, the peptides herein can be formulated as pharmaceutical compositions with additional treatments. In some cases, the additional treatments can include aducanumab, lecanemab, lemternetag, any of their derivatives, any of their biosimilars, or any of their salts. In some cases, the peptides herein can be formulated as a first pharmaceutical composition, and the additional treatment can be formulated as a second pharmaceutical composition. Typical acids for salts

[0078] In some embodiments, a pharmaceutically acceptable salt of a peptide can be formed from the peptide and an acid. In some embodiments, the acid can be at least one of the following: 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-dicarboxylic acid, acetic acid, benzoic acid, camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-dicarboxylic acid, benzoic acid, camphor-10-sulfonic acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), benzoic acid, benzoic acid, benzoic acid, camphor-10-sulfonic acid (+), camphor-10-sulfonic acid (+), benzoic acid, benzoic acid, camphor-10-sulfonic acid, ... Sulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid acid), pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid, or any combination thereof. Typical salt

[0079] In some embodiments, the salt herein can comprise pharmaceutically acceptable salt.In some embodiments, pharmaceutically acceptable salt includes but is not limited to metal salt, for example, sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salt, for example, calcium salt, magnesium salt, etc.; organic amine salt, for example, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.; inorganic acid salt, for example, hydrochloride, hydrobromide, phosphate, sulfate, etc.; organic acid salt, for example, citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate, etc.; sulfonate, for example, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; and amino acid salt, for example, arginate, aspartate, glutamate, etc. In some cases, the salt of the peptide or derivative thereof or compound may be a zwitterionic salt.

[0080] In some embodiments, the pharmaceutical composition comprises a salt of a pharmaceutically active ingredient, wherein the salt comprises an organic salt, an inorganic salt, or any combination thereof. In some cases, the organic salt may comprise a phosphinate (e.g., sodium hypophosphite), a hydrazinium salt, a urate, a diazonium salt, an oxalate, a tartrate, or choline chloride. Examples of inorganic salts may include sodium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, potassium chloride, sodium sulfate, calcium carbonate, calcium phosphate, or any combination thereof.

[0081] In some embodiments, the pharmaceutical composition comprises a salt of a pharmaceutically active ingredient, wherein the salt comprises an HCl salt, ascorbate, mandelate, aspartate, carbonate, citrate, formate, glutamate, lactate, laurate, maleate, borate, bitartrate, palmitate, phosphate, or any combination thereof.

[0082] In some embodiments, pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salts, potassium salts, cesium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate, and the like; sulfonate salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; and amino acid salts such as arginate, aspartate, glutamate, and the like. Typical excipients

[0083] In some embodiments, the carrier, diluent, and / or excipient may include a pharmaceutically acceptable carrier, diluent, and / or excipient. As used herein, "excipient" may refer to a substance formulated with an active ingredient of a drug therapy, included for the purposes of long-term stability, bulking up solid formulations containing small amounts of potent active ingredients, and / or imparting therapeutic enhancement to the active ingredient(s) in the final dosage form. Excipients may facilitate drug absorption, reduce viscosity, or enhance solubility. Excipients may also facilitate handling of the active ingredient, improve in vitro stability, and / or extend the shelf life of the pharmaceutical product. Excipient selection may vary depending on the route of administration for drug delivery, the unit dose, and the active ingredients that make up the composition.

[0084] In some embodiments, the pharmaceutically acceptable excipient is calcium phosphate anhydrous, calcium phosphate dihydrate, hydroxypropyl methylcellulose, croscarmellose sodium, GMO-free croscarmellose sodium, carbomer, magnesium aluminum metasilicate, mannitol, povidone (PVP), crospovidone, sorbitol, dimethicone, sodium stearyl fumarate, sodium starch glycolate, hydroxypropyl cellulose, natural corn starch, modified corn starch, carrageenan, alginate, silicon dioxide, microcrystalline cellulose, sodium carboxymethylcellulose, alginate, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (Na CMC), carbomer, natural gum, sorbitol, maltitol, glucose syrup, silicone, carbomer, fatty alcohol, alcohol, carbohydrate, petrolatum derivative, butter, wax, DMSO. Procipient®, esters, fatty acids, oil-in-water (O / W) emulsifiers, water-in-oil (W / O) emulsifiers, silica, fumed silica, polysorbates, isopropyl myristate, cellulose derivatives, xanthan gum, propylenglycol, noveon AA-1 polycarbophyl, dimethyl isosorbide, polysilicone elastomer 1100, polysilicone elastomer 1148P, preservatives, flavorings, pigments, functional coatings, aesthetic coatings, pharmaceutically acceptable salts of any of these, or any combination thereof.

[0085] In some embodiments, the pharmaceutically acceptable excipient is acacia, acesulfame potassium, glacial acetic acid, acetone, acetyl tributyl citrate, acetyl triethyl citrate, agar, albumin, alcohol, alginic acid, aliphatic polyester, alitame, almond oil, alpha tocopherol, aluminum hydroxide adjuvant, aluminum oxide, aluminum phosphate adjuvant, aluminum stearate, ammonia solution, ammonium alginate, ascorbic acid, ascorbyl palmitate, aspartame, attapulgite, Bentonite, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, boric acid, bronopol, butylated hydroxyanisole, butylated hydroxytoluene, butylparaben, calcium alginate, calcium carbonate, calcium phosphate, calcium hydrogen phosphate anhydrous, calcium hydrogen phosphate dihydrate, tribasic calcium stearate, calcium sulfate, canola oil, carbomer, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, castor Oil, hydrogenated castor oil, cellulose (e.g., microcrystalline, powdered, silicified microcrystalline, acetic acid, acetic acid phthalate), ceratonia, cetostearyl alcohol, cetrimide, cetyl alcohol, cetylpyridinium chloride, chitosan, chlorhexidine, chlorobutanol, chlorocresol, chlorodifluoroethane, chlorofluorocarbons, chloroxylenol, cholesterol, citric acid monohydrate, colloidal silicon dioxide, colorant, copovidone, corn oil, cottonseed oil, cresol, croscarmellose sodium, crospovidone , cyclodextrin, cyclomethicone, denatonium benzoate, dextrate, dextrin, dextrose, dibutyl phthalate, dibutyl sebacate, diethanolamine, diethyl phthalate, difluoroethane, dimethicone, dimethyl ether, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, edetate disodium, docusate sodium, edetic acid, erythorbic acid, erythritol, ethyl acetate, ethyl lactate, ethyl maltol, ethyl oleate, ethyl vanillin, ethyl cellulose,Ethylene glycol palmitostearate, ethylene vinyl acetate, ethylparaben, fructose, fumaric acid, gelatin, glucose, glycerin, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, glycofurol, guar gum, hectorite, heptafluoropropane, hexetidine, hydrocarbons, hydrochloric acid, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl starch, hypromellose, hypromellose acetate succinate, hypromellose phthalate, honey, imidurea, inulin, iron oxides, isomalt, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, kaoli Ingredients: lactic acid, lactitol, lactose anhydrous, lactose monohydrate, spray-dried lactose, lanolin, lanolin alcohol, hydrous lanolin, lauric acid, lecithin, leucine, linoleic acid, macrogol hydroxystearate, magnesium aluminum silicate, magnesium carbonate, magnesium oxide, magnesium silicate, magnesium stearate, magnesium trisilicate, malic acid, maltitol, maltitol solution, maltodextrin, maltol, maltose, mannitol, medium-chain triglycerides, meglumine, menthol, methylcellulose, methylparaben, mineral oil, light mineral oil oil, mineral oil, light, mineral oil) and lanolin alcohol, monoethanolamine, sodium glutamate, monothioglycerol, myristic acid, neohesperidin dihydrochalcone, nitrogen, nitrous oxide, octyldodecanol, oleic acid, oleyl alcohol, olive oil, palmitic acid, paraffin, peanut oil, pectin, petrolatum, petrolatum and lanolin alcohol, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, phosphoric acid, polacrilin potassium, poloxamerPolycarbophil, polydextrose, polyethylene glycol, polyethylene oxide, polymethacrylate, poly(methyl vinyl ether / maleic anhydride), polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyvinyl acetate phthalate, polyvinyl alcohol, potassium alginate, potassium benzoate, potassium bicarbonate, potassium chloride, potassium citrate, potassium hydroxide, potassium metabisulfite, potassium sorbate, povidone, propionic acid, propyl gallate, propylene carbonate, propylene glycol, propylene glycol alginate, propylparaben, 2-pyrrolidone, raffinose, saccharin, saccharin Sodium, saponite, sesame oil, shellac, simethicone, sodium acetate, sodium alginate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium borate, sodium chloride, sodium citrate dihydrate, sodium cyclamate, sodium hyaluronate, sodium hydroxide, sodium lactate, sodium lauryl sulfate, sodium metabisulfite, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium propionate, sodium starch glycolate, sodium stearyl fumarate, sodium sulfite, sorbic acid, sorbitan esters (sorbitan fatty acid esters), sorbitol, soybean oil, starch, starch (e.g., pregelatinized, sterilizable corn) maize), stearic acid, stearyl alcohol, sucralose, sucrose, compressible sugar, powdered sugar, sugar spheres, sulfobutyl ether b-cyclodextrin, sulfuric acid, sunflower oil, suppository base, hard fat, talc, tartaric acid, tetrafluoroethane, thaumatin, thimerosal, thymol, titanium dioxide, tragacanth, trehalose, triacetin, tributyl citrate, triethanolamine, triethyl citrate, vanillin, hydrogenated vegetable oil, water, wax, anionic emulsifier, wax (e.g., carnauba, cetyl esters, microcrystalline, nonionic emulsifier, white, yellow), xanthan gum, xylitol, zein, zinc acetate, zinc stearateor any combination thereof.

[0086] In some embodiments, the pharmaceutically acceptable excipient may include a carbohydrate, alginate, povidone, carbomer, flavoring, natural gum, silicone, alcohol, butter, wax, fatty acid, preservative, pharmaceutically acceptable salt of any of these, or any combination thereof. In some embodiments, the pharmaceutically acceptable excipient may include a carbohydrate. In some embodiments, the carbohydrate may include lactose, microcrystalline cellulose, cellulose, mannitol, sorbitol, starch, starch glycolate, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, cyclodextrin, maltodextrin, croscarmellose sodium, corn starch, carrageenan, sorbitol, maltitol, glucose, pharmaceutically acceptable salt of any of these, or any combination thereof.

[0087] In some embodiments, the weight to weight ratio of a) pharmaceutically acceptable excipient to b) active ingredient(s) ranges from about 1:1 to about 10,000:1. In some embodiments, the weight to weight ratio of a) pharmaceutically acceptable excipient to b) active ingredient(s) is / are in the range of about 1:1 to about 20:1, about 1:1 to about 15:1, about 1:1 to about 10:1, about 1:1 to about 5:1, about 1:1 to about 2:1, about 2:1 to about 20:1, about 2:1 to about 15:1, about 2:1 to about 10:1, about 2:1 to about 5:1, about 5:1 to about 20:1, about 5:1 to about 15:1, about 5:1 to about 10:1, about 10:1 to about 15:1, about 10:1 to about 20:1, about 15:1 to about 20:1, about 18:1 to about 25:1, or about 25:1 to about 30:1. In some embodiments, the weight to weight ratio of a) pharmaceutically acceptable excipient to b) active ingredient(s) can be about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, about 25:1, about 26:1, about 27:1, about 28:1, about 29:1, or about 30:1. In some embodiments, the weight to weight ratio of a) pharmaceutically acceptable excipient to b) active ingredient is in the range of about 1:1 to about 1:10, about 1:1 to about 1:8, about 1:1 to about 1:5, about 1:1 to about 1:2, about 1:2 to about 1:10, about 1:2 to about 1:8, about 1:2 to about 1:5, about 1:5 to about 1:10, about 1:5 to about 1:8, or about 1:8 to about 1:10. Carrier

[0088] In some cases, the pharmaceutically acceptable carrier or diluent may include water. In some embodiments, the water may be sterile. In some embodiments, the water may contain a buffer, a carbohydrate, a salt, a pH adjuster, or any combination thereof. A monosaccharide, such as mannitol, sucrose, glucose, or trehalose, may be added in an amount of 1 to 50 mg / ml to inhibit peptide or peptide aggregation. Citrate may be used as a buffer. In some cases, sodium chloride and phosphate may or may not be used. Larger polysaccharides may also be used to enhance stability.

[0089] In certain instances, a carrier may refer to a reagent, cell, compound, material, composition, dosage form, or any combination thereof that may be compatible with a therapeutically administered agent. In some cases, the carrier may be suitable for use in contact with the tissue of a subject. In some cases, the carrier may not be toxic, irritating, allergic, or any combination thereof. Carriers that may be suitable for use may include liquids, solid materials (e.g., pills or suppositories), or any combination thereof. In some cases, the carrier may be designed to resist degradation within the body (non-biodegradable) or designed to degrade within the body (biodegradable). Biodegradable materials may further be bioresorbable or bioabsorbable. In some cases, biodegradable materials may be degraded and eliminated from the body by conversion to other materials or breakdown and elimination via natural pathways. Oral bioavailability

[0090] In some cases, the peptide, its derivative, or any salt thereof may be orally bioavailable. In some cases, the pharmaceutical composition is formulated for oral administration. The percent oral bioavailability may be at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92% , at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or at least 100%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, or at least at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%,at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 100%, or about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 51%, about 52%, about 53%, about 54%, about The percentage can be 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100%. In some cases, the pharmaceutical compositions herein may be formulated as pills, capsules, liquids, or tablets for oral administration.

[0091] For example, RAP-103 rapidly entered the brain via oral and IV administration in rodents and non-human primates (Rhesus macaques). Non-human primates demonstrated 88% oral bioavailability. RAP-103 preferentially entered the brain via oral administration compared with IV administration (shown in Figure 1A), a feature supporting its use in treating multifactorial neurological disorders, postural instability, or both.

[0092] In some examples, the peptide, derivative, or salt of any of these may be administered to a subject, which may be a subject in need thereof. In some embodiments, the subject has a multifactorial neurological disease. In some embodiments, the subject has postural instability. In some embodiments, the subject may be a human, and may be male or female. In some examples, the subject may be under 18 years of age. In some examples, the subject may be over 18 years of age. In some cases, the subject may be a child, e.g., a subject between about 0 and about 18 years of age. In some cases, the subject may be an adult, e.g., a subject equal to or older than 18 years of age. In some cases, the subject may be between about 18 and about 75 years of age. In some cases, the subject may be between about 65 and about 75 years of age. In some cases, the subject may be between about 18 and about 64 years of age. In some examples, the subject may be between about 1 and about 120 years of age. In some cases, the subject may be equal to or older than 65 years of age. In some embodiments, the subject may be between about 1 day and about 10 months old, between about 9 months and about 24 months old, between about 1 year and about 8 years old, between about 5 years and about 25 years old, between about 20 years and about 50 years old, between about 40 years and about 80 years old, or between about 50 years and about 130 years old. Administration

[0093] In some embodiments, the terms "administer," "administering," "administration," and the like, as used herein, may refer to methods that can be used to enable delivery of a compound, peptide, derivative, or salt of any of these, or a composition described herein to a desired site of biological action. In some cases, delivery may include injection, inhalation, catheterization, gastrostomy tube administration, intravenous administration, intraosseous administration, ocular administration, otic administration, topical administration, transdermal administration, topical administration, oral administration, rectal administration, nasal administration, intravaginal administration, intracavity administration, transurethral administration, buccal administration, sublingual administration, or a combination thereof. In some cases, delivery may include oral administration, intranasal administration, or intravenous administration. In some cases, the pharmaceutical composition may be administered by oral, injection, sublingual, buccal, rectal, vaginal, ocular, otic, nasal, internasal, inhalation, dermal, subcutaneous, intramuscular, intravenous, systemic, topical, transdermal route, or any combination thereof. Delivery may include direct application to affect a tissue or region of the body. Delivery may include parenchymal injection, intrathecal injection, intraventricular injection, or intracisternal injection. The compositions provided herein may be administered by any method. The method of administration may be intraarterial, intraventricular, intracisternal, intramuscular, intraorbital, intraparenchymal, intraperitoneal, intraspinal, intrathecal, intravenous, intraventricular, stereotactic, subcutaneous, epidural, or any combination thereof. Delivery may include parenteral administration (including intravenous, subcutaneous, intrathecal, intraperitoneal, intramuscular, intravascular, or infusion administration). In some embodiments, delivery may include nanoparticles, viral vectors, virus-like particles, liposomes, exosomes, extracellular vesicles, microrobots, microneedles, implants, or combinations thereof. In some cases, delivery may be from a device. In some examples, delivery may be administered by a pump, an infusion pump, or a combination thereof. In some cases, delivery may be by enema, eye drops, nasal spray, ear drops, or any combination thereof. In some cases, delivery may include an inhaler, diffuser, nebulizer, or combination thereof.Delivery can include topical administration (e.g., lotion, cream, patch, gel, spray, drip, liquid formulation, ointment) to the outer surface of a surface, for example, the skin. In some cases, the subject can administer the composition without supervision. In some cases, the subject can administer the composition under the supervision of a medical professional (e.g., a doctor, nurse, physician's assistant, hospital clerk, hospice worker, etc.). In some cases, the medical professional can administer the composition. In some cases, the subject can administer the composition.

[0094] In some embodiments, the administering step may be performed at least about once a day, at least about twice a day, at least about three times a day, at least about four times a day, at least about five times a day, at least about six times a day, or more than at least about six times a day. In some cases, the administering step may be performed daily, weekly, monthly, or as needed. In some embodiments, the administering step may be performed once, twice, three, or four times a day. In some cases, the administering may be performed by the subject (e.g., patient), a healthcare provider, or both.

[0095] Administration or application of the compositions disclosed herein may result in at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48, at least about 49, at least about 50, at least about 51, at least about 52, at least about 53, at least about 54, at least about 55, at least about 56, at least about 57, at least about 58, at least about 59, at least about 60, at least about 61, at least about 62, at least about 63, at least about 64, at least about 65, at least about 66, at least about 67, at least about 68, at least about 69, at least about 70, at least about 71, at least about 72, at least about 73, at least about 74, at least about 75, at least about 76, at least about 77, at least about 78, at least about 79, at least about 80, at least about 81, Also about 82, at least about 83, at least about 84, at least about 85, at least about 86, at least about 87, at least about 88, at least about 89, at least about 90, at least about 91, at least about 92, at least about 93, at least about 94, at least about 95, at least about 96, at least about 97, at least about 98, at least about 99, at least about 100, at least about 150, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800,or for at least about 900 or at least about 1000 continuous or non-continuous days, or for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, The treatment may be administered for a duration of treatment equal to 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 continuous or non-continuous days. In some cases, the treatment duration is from about 1 to about 30 days, from about 2 to about 30 days, from about 3 to about 30 days, from about 4 to about 30 days, from about 5 to about 30 days, from about 6 to about 30 days, from about 7 to about 30 days, from about 8 to about 30 days, from about 9 to about 30 days, from about 10 to about 30 days, from about 11 to about 30 days, from about 12 to about 30 days, from about 13 to about 30 days, from about 14 to about 30 days, from about 15 to about 30 days, from about 16 to about 30 days, from about 17 to about 30 days, from about 18 to about 30 days, from about 19 to about 30 days, from about 20 to about 30 days, from about 21 to about 30 days, from about 22 to about 30 days, from about 23 to about 30 days, from about 24 to about 30 days, from about 25 to about 30 days, from about 26 to about 30 days, from about 27 to about 30 days, from about 28 to about 30 days, from about 29 to about 30 days, from about 31 to about 31 days, from about 32 to about 32 days, from about 33 to about 33 days, from about 34 to about 33 days, from about 35 to about 30 days, from about 36 to about 30 days, from about 37 to about 30 days, from about 38 to about 30 days, from about 39 to about 40 days, from about 41 to about 41 days, from about 42 to about 42 days, from about 43 to about 43 days, from about 44 to about 44 days, from about 45 to about It may be about 30 days, about 19 to about 30 days, about 20 to about 30 days, about 21 to about 30 days, about 22 to about 30 days, about 23 to about 30 days, about 24 to about 30 days, about 25 to about 30 days, about 26 to about 30 days, about 27 to about 30 days, about 28 to about 30 days, about 29 to about 30 days, about 1 to about 90 days, about 30 to about 90 days, about 60 to about 90 days, about 30 to about 180 days, or about 90 to about 190 days.

[0096] The administration or application of the compositions disclosed herein can be carried out for a treatment duration of at least about 1 week, at least about 1 month, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 15 years, at least about 20 years, or for life. Administration can be carried out repeatedly throughout the subject's life, for example, once a month or once a year throughout the subject's life. Administration can be carried out repeatedly for a substantial portion of the subject's life, for example, once a day, once a week, once a month, or once a year for at least about 1 year, 5 years, 10 years, 15 years, 20 years, 25 years, 30 years, or longer.

[0097] The administration or application of the compositions disclosed herein can be performed at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 times in a 24-hour period. In some cases, the administration or application of the compositions disclosed herein can be performed continuously throughout a 24-hour period, for example, when a placement agent can be used for administration. In some cases, the administration or application of the compositions disclosed herein can be performed at least once, at least twice, at least three times, at least four times, at least five times, at least six times, at least seven times, at least eight times, at least nine times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, or at least 21 times per week.In some cases, the administration or application of the compositions disclosed herein is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45 , at least 46, at least 47, at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, at least 60, at least 61, at least 62, at least 63, at least 64, at least 65, at least 66, at least 67, at least 68, at least 69, at least 70, at least 71, at least 72, at least 73, at least 74, at least 75, at least 76, at least 77, at least 78, at least 79, at least 80, at least 81, at least 82, at least 83, at least 84, at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, or more than 90 times. In some cases, the compositions may be administered as a single dose or as divided doses. In some cases, the compositions described herein may be administered at a first time point and a second time point.In some cases, the compositions may be administered such that a first administration may be administered before the other administration by about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 1 day, about 2 days, about 4 days, about 7 days, about 2 weeks, about 4 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year or more difference in administration time.

[0098] In some embodiments, the administering step can be carried out for about 1 day to about 8 days, about 1 week to about 5 weeks, about 1 month to about 12 months, about 1 year to about 3 years, about 3 years to about 10 years, about 10 years to about 50 years, about 25 years to about 100 years, or about 50 years to about 130 years.

[0099] In some embodiments, the compositions may be administered as needed or for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or chronically.

[0100] In some cases, peptide or its derivative or any of its salts can be administered in a pharmaceutical composition that can be in unit dose form.In some examples, the amount of peptide or its derivative or any of its salts can be administered in the range of about 0.0001mg / kg to about 100g / kg of subject body weight; about 0.001mg / kg to about 100g / kg of subject body weight; about 0.01mg / kg to about 10g / kg of subject body weight; about 1mg / kg to about 1g / kg of subject body weight; or about 10mg / kg to about 500mg / kg of subject body weight. In some cases, the dosage of the peptide, derivative thereof, or salt of any of these per subject body weight is 0.0001 gram (g) / kilogram (kg), 0.001 g / kg, 0.01 g / kg, 0.1 g / kg, 0.2 g / kg, 0.3 g / kg, 0.4 g / kg, 0.5 g / kg, 0.6 g / kg, 0.7 g / kg, 0.8 g / kg, 0.9 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg, 10 g / kg, 15 g / kg, 20 g / kg, 25 g / kg, 30 g / kg, 35 g / kg, 40 g / kg, 45 g / kg, 50 ... The dosage may be equivalent to 5g / kg, 60g / kg, 65g / kg, 70g / kg, 75g / kg, 80g / kg, 85g / kg, 90g / kg, 95g / kg, 100g / kg, 200g / kg, 300g / kg, 400g / kg, 500g / kg, 600g / kg, 700g / kg, 800g / kg, 900g / kg or 1000g / kg of the subject's body weight, or about 0.0001 grams (g) / kilogram (kg), about 0.001g / kg, about 0.01g / kg, about 0.1g / kg, about 0.2g / kg, about 0.3g / kg, about 0.4g / kg, about 0.5g / kg, about 0.6g / kg, about 0.7g / kg, about 0.8g / kg, about 0.9g / kg, approximately 1g / kg, approximately 2g / kg, approximately 3g / kg, approximately 4g / kg, approximately 5g / kg, approximately 6g / kg, approximately 7g / kg, approximately 8g / kg, approximately 9g / kg, approximately 10g / kg, approximately 15g / kg, approximately 20g / kg, approximately 2 5g / kg, approximately 30g / kg, approximately 35g / kg, approximately 40g / kg, approximately 45g / kg, approximately 50g / kg, approximately 55g / kg, approximately 60g / kg, approximately 65g / kg, approximately 70g / kg, approximately 75g / kg, approximately 80g / kg, approximately 8 The amount of the saturation agent may be less than 5 g / kg, about 90 g / kg, about 95 g / kg, about 100 g / kg, about 200 g / kg, about 300 g / kg, about 400 g / kg, about 500 g / kg, about 600 g / kg, about 700 g / kg, about 800 g / kg, about 900 g / kg, or about 1000 g / kg of the subject's body weight, or about 0.0001 grams (g) / kilogram (kg), about 0.001 g / kg, about 0.01 g / kg, about 0.1 g / kg, about 0.2 g / kg. kg, approximately 0.3g / kg, approximately 0.4g / kg, approximately 0.5g / kg, approximately 0.6g / kg, approximately 0.7g / kg, approximately 0.8g / kg, approximately 0.9g / kg, approximately 1g / kg, approximately 2g / kg, approximately 3g / kg, approximately 4g / kg, approximately 5g / kg, approximately 6g / kg, approximately 7g / kg, approximately 8g / kg, approximately 9g / kg, approximately 10g / kg, approximately 15g / kg, approximately 20g / kg, approximately 25g / kg, approximately 30g / kg, approximately 35g / kg, approximately 40g / kg, approximately 45g / k g, about 50 g / kg, about 55 g / kg, about 60 g / kg, about 65 g / kg, about 70 g / kg, about 75 g / kg, about 80 g / kg, about 85 g / kg, about 90 g / kg, about 95 g / kg, about 100 g / kg, about 200 g / kg, about 300 g / kg, about 400 g / kg, about 500 g / kg, about 600 g / kg, about 700 g / kg, about 800 g / kg, about 900 g / kg or about 1000 g / kg of the subject's body weight.

[0101] In some cases, the amount of peptide, its derivative, or any salt thereof, which may be a pharmaceutically acceptable salt, administered to a patient may range from 0.00001 mg to 1000 g. In some cases, the amount of peptide, its derivative, or any salt thereof in the composition may range from about 0.005 mg to about 1000 mg. In some cases, the amount of peptide, its derivative, or any salt thereof in the composition may range from 0.0001 g, 0.001 g, 0.01 g, 0.1 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 15 g, 20 g, 25 g, 30 g, 35 g, 40 g, 45 g, 50 g, 55 g, 60 g, 65 g, 70 g, 75 g, 80 g, 85 g, 90 g, 95 g, 100 g, , 200g, 300g, 400g, 500g, 600g, 700g, 800g, 900g or 1000g, or about 0.0001g, about 0.001g, about 0.01g, about 0.1g, about 1g, about 2g, about 3g, about 4g, about 5g, about 6g, about 7g, about 8g, about 9g, about 10g, about 15g, about 20g, about 25g, about 30g, about 35g, about 40g, about 45g, about 50g, about 55g g, about 60 g, about 65 g, about 70 g, about 75 g, about 80 g, about 85 g, about 90 g, about 95 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500 g, about 600 g, about 700 g, about 800 g, about 900 g or about 1000 g, or about 0.0001 g, about 0.001 g, about 0.01 g, about 0.1 g, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g , about 8 g, about 9 g, about 10 g, about 15 g, about 20 g, about 25 g, about 30 g, about 35 g, about 40 g, about 45 g, about 50 g, about 55 g, about 60 g, about 65 g, about 70 g, about 75 g, about 80 g, about 85 g, about 90 g, about 95 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500 g, about 600 g, about 700 g, about 800 g, about 900 g, or about 1000 g. In some cases, the amount of peptide, derivative thereof, or salt of any of these in the composition may be greater than 0.0001 mg, 0.001 mg, 0.01 mg, 0.1mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg , 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31m g, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46 mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61 mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, or 1000mg, or about 0.0001mg, about 0.001mg, about 0.01mg, or about 0.1mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16 mg, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, about 30mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61mg, about 62mg, about 63mg, about 64mg, about 65mg, about 66mg, about 67mg, about 68mg, about 69mg, about 70mg, about 71mg, about 72mg, about 73mg, about 74mg, about 75mg, about 76mg, about 77mg, about 78mg, about 79mg, about 80mg, about 81mg, about 82mg, about 83mg, about 84mg, about 85mg, about 86mg, about 87mg, about 88mg, about 89mg , about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg, or about 0.0001 mg, about 0.001 mg, about 0.01 mg, about 0.1mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg , about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg , about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, About 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, It may be greater than about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some cases, the amount of peptide, derivative, or salt of any of these in the composition may be equal to 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg, may be less than about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, or about 160 mg, or may be more than about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, or about 160 mg. In some cases, the amount of peptide, derivative, or salt of any of these may be between about 0.0001 mg and about 1 mg, between about 0.01 mg and about 1 mg, between about 0.001 mg and about 1 mg, or between about 0.001 mg and about 1 mg.The amount may range from 1 mg to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 160 mg, from about 10 mg to about 100 mg, or from about 100 mg to about 1000 mg. In some cases, the amount of peptide, its derivative, or a salt of either of these in the composition may range from about 0.0001 g to about 1 g, from about 0.01 g to about 1 g, from about 0.1 g to about 1 g, from about 1 g to about 10 g, from about 10 g to about 100 g, or from about 100 g to about 1000 g.

[0102] In some cases, the composition, e.g., pharmaceutical composition, may be in the form of a capsule, tablet, gummy, oil, liquid, tincture, lotion, cream, balm, candy, syrup, food, drink, oil, suppository, or injectable liquid. In some cases, the composition may be in the form of an injectable intravenous liquid, an injectable intramuscular liquid, or a subcutaneous injectable liquid. diagnosis

[0103] In some embodiments, the method may further include diagnosing the subject as having a disease. In some cases, the disease may be a multifactorial neurological disease. In some cases, the disease may include postural instability, gait disturbance, balance problems, loss of bladder control, urinary incontinence, and any combination thereof. In some embodiments, the diagnosing step may include using an in vitro diagnostic method. In some embodiments, the in vitro diagnostic method may be a companion diagnostic method. In some cases, the disease may be mild cognitive impairment or mild dementia. In some cases, the disease may be dementia.

[0104] In some embodiments, diagnosis may include a physical examination, radiological imaging (e.g., imaging modalities), neurological examination, blood, body fluid or tissue tests, hematology tests, clinical chemistry tests, urinalysis tests, antibody tests, or any combination thereof. The diagnostic analyte may be a cytokine, e.g., a pro-inflammatory cytokine or chemokine, or a receptor thereof.

[0105] In some embodiments, diagnosis may include radiological imaging, and radiological imaging may include computed tomography (CT) imaging, X-ray imaging, magnetic resonance imaging (MRI), ultrasound imaging, or any combination thereof. Imaging markers of brain inflammation may be used to support diagnosis or response to treatment. In some cases, diagnosis may include detecting the presence of alpha-synuclein, amyloid beta (Aβ), tau, or any combination thereof using in vitro or in vivo assays. In some cases, synaptic loss may be diagnosed by SVA2 protein imaging in the brain.

[0106] In some aspects, the method may further include diagnosing the subject as having the disease. In some aspects, the diagnosing step may include using an in vitro diagnostic method. In some aspects, the diagnosing step may include using an in vivo diagnostic method. In some aspects, the in vitro diagnostic method may be a companion diagnostic method.

[0107] In some embodiments, the diagnosis may include a physical examination, radiological imaging, blood tests, antibody tests, or any combination thereof. In some embodiments, the diagnosis may include radiological imaging, which may include computed tomography (CT) imaging, X-ray imaging, magnetic resonance imaging (MRI), ultrasound imaging, or any combination thereof. kit

[0108] Also disclosed herein is a kit comprising a pharmaceutical composition at least partially contained in a package (e.g., a container). Also disclosed herein is a method for making a kit comprising a pharmaceutical composition at least partially contained in a package. In some cases, the kit may include a container, such as a metal container, a plastic container, a glass container, or any suitable container. In some cases, the kit may include a peptide disclosed herein and an additional treatment, such as aducanumab, lecanemab, lemternetag, or any combination thereof. In some cases, the kit may include an excipient, a diluent, a carrier, or any combination thereof.

[0109] In some embodiments, the kit may include a peptide disclosed herein in a first container and an additional therapy, such as aducanumab, lecanemab, lemternetag, or any combination thereof, in a second container. In some cases, aducanumab, lecanemab, or lemternetag may be a derivative of any of these, a biosimilar of any of these, or a salt of any of these. Treatment method

[0110] Also disclosed herein are methods of treating a disease or condition, comprising administering a therapeutically effective amount of a pharmaceutical composition, e.g., a peptide disclosed herein. In some embodiments, the compositions and formulations described herein can be used to treat the diseases and conditions disclosed below.

[0111] In some embodiments, the disease is a multifactorial neurological disease. In some examples, the multifactorial neurological disease is mixed dementia. In some cases, mixed dementia may include diseases involving two or more pathogenic proteins, such as alpha-synuclein, tau, and / or amyloid beta. In some cases, the multifactorial neurological disease is Alzheimer's disease with Lewy bodies (LBVAD), Alzheimer's disease-related dementia (ADRD), vascular dementia, or any combination thereof. In some cases, vascular dementia may include subcortical vascular dementia, stroke-related dementia, multi-infarct dementia, mixed dementia, or any combination thereof. In some cases, the multifactorial neurological disease may include vascular disease, alpha-synuclein deposition in the brain, tau deposition in the brain, amyloid beta (Aβ) deposition in the brain, or any combination thereof. In some cases, vascular disease may include reduced blood supply in the brain compared to subjects without vascular disease. In some cases, vascular dementia can include reduced blood supply in the brain compared to subjects without vascular dementia. In some cases, blood supply can be measured by imaging techniques.

[0112] In some cases, the compositions herein can be used to treat multi-infarct dementia (MID). In some cases, MID can include vascular cognitive impairment. In some cases, multi-infarct dementia can occur after repeated small, often "silent" blockages affect blood flow to certain parts of the brain. In some cases, the changes that occur after each blockage may not be obvious, but over time, the combined effects begin to cause symptoms of the disorder. MID typically affects people between the ages of 60 and 75, who have common risk factors such as high blood pressure, diabetes, and smoking. In some cases, amyloid beta can be present in the brains of MID patients and exacerbate vascular pathology. In some cases, the symptoms of multi-infarct dementia can begin suddenly, including confusion or problems with short-term memory, wandering or getting lost in familiar places, walking with rapid shuffling steps, loss of bladder or bowel control, laughing or crying at inappropriate times, difficulty following instructions, and problems with accounting and financial transactions. In some cases, the symptoms and / or pathology of multi-infarct dementia may differ from other dementias, for example, Alzheimer's disease is characterized by memory loss, while Lewy body dementia is characterized by visual hallucinations and Parkinsonian-like symptoms.

[0113] In some embodiments, the compositions and formulations can be used to treat tauopathy. In some cases, the tauopathy can include primary tauopathy. In some cases, the tauopathy can include secondary tauopathy. In some cases, the compositions and formulations can be used to treat progressive supranuclear palsy, frontotemporal lobar degeneration, chronic traumatic encephalopathy. In some embodiments, the compositions and formulations can be used to treat parkinsonism. In some cases, parkinsonism can be a collection of signs and symptoms that are characteristically observed in Parkinson's disease but are not caused by Parkinson's disease. In some cases, parkinsonism is a primary hypokinetic movement disorder that manifests as rigidity, tremor, bradykinesia, or any combination thereof.

[0114] In some embodiments, compositions and preparations can be used to treat mild cognitive impairment and / or mild dementia.In some cases, mild cognitive impairment and / or mild dementia can comprise Alzheimer's disease, mixed dementia, vascular dementia, disease involving amyloid beta, or any combination thereof.In some cases, mild cognitive impairment or mild dementia comprises the deposition of alpha synuclein, tau, amyloid beta, or any combination thereof in the brain.

[0115] In some embodiments, the compositions and formulations may be used to treat early-onset dementia, early-onset dementia, atypical Alzheimer's disease, frontal lobe AD (fvAD), posterior cortical atrophy (PCA), Benson's syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts, corticobasal syndrome, normal pressure hydrocephalus, primary progressive aphasia, progressive supranuclear palsy, Wernicke-Korsakoff syndrome, argyrophilic grain disease, Richardson's syndrome, or any combination thereof.

[0116] In some embodiments, the compositions and formulations can be used to treat Pick's disease, Huntington's disease, leukoencephalopathy, chronic traumatic encephalopathy dementia, diabetes-related cognitive decline, amyotrophic lateral sclerosis, or any combination thereof. In some embodiments, the compositions and formulations can be used to treat liver disease, such as cirrhosis. In some embodiments, the compositions and formulations herein can be used to treat dementia resulting from cirrhosis. In some cases, cirrhosis can include hepatitis, alcohol abuse, non-alcoholic fatty liver disease, or any combination thereof. In some cases, cirrhosis can include stage I, stage II, stage III, or stage IV cirrhosis. In some cases, cirrhosis can be hepatitis C cirrhosis, hepatitis B cirrhosis, alcohol-related liver disease, non-alcoholic fatty liver disease, or any combination thereof. In some cases, the compositions and formulations herein can be used to treat cirrhosis and dementia.

[0117] In some embodiments, the compositions and formulations may be used to treat Alzheimer's disease-related dementia (ADRD), Alzheimer's disease, Parkinson's disease, multiple-etiology dementia, mixed-etiology dementia, mixed dementia, multifactorial dementia, corticobasal degeneration (CBD), cortical atrophy (e.g., cerebral atrophy), posterior cortical atrophy, multiple system atrophy (MSA), frontotemporal degeneration, frontotemporal dementia, vascular dementia, Parkinson's disease dementia, dementia with Lewy bodies (e.g., Lewy body dementia), HIV-associated neurocognitive disorder (HAND), long COVID (e.g., post-COVID), alcohol-related dementia, Creutzfeldt-Jakob disease, prion dementia, Down syndrome, or any combination thereof. In some embodiments, the compositions and formulations may be used to treat transmissible spongiform encephalopathies, such as Creutzfeldt-Jakob disease. In some cases, the transmissible spongiform encephalopathy may include a prion disease. In some cases, the transmissible spongiform encephalopathy may include variant Creutzfeldt-Jakob disease (vCJD), bovine spongiform encephalopathy, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, kuru, or any combination thereof. In some embodiments, the compositions and formulations may be used to treat vascular contribution to cognitive impairment and dementia (VCID). In some cases, long COVID may include difficulty thinking, difficulty concentrating, brain fog, or any combination thereof. In some embodiments, the compositions and formulations may be used to treat macular degeneration. In some cases, the macular degeneration may include age-related macular degeneration. In some cases, the macular degeneration may include dry macular degeneration. In some cases, the macular degeneration may include wet macular degeneration. In some embodiments, the compositions and formulations can be used to treat post-traumatic stress disorder (PTSD), depression, or both. In some cases, depression can include major depressive disorder, persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, depressive disorder due to hypothyroidism or Parkinson's disease, or any combination thereof. In some embodiments, the compositions and formulations can be used to treat PrP CIn some embodiments, the compositions and formulations can be used to treat NOX-dependent pathway-related diseases, excitotoxic glutamate-related diseases, or any combination thereof. In some embodiments, the compositions and formulations can be used to treat NOX-dependent pathway-related diseases or PrP C The compositions and formulations may be used to treat addiction pathway diseases. In some cases, the compositions herein may be used to treat diseases associated with GPCR mGluR5, PirB, or any combination thereof. In some embodiments, the compositions and formulations may be used to treat dementia associated with Lewy bodies and amyloid beta (Aβ). In some embodiments, the compositions and formulations may be used to treat dementia associated with alpha-synuclein and amyloid beta (Aβ). In some embodiments, the compositions and formulations may be used to treat idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD). In some embodiments, the compositions and formulations may be used to treat REM sleep behavior disorder. In some embodiments, the compositions and formulations may be used to treat diseases caused by elevated IL-6. In some cases, diseases caused by elevated IL-6 may include multifactorial neurological diseases.

[0118] In some embodiments, the compositions and formulations can be used to treat hallucinations, sleep disorders, cognitive decline, sleep disorders, ataxia, gait disorders, postural instability, balance problems, tremors, loss of bladder control, urinary incontinence, eye movement disorders, or any combination thereof. In some embodiments, the disease is postural instability. In some cases, hallucinations can include visual hallucinations, auditory hallucinations, olfactory hallucinations, tactile hallucinations, gustatory hallucinations, general somatic hallucinations, or any combination thereof. In some cases, sleep disorders can include rapid eye movement sleep behavior disorder, apnea, prolonged resting, habitual napping, or any combination thereof. In some cases, balance problems can include benign paroxysmal positional vertigo, vertigo, labyrinthitis, Meniere's disease, vestibular neuritis, perilymphatic fistula, Mal de Debarquement Syndrome, or any combination thereof. In some cases, the tremor may include postural tremor, kinetic tremor, intention tremor, task-specific tremor, isometric tremor, essential tremor, dystonic tremor, cerebellar tremor, psychogenic tremor, physiological tremor, enhanced physiological tremor, Parkinson's tremor, orthostatic tremor, or any combination thereof. In some cases, the urinary incontinence may include stress urinary incontinence, urge urinary incontinence, overflow urinary incontinence, functional urinary incontinence, mixed urinary incontinence, or any combination thereof. In some cases, the loss of bladder control includes overactive bladder. In some cases, the eye movement disorder may include strabismus, nystagmus, amblyopia, esotropia, exotropia, hypertropia, or any combination thereof. In some cases, the ataxia may include Friedreich's ataxia, ataxia-telangiectasia, spinocerebellar ataxia, episodic ataxia, acquired ataxia, idiopathic late-onset cerebellar ataxia, degenerative ataxia, hereditary ataxia, or any combination thereof.In some cases, the gait disturbance may include lunging, scissoring, spastic, steppage, or swaying gait, or any combination thereof. In some cases, the postural instability may be due to a neurological disorder, such as Parkinson's disease. In some cases, the postural instability is not due to Parkinson's disease. In some embodiments, the compositions and formulations may be used to treat spastic paraplegia, spasticity, or any combination thereof. In some embodiments, the compositions and formulations may be used to treat behavioral changes, such as inappropriate social behavior, loss of empathy, lack of judgment, loss of inhibition, apathy, blunted affect, obsessive-compulsive behavior, decreased personal hygiene, changes in eating habits (e.g., excessive consumption of sweets and / or carbohydrates), eating objects, or any combination thereof. In some embodiments, the compositions and formulations may be used to treat language problems, such as increased difficulty understanding written or spoken language, difficulty naming objects, hesitant speech, errors in sentence construction, or any combination thereof. In some embodiments, the compositions and formulations may be used to treat movement conditions such as tremors (as described above), rigidity, muscle spasms, muscle cramps, incoordination, difficulty swallowing, muscle weakness, inappropriate laughing, inappropriate crying, falls, difficulty walking, or any combination thereof.

[0119] In some embodiments, the compositions and formulations can be used to treat emotional lability, depression, anxiety, panic attacks, suicidal ideation, or any combination thereof. In some cases, emotional lability can include a range of emotions, such as rage, sadness, shame, panic, fear, emptiness, loneliness, or any combination thereof. In some cases, emotional lability can include emotionally unstable personality disorder. In some cases, depression can include major depressive disorder, bipolar depression, perinatal depression, postpartum depression, persistent depressive disorder, premenstrual dysphoric disorder, psychotic depression, seasonal affective disorder, atypical depression, or any combination thereof. In some cases, anxiety can include generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, agoraphobia, phobia, social anxiety disorder, specific phobia, or any combination thereof. In some cases, panic attacks can include anticipated or unexpected panic attacks. In some cases, suicidal ideation may include active or passive suicidal ideation.

[0120] Also disclosed herein is a method for treating side effects from treatment for dementia.For example, the peptides herein can be used to treat side effects from aducanumab, lecanemab, lemternetag, any of these 44 derivatives, any of these biosimilars, or any of these salts.In some cases, side effects can include cerebral hemorrhage, cerebral swelling, small cerebral hemorrhage, headache, fall, diarrhea, amyloid-related imaging abnormalities (ARIA)-edema (ARIA-E), ARIA-hemosiderosis (ARIA-H) microbleeds, ARIA-H superficial siderosis, dizziness, confusion, delirium, altered mental status, disorientation, hypersensitivity, angioedema, urticaria, immunogenicity, hot flashes, chills, fever, rash, changes in blood pressure, visual changes, joint pain, nausea, vomiting, shortness of breath, rash, body aches, or any combination thereof. Co-therapy

[0121] In some embodiments, the method may further include administering a second treatment to the subject. In some cases, the pharmaceutical composition may further include a second treatment. In some aspects, the second treatment may include carbidopa-levodopa, carbidopa, levodopa, a dopamine agonist, pramipexole, rotigotine, apomorphine, an MAO-B inhibitor, selegiline, rasagiline, safinamide, a catechol O-methyltransferase (COMT) inhibitor, entacapone, opicapone, an anticholinergic, benztropine, trihexyphenidyl, amantadine, an adenosine receptor antagonist, istradefylline, pimavanserin, a derivative of any of these, a salt of any of these, or any combination thereof. In some cases, the second treatment may include deep brain stimulation or surgery.

[0122] In some embodiments, the methods herein can include treating a disease herein in a subject in need thereof. In some cases, the methods can include administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the disease. In some cases, the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, or DAPTA or a salt thereof, wherein the peptide comprises at least five consecutive amino acids or derivatives thereof comprising the general formula: EFGHI, and E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any four of these; F is D-Ser, D-Asp, or D-Asn, or a derivative of any one of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any one of these; H is D-Tyr or a derivative thereof; and II) lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these.

[0123] In some embodiments, the methods herein can include treating a disease herein in a subject in need thereof. In some cases, the methods can include administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the disease. In some cases, the pharmaceutical composition comprises: I) a peptide, a derivative, or a salt thereof, or DAPTA or a salt thereof, wherein the peptide comprises at least five consecutive amino acids or derivatives thereof comprising the general formula: EFGHI, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr or a derivative thereof; and II) aducanumab, a derivative, a biosimilar, or a salt of any of these.

[0124] In some embodiments, the methods herein can include treating a disease herein in a subject in need thereof. In some cases, the methods can include administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the disease. In some cases, the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, or DAPTA or a salt thereof, wherein the peptide comprises at least five consecutive amino acids or derivatives thereof comprising the general formula: EFGHI, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and II) a remterne tag, a derivative thereof, a biosimilar thereof, or a salt of any of these.

[0125] In some embodiments, the method herein may include treating a disease herein in a subject in need thereof. In some cases, the method includes: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least 5 consecutive amino acids or derivatives thereof having the general formula: EFGHI, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative thereof; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative thereof; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D- and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these; and II) administering to a subject a therapeutically effective amount of lecanemab, lemternetag, aducanumab, a derivative of any of these, a biosimilar of any of these, or a salt of any of these to treat a disease. In some cases, the peptide, derivative of any of these, or a salt thereof and lecanemab, lemternetag, aducanumab, a derivative of any of these, a biosimilar of any of these, or a salt of any of these are administered separately.

[0126] In some embodiments, the second treatment may include a cholinesterase inhibitor. In some cases, the cholinesterase inhibitor may include galantamine, rivastigmine, donepezil, any salt thereof, or any combination thereof. In some cases, the second treatment may include aducanumab, a derivative thereof, a biosimilar thereof, or a salt thereof. In some cases, the second treatment may include an N-methyl D-aspartate antagonist, or a salt thereof. In some cases, the N-methyl D-aspartate antagonist may include memantine, or a salt thereof. In some cases, the second treatment may include lecanemab, a derivative thereof, a biosimilar thereof, or a salt thereof. In some cases, the second treatment may include donepezil and memantine, or a salt thereof. In some cases, the second treatment may include remternetag, a derivative thereof, a biosimilar thereof, or a salt thereof.

[0127] In some embodiments, the second treatment may include tetrabenazine, deutetrabenazine, any salt thereof, or any combination thereof. In some embodiments, the second treatment may include an antipsychotic. In some cases, the antipsychotic may include haloperidol, fluphenazine, olanzapine, aripiprazole, any salt thereof, or any combination thereof. In some cases, the second treatment may include amantadine, levetiracetam, clonazepam, any salt thereof, or any combination thereof. In some embodiments, the second treatment may include an antidepressant. In some cases, the antidepressant may include citalopram, escitalopram, fluoxetine, sertraline, any salt thereof, or any combination thereof. In some embodiments, the second treatment may include an antipsychotic 4 drug. In some cases, the antipsychotic may include quetiapine, olanzapine, any salt thereof, or any combination thereof. In some cases, the second treatment may include divalproex, carbamazepine, lamotrigine, any salt thereof, or any combination thereof. In some embodiments, the second treatment may include maraviroc, plerixafor (AMD3100), any salt thereof, or any combination thereof. In some embodiments, the compositions described herein for use in treating diseases may include maraviroc, plerixafor (AMD3100), any salt thereof, or any combination thereof.

[0128] In some embodiments, the second treatment may include hypertension medication, high cholesterol medication, anticoagulant medication, or diabetes medication. In some cases, the second treatment may include aspirin, clopidogrel, niacin, or any combination thereof. In some cases, the high cholesterol medication may include a bile acid sequestrant, a cholesterol absorption inhibitor, a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor, an adenosine triphosphate-citrate lyase (ACL) inhibitor, a medication for treating familial hypercholesterolemia, any salt thereof, or any combination thereof. In some cases, the high cholesterol medication may include a statin or a salt thereof. In some cases, the statin may include atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, rosuvastatin, simvastatin, any salt thereof, or any combination thereof. In some cases, the hypertension medication may include a diuretic. In some cases, the diuretic may include chlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide, metolazone, amiloride, spironolactone, triamterene, bumetanide, furosemide, torsemide, any salt thereof, or any combination thereof. In some cases, the hypertension medication may include a beta-blocker. In some cases, the beta-blocker may include acebutolol, atenolol, betaxolol, bisoprolol, bisoprolol / hydrochlorothiazide, metoprolol, metoprolol tartrate or succinate, nadolol, pindolol, propranolol, sotalol, timolol, any salt thereof, or any combination thereof. In some cases, the hypertension medication may include an angiotensin-converting enzyme (ACE) inhibitor. In some cases, the ACE inhibitor may include benazepril, captopril, enalapril, afosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, a salt of any of these, or any combination thereof.In some cases, the hypertension medication may include an angiotensin II receptor blocker. In some cases, the angiotensin II receptor blocker may include candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan, any salt thereof, or any combination thereof. In some cases, the hypertension medication may include a calcium channel blocker. In some cases, the calcium channel blocker may include amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, any salt thereof, or any combination thereof. In some cases, the hypertension medication may include an alpha-blocker or an alpha-beta-blocker. In some cases, the alpha-blocker or alpha-beta-blocker may include doxazosin, prazosin, terazosin, carvedilol, labetalol, any salt thereof, or any combination thereof. In some cases, the hypertension medication may include a vasodilator, such as hydralazine, minoxidil, any salt thereof, or any combination thereof. In some cases, the hypertension medication may include aliskiren, eplerenone, spironolactone, methyldopa, clonidine, guanfacine, any salt thereof, or any combination thereof. In some cases, the anticoagulant medication may include warfarin, rivaroxaban, dabigatran, apixaban, edoxaban, enoxaparin, fondaparinux, any salt thereof, or any combination thereof. In some cases, diabetes medications may include insulin, tolbutamide, glimepiride, glipizide, glyburide, repaglinide, nateglinide, metformin, acarbose, pioglitazone, rosiglitazone, exenatide, liraglutide, albiglutide, dulaglutide, alogliptin, sitagliptin, saxagliptin, linagliptin, canagliflozin, dapagliflozin, empagliflozin, a salt of any of these, or any combination thereof.In some cases, the insulin may include rapid-acting insulin, short-acting insulin, intermediate-actin insulin, premixed insulin, or long-acting insulin.

[0129] In some embodiments, the second treatment may include psychotherapy, speech therapy, physical therapy, occupational therapy, or any combination thereof.

[0130] In some embodiments, the method may include administering one, two, three, four, five, six, or more than six additional treatments. In some examples, any second treatment disclosed herein may be used as the additional treatment. In some cases, the second or additional treatment may be administered concurrently or continuously with the peptide disclosed herein. For example, lecanemab, a derivative thereof, a biosimilar thereof, or a salt thereof may be administered concurrently or continuously with the peptide disclosed herein. In some cases, lecanemab, a derivative thereof, a biosimilar thereof, or a salt thereof may be included in a pharmaceutical composition together with the peptide disclosed herein. In some cases, lecanemab, a derivative thereof, a biosimilar thereof, or a salt thereof may be included in a pharmaceutical composition separate from the peptide disclosed herein. In another example, aducanumab, a derivative thereof, a biosimilar thereof, or a salt thereof may be administered concurrently or continuously with the peptide disclosed herein. In some cases, aducanumab, its derivatives, biosimilars, or any salts thereof are included in a pharmaceutical composition together with the peptide of the present disclosure.In some cases, aducanumab, its derivatives, biosimilars, or any salts thereof are included in a pharmaceutical composition separate from the peptide of the present disclosure.In another example, lemterne tag, its derivatives, biosimilars, or any salts thereof can be administered simultaneously or continuously with the peptide of the present disclosure.In some cases, lemterne tag, its derivatives, biosimilars, or any salts thereof are included in a pharmaceutical composition together with the peptide of the present disclosure.In some cases, lemterne tag, its derivatives, biosimilars, or any salts thereof are included in a pharmaceutical composition separate from the peptide of the present disclosure.

[0131] In some embodiments, the second or further therapy may be administered as needed or for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or chronically.

[0132] In some embodiments, the second or additional treatment comprises a unit dose of about 500 μg (micrograms) to about 1000 mg, about 10 μg to about 50 μg, about 40 μg to about 90 μg, about 80 μg to about 120 μg, about 100 μg to about 150 μg, about 140 μg to about 190 μg, about 150 μg to about 220 μg, about 200 μg to about 250 μg, about 240 μg to about 300 μg, about 290 μg to about 350 μg, about 340 μg to about 410 μg, about 400 μg to about 450 μg, about 440 μg It may be administered in the range of about 500 μg to about 500 μg, about 500 μg to about 700 μg, about 600 μg to about 900 μg, about 800 μg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 5 mg to about 15 mg, about 12 mg to about 25 mg, about 20 mg to about 50 mg, about 40 mg to about 80 mg, about 70 mg to about 100 mg, about 90 mg to about 150 mg, about 125 mg to about 250 mg, about 200 mg to about 500 mg, about 400 mg to about 750 mg, about 700 mg to about 900 mg, or about 850 mg to about 1000 mg.In some cases, the unit dose ranges are 10 μg, 25 μg, 50 μg, 75 μg, 100 μg, 150 μg, 200 μg, 220 μg, 250 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg, 1000 μg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg g, which may be equivalent to 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg or 25 mg, about 10 μg, about 25 μg, about 50 μg, about 75 μg, about 100 μg, about 150 μg, about 200 μg, about 220 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 550 μg, about 600 μg, about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg, about 900 μg, about 950 μg, about 1000 μg, about 2 mg, about 3 mg g, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg or about 25 mg, or about 10 μg, about 25 μg, about 50 μg, about 75 μg, about 100 μg, about 150 μg, about 200 μg, about 220 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg , about 500 μg, about 550 μg, about 600 μg, about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg, about 900 μg, about 950 μg, about 1000 μg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg or about 25 mg.In some cases, the unit dose range is about 10 μg, about 25 μg, about 50 μg, about 75 μg, about 100 μg, about 150 μg, about 200 μg, about 220 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 550 μg, about 600 μg, about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg, about 900 μg, about 1000 μg, about 1100 μg, about 1200 μg, about 1300 μg, about 1400 μg, about 1500 μg, about 1600 μg, about 1700 μg, about 1800 μg, about 1900 μg, about 2100 μg, about 2200 μg, about 250 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 550 μg, about 600 μg, about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg, about 900 μg, about 1000 μg, about 1500 μg, about 1600 μg, about 1750 μg, about 1800 μg, about 1900 μg, about 2100 μg, about 2200 μg, about 250 μg, about 2500 μg, about 2600 μg, about 27 The amount of the ion exchangeable agent may be less than about 1000 μg, about 950 μg, about 1000 μg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg or about 25 mg.

[0133] In some cases, the second or additional therapy may be administered such that the active ingredient or a pharmaceutically acceptable salt thereof in a unit dose is in the range of about 0.0001 mg / kg to about 1000 g / kg of subject's body weight; about 0.001 mg / kg to about 100 g / kg of subject's body weight; about 0.01 mg / kg to about 10 g / kg of subject's body weight; about 1 mg / kg to about 1 g / kg of subject's body weight; or about 10 mg / kg to about 500 mg / kg of subject's body weight. In some cases, the dosage of the second or additional treatment per subject's body weight is 0.0001 gram (g) / kilogram (kg), 0.001 g / kg, 0.01 g / kg, 0.1 g / kg, 0.2 g / kg, 0.3 g / kg, 0.4 g / kg, 0.5 g / kg, 0.6 g / kg, 0.7 g / kg, 0.8 g / kg, 0.9 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg, 10 g / kg, 15 g / kg, 20 g / kg, 25 g / kg, 30 g / kg, 35 g / kg, 40 g / kg, 45 g / kg, 50 g / kg, 55 g / kg, The dosage may be about 0.0001 grams (g) per kilogram (kg), which may be equivalent to 60g / kg, 65g / kg, 70g / kg, 75g / kg, 80g / kg, 85g / kg, 90g / kg, 95g / kg, 100g / kg, 200g / kg, 300g / kg, 400g / kg, 500g / kg, 600g / kg, 700g / kg, 800g / kg, 900g / kg, or 1000g / kg of the subject's body weight, about 0.0001 grams (g) per kilogram (kg), about 0.001g / kg, about 0.01g / kg, about 0.1g / kg, about 0.2g / kg, about 0.3g / kg, about 0.4g / kg, about 0.5g / kg, about 0.6g / kg, about 0.7g / kg, about 0.8g / kg, or about 0.9g / kg, approximately 1g / kg, approximately 2g / kg, approximately 3g / kg, approximately 4g / kg, approximately 5g / kg, approximately 6g / kg, approximately 7g / kg, approximately 8g / kg, approximately 9g / kg, approximately 10g / kg, approximately 15g / kg, approximately 20g / kg, approximately 2 5g / kg, approximately 30g / kg, approximately 35g / kg, approximately 40g / kg, approximately 45g / kg, approximately 50g / kg, approximately 55g / kg, approximately 60g / kg, approximately 65g / kg, approximately 70g / kg, approximately 75g / kg, approximately 80g / kg, approximately 8 The amount of the saturation agent may be less than 5 g / kg, about 90 g / kg, about 95 g / kg, about 100 g / kg, about 200 g / kg, about 300 g / kg, about 400 g / kg, about 500 g / kg, about 600 g / kg, about 700 g / kg, about 800 g / kg, about 900 g / kg, or about 1000 g / kg of the subject's body weight, or about 0.0001 grams (g) / kilogram (kg), about 0.001 g / kg, about 0.01 g / kg, about 0.1 g / kg, about 0.2 g / kg. kg, approximately 0.3g / kg, approximately 0.4g / kg, approximately 0.5g / kg, approximately 0.6g / kg, approximately 0.7g / kg, approximately 0.8g / kg, approximately 0.9g / kg, approximately 1g / kg, approximately 2g / kg, approximately 3g / kg, approximately 4g / kg, approximately 5g / kg, approximately 6g / kg, approximately 7g / kg, approximately 8g / kg, approximately 9g / kg, approximately 10g / kg, approximately 15g / kg, approximately 20g / kg, approximately 25g / kg, approximately 30g / kg, approximately 35g / kg, approximately 40g / kg, approximately 45g / k g, about 50 g / kg, about 55 g / kg, about 60 g / kg, about 65 g / kg, about 70 g / kg, about 75 g / kg, about 80 g / kg, about 85 g / kg, about 90 g / kg, about 95 g / kg, about 100 g / kg, about 200 g / kg, about 300 g / kg, about 400 g / kg, about 500 g / kg, about 600 g / kg, about 700 g / kg, about 800 g / kg, about 900 g / kg or about 1000 g / kg of the subject's body weight. Numbered Embodiments

[0134] Several methods, compositions, and kits are disclosed herein. Specific exemplary embodiments of these methods, compositions, and kits are disclosed below. The following embodiments list non-limiting permutations of the combinations of features disclosed herein. Other permutations of the combinations of features are also contemplated. In particular, each of these numbered embodiments is contemplated to be dependent on or related to all previous or subsequent numbered embodiments, regardless of their listed order.

[0135] Embodiment 1. A method of treating a multifactorial neurological disease in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the multifactorial neurological disease, wherein the pharmaceutical composition comprises a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five consecutive amino acids having the general formula: EFGHI or a derivative thereof, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; and F is D-Ser, D-Thr, D-Asp, or wherein G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these, and the multifactorial neurological disease is selected from the group consisting of Alzheimer's disease with Lewy bodies (LBVAD), Alzheimer's disease-related dementia (ADRD), and vascular dementia.

[0136] Embodiment 2. The method of embodiment 1, wherein the peptide, derivative, or salt thereof comprises at least 8 consecutive amino acids or derivatives thereof comprising the general formula ABCEFGHI, wherein A is D-Ala or a derivative thereof; B is D-Ser or D-Thr, or a derivative of any of these; C is D-Ser or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these.

[0137] Embodiment 3 The method of embodiment 1 or embodiment 2, wherein the peptide or salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr, or a salt thereof.

[0138] Embodiment 4. The method of any one of embodiments 1 to 3, comprising a derivative of I, wherein I is esterified, glycosylated, or amidated at the C-terminus.

[0139] Embodiment 5 The method of any one of embodiments 1 to 4, wherein the multifactorial neurological disease is vascular dementia.

[0140] Embodiment 6 The method of any one of embodiments 1 to 4, wherein the multifactorial neurological disease is ADRD.

[0141] Embodiment 7 The method of any one of embodiments 1 to 4, wherein the multifactorial neurological disease is LBVAD.

[0142] Embodiment 8. The method of embodiment 5, wherein the vascular dementia comprises subcortical vascular dementia, stroke-related dementia, multi-infarct dementia, mixed dementia, or any combination thereof.

[0143] Embodiment 9. The method of any one of embodiments 1 to 8, wherein the pharmaceutical composition is in unit dose form.

[0144] Embodiment 10. The method of any one of embodiments 1 to 9, wherein the pharmaceutical composition further comprises an excipient, a diluent, a carrier, or a combination thereof.

[0145] Embodiment 11. The method of any one of embodiments 1 to 10, wherein the multifactorial neurological disease comprises a vascular disease, alpha synuclein deposition in the brain, tau deposition in the brain, amyloid beta (Aβ) deposition in the brain, or any combination thereof.

[0146] Embodiment 12 The method of any one of embodiments 11, wherein the vascular disease comprises reduced blood supply in the brain.

[0147] Embodiment 13. The method of any one of embodiments 1 to 12, wherein the administering step is daily, weekly, or monthly.

[0148] Embodiment 14. The method of any one of embodiments 1 to 13, wherein the administering step is once, twice, three times, or four times daily.

[0149] Embodiment 15. The method of any one of embodiments 1 to 14, wherein the pharmaceutical composition is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong.

[0150] Embodiment 16. The method of any one of embodiments 1 to 15, wherein the pharmaceutical composition comprises the peptide, its derivative, or its salt in an amount of about 0.005 mg to about 1000 mg.

[0151] Embodiment 17. The method of any one of embodiments 1 to 16, wherein the pharmaceutical composition is administered by oral, injection, sublingual, buccal, rectal, vaginal, ocular, aural, nasal, internasal, inhalation, dermal, subcutaneous, intramuscular, intravenous, systemic, topical, transdermal route, or any combination thereof.

[0152] Embodiment 18 The method of any one of embodiments 1 to 17, wherein the pharmaceutical composition is formulated for oral administration.

[0153] Embodiment 19. The method of embodiment 18, wherein the pharmaceutical composition is in the form of a pill or liquid.

[0154] Embodiment 20. The method of any one of embodiments 1 to 19, wherein the second treatment is administered concurrently or sequentially.

[0155] Embodiment 21. The method of embodiment 20, wherein the second therapy comprises carbidopa, levodopa, a cholinesterase inhibitor, an N-methyl D-aspartate antagonist, a catechol O-methyltransferase (COMT) inhibitor, an MAO-B inhibitor, aducanumab, lecanemab, lemternetag, a high blood pressure medication, a high cholesterol medication, an anticoagulant medication, a diabetes medication, a salt of any of these, or any combination thereof.

[0156] Embodiment 22 The method of any one of embodiments 20 to 21, wherein the pharmaceutical composition further comprises a second treatment.

[0157] Embodiment 23 The method of any one of embodiments 1 to 22, wherein the subject has been diagnosed with a multifactorial neurological disease prior to administration.

[0158] Embodiment 24. The method of embodiment 23, wherein the diagnosis comprises an in vitro test, a physical examination, an imaging diagnostic method, or a combination thereof.

[0159] Embodiment 25 The method of any one of embodiments 1 to 24, wherein the subject is a mammal.

[0160] Embodiment 26 The method of embodiment 25, wherein the mammal is a human.

[0161] Embodiment 27. A method of treating a disease in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the disease, wherein the pharmaceutical composition comprises a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five consecutive amino acids having the general formula: EFGHI, or a derivative thereof, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; and F is D-Ser, D-Thr, D-Asp, or D-Asp. sn, or any derivative thereof; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or any derivative thereof; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or any derivative thereof, and the disease is selected from the group consisting of postural instability, gait disturbance, balance problems, post-traumatic stress disorder (PTSD), urinary incontinence, and any combination thereof.

[0162] Embodiment 28. The method of embodiment 27, wherein the peptide, its derivative or its salt comprises at least 8 consecutive amino acids or derivatives thereof comprising the general formula ABCEFGHI, wherein A is D-Ala or a derivative thereof; B is D-Ser or D-Thr or a derivative of any of these; C is D-Ser or D-Thr or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys or D-Trp or a derivative of any of these; H is D-Tyr or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly or a derivative of any of these.

[0163] Embodiment 29. The method of embodiment 27 or embodiment 28, wherein the peptide or salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr, or a salt thereof.

[0164] Embodiment 30. The method of any one of embodiments 27 to 29, comprising a derivative of I, wherein I is esterified, glycosylated or amidated at the C-terminus.

[0165] Embodiment 31. The method of any one of embodiments 27 to 30, wherein the disease is postural instability.

[0166] Embodiment 32 The method of any one of embodiments 27 to 30, wherein the disease is a gait disorder.

[0167] Embodiment 33 The method of any one of embodiments 27 to 30, wherein the disease is a balance problem.

[0168] Embodiment 34. The method of any one of embodiments 27 to 30, wherein the disease is PTSD.

[0169] Embodiment 35. The method of any one of embodiments 27 to 30, wherein the disease is urinary incontinence.

[0170] Embodiment 36 The method of any one of embodiments 27 to 35, wherein the pharmaceutical composition is in unit dose form.

[0171] Embodiment 37. The method of any one of embodiments 27 to 36, wherein the pharmaceutical composition further comprises an excipient, a diluent, a carrier, or a combination thereof.

[0172] Embodiment 38. A method for treating a disease in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the disease, wherein the pharmaceutical composition comprises a peptide, a derivative thereof, or a salt thereof, and the peptide comprises i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2 or a derivative thereof, wherein the first amino acid is a D stereoisomer, the remaining amino acids are L stereoisomers, and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr or a derivative thereof, wherein the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof, and the disease is selected from the group consisting of postural instability, gait disturbance, balance problems, post-traumatic stress disorder (PTSD), urinary incontinence, Alzheimer's disease with Lewy bodies (LBVAD), Alzheimer's disease-related dementia (ADRD), vascular dementia, and any combination thereof.

[0173] Embodiment 39. A method for treating mild cognitive impairment or mild dementia in a subject in need thereof, comprising: administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat mild cognitive impairment or mild dementia, wherein the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least 5 consecutive amino acids having the general formula: EFGHI or a derivative thereof, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; and F is D-Ser, D-T and II) a peptide, derivative, or salt thereof, wherein G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, D-Trp, or a derivative of any of these; H is D-Tyr or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these; and II) lecanemab, a derivative, a biosimilar, or a salt of any of these.

[0174] Embodiment 40. The method of embodiment 39, wherein the peptide, its derivative or its salt comprises at least 8 consecutive amino acids or derivatives thereof comprising the general formula ABCEFGHI, wherein A is D-Ala or a derivative thereof; B is D-Ser or D-Thr or a derivative of any of these; C is D-Ser or D-Thr or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys or D-Trp or a derivative of any of these; H is D-Tyr or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly or a derivative of any of these.

[0175] Embodiment 41. The method of embodiment 39 or embodiment 40, wherein the peptide or salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr and D-Thr, or a salt thereof.

[0176] Embodiment 42. The method of any one of embodiments 39 to 41, comprising a derivative of I, wherein I is esterified, glycosylated or amidated at the C-terminus.

[0177] Embodiment 43 The method of any one of embodiments 39 to 42, wherein the mild cognitive impairment or mild dementia is a disease involving amyloid beta (Aβ).

[0178] Embodiment 44 The method of any one of embodiments 39 to 42, wherein the mild cognitive impairment or mild dementia is Alzheimer's disease.

[0179] Embodiment 45. The method of any one of embodiments 39 to 42, wherein the mild cognitive impairment or mild dementia is mixed dementia.

[0180] Embodiment 46 The method of any one of embodiments 39 to 42, wherein the mild cognitive impairment or mild dementia is vascular dementia.

[0181] Embodiment 47. The method of any one of embodiments 39 to 46, wherein the pharmaceutical composition is in unit dose form.

[0182] Embodiment 48. The method of any one of embodiments 39 to 47, wherein the pharmaceutical composition further comprises an excipient, a diluent, a carrier, or a combination thereof.

[0183] Embodiment 49 The method of any one of embodiments 39 to 48, wherein the mild cognitive impairment or mild dementia comprises deposits of alpha synuclein, tau, or both in the brain.

[0184] Embodiment 50. The method of any one of embodiments 39 to 49, wherein the administering step is daily, weekly, or monthly.

[0185] Embodiment 51. The method of any one of embodiments 39 to 50, wherein the administering step is once, twice, three times, or four times daily.

[0186] Embodiment 52. The method of any one of embodiments 39 to 51, wherein the pharmaceutical composition is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong.

[0187] Embodiment 53. The method of any one of embodiments 39 to 52, wherein the pharmaceutical composition comprises the peptide, its derivative, or its salt in an amount of about 0.005 mg to about 1000 mg.

[0188] Embodiment 54. The method of any one of embodiments 39 to 53, wherein the pharmaceutical composition is administered by oral, injection, sublingual, buccal, rectal, vaginal, ocular, aural, nasal, internasal, inhalation, dermal, subcutaneous, intramuscular, intravenous, systemic, topical, transdermal route, or any combination thereof.

[0189] Embodiment 55. The method of any one of embodiments 39 to 54, wherein the pharmaceutical composition is formulated for oral or intravenous administration.

[0190] Embodiment 56. The method of embodiment 55, wherein the pharmaceutical composition is in the form of a pill or liquid.

[0191] Embodiment 57. The method of any one of embodiments 39 to 56, wherein the pharmaceutical composition is in liquid form.

[0192] Embodiment 58. The method of any one of embodiments 39 to 57, wherein the subject has been diagnosed with mild cognitive impairment or mild dementia prior to administration.

[0193] Embodiment 59. The method of embodiment 58, wherein the diagnosis comprises an in vitro test, a physical examination, an imaging diagnostic method, or a combination thereof.

[0194] Embodiment 60 The method of any one of embodiments 39 to 59, wherein the subject is a mammal.

[0195] Embodiment 61 The method of embodiment 60, wherein the mammal is a human.

[0196] Embodiment 62. A method for treating a disease in a subject in need thereof, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition to the subject to treat the disease, wherein the pharmaceutical composition is a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises: i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2 or a derivative thereof, wherein the first amino acid is a D stereoisomer, the remaining amino acids are L stereoisomers, and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr or a derivative thereof, wherein the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof; and lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of them, and the disease is mild cognitive impairment or mild dementia.

[0197] Embodiment 63. I) A peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least 5 consecutive amino acids comprising the general formula: EFGHI, or a derivative thereof, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and II) a pharmaceutical composition comprising lecanemab, aducanumab, lemternetag, a derivative of any of these, a biosimilar of any of these, or a salt of any of these.

[0198] Embodiment 64. The peptide, its derivative or salt thereof, comprises at least 8 consecutive amino acids or derivatives thereof having the general formula ABCEFGHI,

[0199] 64. The pharmaceutical composition of embodiment 63, wherein A is D-Ala or a derivative thereof; B is D-Ser or D-Thr, or a derivative of any of these; C is D-Ser or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these.

[0200] Embodiment 65. The pharmaceutical composition of embodiment 63 or embodiment 64, wherein the peptide or its salt is D-Thr, D-Thr, D-Asn, D-Tyr, or D-Thr, or a salt thereof.

[0201] Embodiment 66. A pharmaceutical composition according to any one of embodiments 63 to 65, comprising a derivative of I, wherein I is esterified, glycosylated or amidated at the C-terminus.

[0202] Embodiment 67. The pharmaceutical composition of any one of embodiments 63 to 66, further comprising an excipient, diluent, carrier, or a combination thereof.

[0203] Embodiment 68. A pharmaceutical composition according to any one of embodiments 63 to 67, comprising a pharmaceutical composition comprising lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these.

[0204] Embodiment 69. A pharmaceutical composition according to any one of embodiments 63 to 67, comprising a pharmaceutical composition comprising aducanumab, a derivative thereof, a biosimilar thereof, or a salt of any of these.

[0205] Embodiment 70. A pharmaceutical composition according to any one of embodiments 63 to 67, comprising a pharmaceutical composition comprising a remterne tag, a derivative thereof, a biosimilar thereof, or a salt of any of these.

[0206] Embodiment 71. A pharmaceutical composition according to any one of embodiments 63 to 70, in unit dose form.

[0207] Embodiment 72. A pharmaceutical composition according to any one of embodiments 63 to 71, comprising the peptide, its derivative or its salt in an amount of from about 0.005 mg to about 1000 mg.

[0208] Embodiment 73. The pharmaceutical composition of any one of embodiments 63 to 72, comprising lecanemab, aducanumab, lemternetag, a derivative thereof, a biosimilar thereof, or a salt of any of these, in an amount of about 1 mg to about 500 mg.

[0209] Embodiment 74. A pharmaceutical composition according to any one of embodiments 63 to 73, comprising lecanemab, aducanumab, lemternetag, a derivative thereof, a biosimilar thereof, or a salt of any of these in an amount of about 10 mg / kg.

[0210] Embodiment 75. The pharmaceutical composition of any one of embodiments 63 to 74, which is formulated for intravenous or oral delivery.

[0211] Embodiment 76. A pharmaceutical composition according to any one of embodiments 63 to 75, in the form of a pill or liquid.

[0212] Embodiment 77. A pharmaceutical composition comprising a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises: i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2 or a derivative thereof, wherein the first amino acid is a D stereoisomer, the remaining amino acids are L stereoisomers, and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr or a derivative thereof, wherein the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof; and lecanemab, aducanumab, lemternetag, a derivative of any of these, a biosimilar of any of these, or a salt of any of these, and, optionally, an excipient, diluent, carrier, or any combination thereof.

[0213] Embodiment 78. A kit comprising the pharmaceutical composition of any one of embodiments 63 to 77 and a container.

[0214] Embodiment 79. I) A peptide, derivative thereof or salt thereof in a first container, wherein the peptide comprises at least five consecutive amino acids or derivatives thereof comprising the general formula: EFGHI, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; and G is D-Thr, D-Ser, D-Asn, D-Arg, D-G H is D-Tyr or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these; or a salt thereof; and II) a kit comprising one or more of lecanemab, aducanumab, lemternetag, a derivative of any of these, a biosimilar of any of these, or a salt of any of these in a second container.

[0215] Embodiment 80. A method for treating dementia in a subject in need thereof, comprising: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least 5 consecutive amino acids or derivatives thereof having the general formula: EFGHI, wherein E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-T H is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys or D-Trp, or a derivative of any of these; H is D-Tyr or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these; and II) a therapeutically effective amount of lecanemab, a derivative thereof, a biosimilar thereof or a salt of any of these to a subject to treat dementia.

[0216] Embodiment 81. The method of embodiment 80, wherein the peptide, its derivative or its salt comprises at least 8 consecutive amino acids or derivatives thereof, comprising the general formula ABCEFGHI, wherein A is D-Ala or a derivative thereof; B is D-Ser or D-Thr, or a derivative of any of these; C is D-Ser or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys or D-Trp, or a derivative of any of these; H is D-Tyr or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these.

[0217] Embodiment 82. The method of embodiment 80 or 81, wherein the peptide, its derivative or its salt is in unit dose form.

[0218] Embodiment 83 The method of any one of embodiments 80 to 82, wherein the lecanemab, its derivative, its biosimilar, or a salt of any of these is in unit dose form.

[0219] Embodiment 84. The method of any one of embodiments 80 to 83, wherein the pharmaceutical composition is administered by oral, injection, sublingual, buccal, rectal, vaginal, ocular, aural, nasal, internasal, inhalation, dermal, subcutaneous, intramuscular, intravenous, systemic, topical, transdermal route, or any combination thereof.

[0220] Embodiment 85. The method of any one of embodiments 80 to 84, wherein the pharmaceutical composition is formulated for intravenous or oral administration.

[0221] Embodiment 86. The method of any one of embodiments 80 to 85, wherein the lecanemab, its derivative, its biosimilar or a salt of any of these is in the form of a pill or liquid, and the peptide, its derivative or a salt thereof is in the form of a pill or liquid.

[0222] Embodiment 87. The method of any one of embodiments 80 to 86, wherein lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these is administered concurrently or sequentially with the peptide, a derivative thereof, or a salt thereof.

[0223] Embodiment 88. The method of any one of embodiments 80 to 87, wherein the peptide, its derivative or its salt is in an amount of about 0.005 mg to about 1000 mg.

[0224] Embodiment 89. The method of any one of embodiments 80 to 88, wherein the lecanemab, its derivative, its biosimilar, or a salt of any of these is in an amount of about 1 mg to about 500 mg.

[0225] Embodiment 90. The method of any one of embodiments 80 to 89, wherein lecanemab, its derivative, its biosimilar, or a salt of any of them is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong.

[0226] Embodiment 91. The method of any one of embodiments 80 to 90, wherein the peptide, its derivative or salt thereof is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong.

[0227] Embodiment 92. The method of any one of embodiments 80 to 91, wherein the administration of the peptide, its derivative or its salt is daily, weekly or monthly.

[0228] Embodiment 93 The method of any one of embodiments 80 to 92, wherein the administration of lecanemab, its derivative, its biosimilar, or a salt of any of these is daily, weekly, or monthly. [Example]

[0229] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure. Example 1

[0230] The synthetic process used to prepare RAP-103 acetate involves the following steps according to the Merrifield FMOC synthesis method SPPS (Solid Phase Peptide Synthesis) using common commercially available coupling reagents, resins and deblocking reagents:

[0231] Step 1: Peptide synthesis: Solid phase peptide synthesis (SPPS) of protected peptides

[0232] Step 2: Cleavage and deprotection: Trifluoroacetic acid (TFA) cleavage of the protecting groups from the peptide and cleavage of the peptide from the resin

[0233] Step 3: Purification and in-process lyophilization: Peptide purification and in-process lyophilization

[0234] Step 4: Ion exchange (salt exchange) and final lyophilization: Ion exchange (salt exchange) of TFA to acetate and final lyophilization.

[0235] A schematic of the synthesis method for RAP-103 is shown in Figure 2 and includes the following steps: 2-chlorotrityl chloride resin SPPS, cleavage and deprotection, purification and in-process lyophilization, ion exchange (salt exchange), and final lyophilization. The following components are the equipment and components used in the synthesis: reaction vessel

[0236] The synthesis was carried out at room temperature in a custom-designed glass vessel containing a coarse-porosity fritted disc at the bottom. The size of the reactor depended on the amount of polymer used in the synthesis. The reactor was designed to facilitate the addition of amino acid derivatives, solvents, and reagents as needed. The reaction vessel was equipped with a mechanical stirrer to allow efficient peptide-resin mixing. None of the equipment or instrument components utilized in the synthesis process were composed of materials that could cause product adulteration. Solid support: 2-chlorotrityl chloride resin was used in the synthesis. Protected Amino Acids

[0237] In solid-phase peptide synthesis, reactive functional groups of amino acids were protected to avoid undesired side reactions. Protecting groups were of two natures: acid-labile and base-labile. Base-labile protecting groups were used to block the α-amino group during the coupling reaction and were removed in the deblocking step to allow the introduction of the next amino acid in the sequence. Fmoc (9-fluorenylmethyloxycarbonyl) was used as the base-labile α-amino protecting group. Acid-labile protecting groups were used to protect the side-chain reactive functional groups of amino acids during synthesis, which must be resistant to the deblocking mixture (20% piperidine in DMF). After peptide synthesis, these protecting groups were removed with strong acid (aqueous trifluoroacetic acid with scavengers). Acid-labile protecting groups for this process are t-butyl (tBu) and trityl (Trt).

[0238] The following amino acids were used in the synthesis of RAP-103 acetate: Fmoc-D-Tyr(tBu)-OH, Fmoc-D-Asn(Trt)-OH, and Fmoc-D-Thr(tBu)-OH.

[0239] Step 1: Peptide synthesis:

[0240] Resin loading—2-chlorotrityl chloride (CTC) resin was activated with acetyl chloride (AcCl) and then treated with Fmoc-D-Thr(tBu)-OH and diisopropylethylamine (DIPEA), followed by a solution mixture of dichloromethane (DCM), methanol (MeOH), and diisopropylethylamine (DIPEA).

[0241] Solid phase peptide synthesis according to the Fmoc strategy can be divided into the following steps: Fmoc deprotection:

[0242] During the deprotection step, the base-labile temporary protecting group (Fmoc) was cleaved from the α-amino function of the N-terminal amino acid on the growing peptide chain by treating the resin twice with a solution of 20% piperidine in dimethylformamide (DMF). Two deprotection treatments were performed, with the first deprotection stirring time being approximately 10 minutes and the second deprotection stirring time being approximately 30 minutes. Wash Cycle:

[0243] Washing steps were performed to remove excess reagents used in the preceding step. The solvents selected for each step were carefully chosen to ensure that excess reagents were removed as efficiently as possible without the risk of introducing undesired side reactions. The duration of each wash step was timed to allow thorough contact of the peptide-resin with the solvent and provide sufficient time for reagent extraction. DMF was used after deblocking as well as after coupling because it has excellent solubilizing and swelling properties for all reagents used in the coupling step. Conversely, isopropanol (IPA) was utilized after the coupling reaction because it shrinks the resin and also aids in the removal of excess solvent and reagents. Activation and Coupling:

[0244] During the activation and coupling step, the deprotected α-amino group is acylated with the next activated amino acid in the sequence. The reagents used to achieve acylation were carefully selected to yield optimal reaction conditions and easy removal of excess reagents at the end of the coupling reaction.

[0245] Activation of Fmoc-Tyr(tBu)-OH was carried out by dissolving the protected amino acid in the coupling reagents 1-H-benzotriazolium, 1-[bis(dimethylamino)methylene]-5-chloro-tetrafluoroborate(1-),3-oxide (TCTU) and diisopropylethylamine (DIPEA) in DMF. The solution of the activated amino acid was then added to the peptide-resin. The mixture was stirred at room temperature for 20 minutes, and then DIPEA in DMF was added thereto. The mixture was allowed to react for approximately 160 minutes.

[0246] Activation of the remaining amino acid derivatives was carried out by dissolving the protected amino acids in the coupling reagent Oxima (Oxymapure) and 1,3-diisopropylcarbodiimide (DIC) in DMF. The solution of the activated amino acids was then added to the peptide-resin. The suspension was stirred at room temperature for 20 minutes, after which a second aliquot of DIC was added to the reaction mixture. The mixture was stirred and allowed to react for approximately 160 minutes. Recoupling and acetylation:

[0247] After a minimum reaction time of 1 hour, the presence of remaining unreacted amino groups was monitored using the qualitative TNBS (trinitrobenzene sulfonic acid) test or the ninhydrin test. The TNBS test is performed by adding a few drops of trinitrobenzene sulfonic acid to the peptide-resin in a test tube sample and allowing the two to react for 3 minutes. The presence of free amino groups causes a colored reaction; orange-colored beads indicate incomplete coupling and the presence of unreacted amines. Similarly, for the ninhydrin test, a few drops of ninhydrin reagent were added to the peptide-resin sample in a small test tube. Blue-stained resin beads indicate the presence of unreacted amines.

[0248] If any residual amino groups were detected by any of the above tests, the coupling reaction was repeated using half the amount of amino acid derivative required for the initial coupling reaction. A ninhydrin test was performed after each coupling to visualize the presence of unreacted α-amino functionality. No recoupling reactions were required during the production of RAP-103 acetate lot 1000008388.

[0249] If unreacted α-amino functionalities were still present after recoupling, they were acetylated using acetic anhydride to avoid undesired deletion sequences in the next cycle. An acetylation reaction was not required during the production of RAP-103 acetate lot 1000008388.

[0250] After coupling of the last amino acid in the sequence was complete, the peptide-resin was washed extensively with isopropyl alcohol (IPA) and weighed. Step 2: Cleavage and deprotection:

[0251] During the cleavage procedure, the peptide was removed from the resin with concomitant cleavage of the side-chain protecting groups. This was achieved by treatment of the peptide-resin with trifluoroacetic acid (TFA) and trifluoroethanol (TFE) in TFA and dichloromethane (DCM) in the presence of scavengers. Triethylsilane (TES) and water acted as scavengers and were used to provide a protonated cleavage environment, which subsequently yielded a higher quality crude product. After the cleavage procedure, the peptide was precipitated using cold isopropyl ether (IPE) and filtered using a Buchner funnel equipped with filter paper. The precipitated peptide was washed with IPE and dried at room temperature in a vacuum oven. After drying was complete, the crude peptide was weighed and recorded. Step 3: Purification and in-process lyophilization:

[0252] Purification is carried out by preparative reversed-phase high performance chromatography (RP-HPLC). Device:

[0253] The purification device was based on the principle of compression, where the chromatographic support was packed into a compression module. A constant pressure was applied to the column. Different column sizes were available, and the choice of which to use was based on the amount of material to be processed. The solvent was delivered via a pump, and the required gradient was created manually or using an automatic gradient maker. Support properties:

[0254] Purification of the crude peptides was achieved by preparative HPLC using reversed-phase materials as supports. The reversed-phase materials consist of silica gel coated with aliphatic chains; the remaining free silanol groups are end-capped to avoid undesired ionic interactions / bonding between the mixture to be purified and the support. Separation was based on hydrophobic interactions between the peptides and the resin support. The use of different buffer systems in subsequent purification steps also improved the separation efficiency. Purification using an aqueous TFA / acetonitrile buffer gradient:

[0255] A typical purification run consisted of three steps: equilibrating the Luna C18 column, loading and eluting the product, and washing the column to prepare it for the next run. Equilibration of the column was achieved by washing it with aqueous TFA. The crude peptide was dissolved in aqueous TFA, filtered, and then loaded onto the column. Product elution was achieved using a gradient of aqueous TFA and acetonitrile (CH3CN) buffer solutions. After product elution, the column was washed with aqueous acetonitrile to check for the absence of product. The quality of each different fraction collected as the peptide eluted from the column was monitored by analytical HPLC. Fractions that met the acceptance criteria for purity were pooled as a main pool and carried on to the next step. In-process freeze-drying:

[0256] The main pool of product from the TFA purification step was filtered through a 0.45 μm membrane filter and lyophilized.

[0257] Step 4: Ion exchange (salt exchange) and final freeze-drying:

[0258] Ion exchange (salt exchange):

[0259] Ion exchange, also known as the salt exchange step, converts the peptide to the required salt form (acetate). Preparation of the ion exchange resin (AMBERLITE IRN 78) was achieved by sequentially washing the resin with methanol (MeOH), USP water, 2N sodium hydroxide (NaOH), USP water, acetic acid (AcOH - 20% in USP water), and USP water until neutral. The peptide from the lyophilization step in the manufacturing process was dissolved in USP water and loaded onto the previously prepared ion exchange resin. After 2 hours of circulation, the peptide solution was eluted and collected in a fraction collection bottle. After analysis by HPLC, all fractions that met the established criteria were collected and pooled together. Final freeze-drying

[0260] The main pool of peptide solution from the ion exchange (salt exchange) step was filtered through a 0.45 μm membrane filtration cap, and the resulting filtrate (peptide solution) was lyophilized to obtain bulk RAP-103 acetate peptide. Example 2

[0261] A female subject in her mid-80s was diagnosed with advanced dementia and postural instability, with an estimated life expectancy of approximately 5 years. The advanced dementia was likely to be dementia associated with Lewy bodies and amyloid beta (Aβ). A peptide multi-chemokine receptor antagonist of the present disclosure was administered to the female subject by daily nasal spray administration for 18 months. After administration, the female subject had improved cognitive function and increased postural stability, and survived for 10 years. Administration of the peptide of the present disclosure surprisingly and unexpectedly increased the female subject's life span (by approximately 5 years) and improved the symptoms of advanced dementia. Therefore, the peptide of the present disclosure is effective for treating dementia associated with Lewy bodies and amyloid beta (Aβ). Example 3

[0262] Animals (rats, guinea pigs, and non-human primates (Rhesus macaques; Macaca mulatta)) were administered RAP-103 via oral gavage and IV routes. Blood samples were collected into K2EDTA MAP tubes, placed on ice, processed to plasma within 60 minutes of collection (in a centrifuge set to maintain 2000 g for 15 minutes at 4°C), and stored in a freezer set to maintain -80°C until analysis. Samples were analyzed using a qualified high-performance liquid chromatography (HPLC) with mass spectrometry (MS / MS) detection to determine RAP-103 concentrations. Administration of the dosage form to animals demonstrates that RAP-103 rapidly entered the brain (rats and guinea pigs) via IV or oral gavage administration and persisted at therapeutic levels for at least 24 hours, as shown in Figure 1A. RAP-103 preferentially enters the brain compared to plasma levels. In non-human primates (rhesus monkeys), RAP-103 was administered by intravenous bolus injection at 1 mg / kg once on day 1, and plasma levels were determined. Cmax and AUC 0-T were comparable in male and female monkeys. RAP-103 was highly bioavailable at the 1 mg / kg dose level, with absolute bioavailability values ​​of 88% and 89% in female and male monkeys. Drug in plasma after a single IV dose (1 mg / kg) was still measurable at expected therapeutic levels 96 hours after dosing in non-human primates, as shown in Figure 1B. No RAP-103-related changes were noted in clinical observations or body weight over a 7-day period, indicating a lack of acute toxicity. Example 4

[0263] The subject is diagnosed with advanced mixed dementia.The peptide (R-103) described herein is administered to the subject via capsule.The capsule contains excipients to enhance stability, dissolution and absorption.An enteric coating is applied to control delivery and maintain therapeutic levels.The subject has increased memory retention after administration of the peptide compared to memory retention before administration, as determined by cognitive assessment. Example 5

[0264] A 59-year-old female subject was diagnosed with human retroviral neurocognitive disorder. The patient also suffered from a 9-year history of progressive spastic paraplegia and incontinence. The peptide multi-chemokine receptor antagonist (DAPTA) of the present disclosure was administered at a dose of approximately 6 mg per day for 10 weeks. After two weeks of administration, the female subject experienced improvements in urinary incontinence and gait, which continued until the end of the 10th week. Initially, it took 65 seconds to walk 10 meters, but by the end of the 10th week, it took 15 seconds. Four weeks after treatment was stopped, the stiffness and difficulty walking returned. Administration of the peptide of the present disclosure surprisingly and unexpectedly improved spasticity and urinary incontinence. Example 6

[0265] The subject is diagnosed with mild cognitive impairment.The peptide (for example, R-103) and lecanemab described herein are administered to the subject to treat cognitive impairment.When the subject is determined by cognitive assessment, after the administration of the peptide and lecanemab, the memory retention is increased compared with the memory retention before administration.In addition, this peptide reduces the side effect of lecanemab.For example, R-103 reduces the side effect of cerebral hemorrhage and / or cerebral swelling associated with lecanemab. Example 7

[0266] The subject is diagnosed with dementia.The peptide (for example, R-103) and aducanumab described herein are administered to the subject to treat dementia.When the subject is determined by cognitive assessment, after the administration of the peptide and aducanumab, the memory retention is increased compared with the memory retention before administration.In addition, this peptide reduces the side effects of aducanumab.For example, R-103 reduces the side effects of cerebral hemorrhage and / or cerebral swelling associated with aducanumab. Example 8

[0267] The subject is diagnosed with Alzheimer's disease.The peptide (for example, R-103) and Remterne Tag described herein are administered to the subject to treat Alzheimer's disease.When the subject is determined by cognitive assessment, after administration of the peptide and Remterne Tag, memory retention is increased compared to memory retention before administration.In addition, this peptide reduces the side effects of Remterne Tag.For example, R-103 reduces the side effects of cerebral hemorrhage and / or cerebral swelling associated with Remterne Tag. Example 9

[0268] Rodent hippocampal neuron cultures and human neurons derived from WTC-11 iPSCs possessed active glutamatergic synapses. Both rodent and human neuronal cultures were grown to maturity in glia-conditioned medium in 24-well glass-bottom plates and used to assess the ability of RAP-103 to protect against spine and synapse loss caused by prolonged (5-day) Aβd / t treatment. MAP2-immunolabeled dendrites with associated PSD95-stained postsynaptic densities are shown as overlays of mouse neurons in Figure 3B. While PSD95 puncta are present within dendrites (see Figures 3A-3B), many dendrites were weakly immunolabeled for MAP2 and disappeared on the images due to the increased transparency required for the construction of these overlays. Spine processes contained MAP2 and most had associated PSD95 labeling, although a few PSD95 puncta appeared along dendrites without underlying MAP2 immunolabeling. Cultures treated with Aβd / t for 5 days, in which PSD95 puncta were normalized to MAP2 area, showed a significant reduction in spines, as shown in Figure 3D, which did not occur in the presence of RAP-103. These results indicate that RAP-103 inhibits Aβd / t-induced dendritic spine and synapse loss in neuronal cultures.

[0269] Synapses (directly apposed or overlapping VGLUT / PSD95 immunolabeling) were quantified in mouse neuron cultures and normalized to MAP2 area to correct for different neurite densities within each field. Synapses were also quantified in human neurons. Cultures were fixed at day 55 and immunolabeled for VGLUT / PSD95 for synapse and spine quantification. Figure 4A shows a human neuron at day 55 immunolabeled for VGLUT and PSD95; the enlarged boxed area is shown in the inset. Figure 4B shows that treatment with Aβd / t and RAP-103 increased the number of synapses per field, comparable to that of the control. In contrast, treatment with Aβd / t alone decreased the number of synapses per field. Similar results were observed for dendritic spines per field (Figure 4B). Example 10

[0270] To test for the reversal of cofilin rod formation, mouse hippocampal neurons were treated with Aβ (1 nM) to induce rod formation. Cells were incubated overnight and then treated with 0.1 nM RAP-103 or 50 nM AMD3100 (a known CXCR4 receptor antagonist). Rods were imaged at 4-minute intervals by fluorescence microscopy. Representative images are shown in Figure 5A, which demonstrate the elimination of preformed rods throughout the treatment period. Figure 5B shows the percent reduction in initial rod area after treatment with RAP-103 or AMD3100. RAP-103 was able to induce rod disassembly more rapidly than AMD3100 and at a concentration 500-fold lower than AMD3100. Figures 5A-5B show that rod formation was reversed during RAP-103 treatment. Example 11

[0271] To test for the prevention of memory impairment, RAP-103 was administered to an alpha-synuclein animal model (Thy1-aSyn mice). Thy1-aSyn mice, which overexpress human alpha-synuclein under the Thy1 promoter, were tested for memory impairment in the Morris water maze assay (as seen in Figures 6A-6D) compared with healthy control mice. Both types of mice were treated with RAP-103 or vehicle control. Figure 6B shows that the total distance spent in the target (%) in RAP-103-treated Thy1-aSyn mice was comparable to that in control mice (WT and R103-treated WT). In contrast, Thy1-aSyn mice and vehicle control-treated mice had significantly reduced distance spent in the target. Similar results were seen for time spent in the target and target crossing (Figures 6C-6D). These results indicate that RAP-103-treated Thy1-aSyn mice were able to maintain their ability to remember the platform location compared with vehicle-treated Thy1-aSyn mice, suggesting that RAP-103 can be used to enhance memory in diseases involving alpha-synuclein. Example 12

[0272] To determine whether rod inhibition by RAP-peptide could be acting downstream of the receptor by directly targeting cofilin-actin interactions, we tested the ability of RAP-310 to inhibit rods induced by excitotoxic concentrations of glutamate via AMPA receptors. As shown in Figure 7A, the RAP peptide completely inhibited Aβd / t-induced rods but not glutamate-induced rods. To determine whether RAP-103 inhibited rods induced by other ligands and well-characterized receptors in human neurons, rods were induced with the cytokine interleukin 6 (IL-6), as shown in Figure 7B. Similar to Aβd / t, RAP-103 inhibited rod formation with an EC50 of approximately 0.1 pM. This data indicates that the peptides herein can be used to treat IL-6-associated diseases, such as multifactorial neurological disorders. Example 13

[0273] To determine whether RAP-103 can reduce alpha-synuclein-induced rod formation in neurons, hippocampal neurons were exposed to PBS (control) or 1 μg / ml alpha-synuclein preformed fibrils (PFFs) and HO control or RAP-103 treatment (50 pM) for 24 hours. Results for the percentage of rod-bearing hippocampal neurons (fold change compared to the treated control) after 7 days of in vitro growth (DIV7) showed that RAP-103 treatment in alpha-synuclein-treated cells reduced the number of rod-bearing neurons, which was comparable to that of control-treated cells, as shown in Figure 8. Similarly, after 14 days of in vitro growth (DIV14), cells treated with alpha-synuclein and RAP-103 showed a reduced rod index compared to cells treated with alpha-synuclein alone. The rod index of RAP-103 and alpha-synuclein-treated cells was comparable to that of PBS-treated control cells. These results indicate that RAP-103 can reduce alpha-synuclein-induced rod formation in neurons. Example 14

[0274] RAP-103 and RAP-310 were tested to determine the concentrations at which they inhibited Aβd / t-induced rod formation. As shown in Figures 9A-9D, rodent and human neurons were dosed with Aβd / t along with RAP-103. Rod quantification in DIV6 mouse hippocampal neurons is shown in Figures 9A and 9B. Rod quantification in day 55 human neurons is shown in Figures 9C and 9D. Cells were treated with Aβd / t for 24 hours along with the indicated concentrations of RAP-103 (Figures 9A and 9C) or RAP-310 (Figures 9B and 9D). Figure 9A shows that RAP-103 inhibited rod formation in mouse hippocampal neurons at a dose of approximately 1 pM. Figure 9B shows that RAP-310 inhibited rod formation in mouse hippocampal neurons at doses ranging from approximately 0.33 pM to approximately 1 pM. Figure 9C shows that RAP-103 inhibited rod formation in human neurons at a dose of approximately 0.1 pM. Figure 9D shows that RAP-310 inhibited rod formation in human neurons at a dose of approximately 0.1 pM. Both RAP peptides had nearly similar rod-inhibitory activity and were approximately 10-fold more effective at blocking rod formation in human neurons than in mouse neurons. The EC50 values ​​for Aβd / t-induced rod inhibition were estimated from semilogarithmic plots of these data to be approximately 1 pM in mouse hippocampal neurons and approximately 0.1 pM in human neurons. Example 15

[0275] RAP-103 was tested for the inhibition of rods induced by other initiators. Figure 10A shows that rod formation induced by adenovirus-mediated overexpression of PrPc in rat hippocampal neurons infected with 100 moi of AdPrPc on DIV2, treated with RAP-103 [50 pM] either simultaneously (day 4) or on DIV5 (day 1), and fixed and immunolabeled on DIV6 was prevented (day 4) or reversed (day 1) by RAP-103 treatment. Figure 10B shows that rod formation induced in human neurons treated with 500 pM of dual tropic gp120 on day 54 and fixed on day 55 was inhibited by RAP-103 [10 pM]. These results indicate that RAP-103 can prevent and / or reverse rod formation induced by different initiators. Example 16

[0276] RAP-103 was tested for inhibition of synergistic TNF-alpha release by amyloid beta (Aβ) and alpha-synuclein (α-Syn). Cultured THP.1 human monocytes (cultured in 24-well trays at 300,000 cells per well) were treated with low doses of preformed fibrils (PFFs) of Aβ and / or α-Syn (1 μg / ml, alone or in combination) in the presence of γIFN 10 ng / ml for 48 hours at 37°C, and TNFα release in the supernatant was determined by multiplex-luminex assay. Controls included γIFN, RAP-103 alone, and medium alone. The results of this experiment are shown in Figure 11. The combination of Aβ and α-Syn elicited a synergistic increase in TNFα release (59%; ***P=0.002). RAP-103 reduced the increase in TNFα release caused by combined Aβ and α-Syn by approximately 70%, to levels below those of Aβ alone. RAP-103 itself did not induce TNFα release. Thus, surprisingly, RAP-103 was effective in reducing TNFα release caused by the combination of Aβ and α-Syn used herein as a model of mixed dementia in humans. Activation of TNFα release was specific to Aβ and α-Syn PFFs and not by the costimulator γIFN. This example demonstrates that α-Syn synergistically enhances Aβ fiber-mediated TNFα release, a mediator of neuronal damage and synaptic loss that subsequently causes enhanced pathological effects in humans. Unexpectedly, RAP-103 blocks TNFα release driven by combined Aβ and α-Syn fibers, and this effect treats multifactorial neurological diseases. Data in Figure 11 are presented as mean fluorescence intensity (MFI) of supernatants diluted 1 / 10. Comparisons were by unpaired t-test using Prism GraphPad. ** P = .01; * P = .03, *** P < .002, ns = not significant.

[0277] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein can be used in carrying out the methods presented in this disclosure. It is intended that the following claims define the scope of the disclosure, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. A method of treating a multifactorial neurological disease in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the multifactorial neurological disease, wherein the pharmaceutical composition comprises a peptide, a derivative thereof or a salt thereof, wherein the peptide comprises at least 5 consecutive amino acids having the general formula: E-F-G-H-I or a derivative thereof; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these; The method, wherein the multifactorial neurological disease comprises Lewy body variant of Alzheimer's disease (LBVAD) or vascular dementia.

2. the peptide, the derivative thereof, or the salt thereof comprises at least 8 consecutive amino acids having the general formula ABCEFGHI or a derivative thereof; A is D-Ala, or a derivative thereof; B is D-Ser or D-Thr, or a derivative of either of these; C is D-Ser or D-Thr, or a derivative of either of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these. The method of claim 1.

3. 2. The method of claim 1, wherein the peptide or the salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr, or a salt thereof.

4. 2. The method of claim 1, comprising the derivative of I, wherein I is esterified, glycosylated, or amidated at the C-terminus.

5. 2. The method of claim 1, wherein the multifactorial neurological disease is vascular dementia.

6. 10. The method of claim 1, wherein the administering step is daily.

7. 2. The method of claim 1, wherein the multifactorial neurological disease is the LBVAD.

8. 6. The method of claim 5, wherein the vascular dementia comprises subcortical vascular dementia or multi-infarct dementia.

9. The method of claim 1 , wherein the pharmaceutical composition is in a unit dose form.

10. 10. The method of claim 1, wherein the pharmaceutical composition further comprises an excipient, a diluent, a carrier, or a combination thereof.

11. The method of claim 1 , wherein the pharmaceutical composition further comprises an excipient.

12. The method of claim 1 , wherein the pharmaceutical composition further comprises a carrier.

13. 10. The method of claim 1, wherein the administering step is weekly or monthly.

14. 10. The method of claim 1, wherein the administering step is once, twice, three times, or four times daily.

15. 10. The method of claim 1, wherein the pharmaceutical composition is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong.

16. 10. The method of claim 1, wherein the pharmaceutical composition comprises the peptide, the derivative thereof, or the salt thereof in an amount of about 0.005 mg to about 1000 mg.

17. 10. The method of claim 1, wherein the pharmaceutical composition is administered by oral, injection, sublingual, buccal, rectal, vaginal, ocular, aural, nasal, internasal, inhalation, dermal, subcutaneous, intramuscular, intravenous, systemic, topical, transdermal route, or any combination thereof.

18. 10. The method of claim 1, wherein the pharmaceutical composition is formulated for oral administration.

19. 19. The method of claim 18, wherein the pharmaceutical composition is in the form of a pill or liquid.

20. 10. The method of claim 1, wherein the second treatment is administered concurrently or sequentially.

21. 21. The method of claim 20, wherein the second therapy comprises carbidopa, levodopa, a cholinesterase inhibitor, an N-methyl D-aspartate antagonist, a catechol O-methyltransferase (COMT) inhibitor, an MAO-B inhibitor, aducanumab, lecanemab, lemternetag, a high blood pressure medication, a high cholesterol medication, an anticoagulant medication, a diabetes medication, a salt of any of these, or any combination thereof.

22. 21. The method of claim 20, wherein the pharmaceutical composition further comprises the second treatment.

23. 10. The method of claim 1, wherein the subject has been diagnosed with the multifactorial neurological disease prior to the administration.

24. 24. The method of claim 23, wherein the diagnosis comprises an in vitro test, a physical examination, an imaging diagnostic method, or a combination thereof.

25. The method of claim 1 , wherein the subject is a mammal.

26. 26. The method of claim 25, wherein the mammal is a human.

27. 1. A method of treating a disease in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the disease, wherein the pharmaceutical composition comprises a peptide, a derivative thereof or a salt thereof, and the peptide comprises at least 5 consecutive amino acids having the general formula: E-F-G-H-I or a derivative thereof; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these; The disorder is selected from the group consisting of postural instability, gait disturbances, balance problems, post-traumatic stress disorder (PTSD), urinary incontinence, and any combination thereof. method.

28. the peptide, the derivative thereof, or the salt thereof comprises at least 8 consecutive amino acids having the general formula ABCEFGHI or a derivative thereof; A is D-Ala, or a derivative thereof; B is D-Ser or D-Thr, or a derivative of either of these; C is D-Ser or D-Thr, or a derivative of either of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these.

28. The method of claim 27.

29. 28. The method of claim 27, wherein the peptide or the salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr and D-Thr, or a salt thereof.

30. 28. The method of claim 27, comprising the derivative of I, wherein I is esterified, glycosylated, or amidated at the C-terminus.

31. 28. The method of claim 27, wherein the disorder is postural instability.

32. 28. The method of claim 27, wherein the disease is a gait disorder.

33. 28. The method of claim 27, wherein the disorder is a balance problem.

34. 28. The method of claim 27, wherein the disease is PTSD.

35. 28. The method of claim 27, wherein the disease is urinary incontinence.

36. 28. The method of claim 27, wherein the pharmaceutical composition is in a unit dose form.

37. 28. The method of claim 27, wherein the pharmaceutical composition further comprises an excipient, a diluent, a carrier, or a combination thereof.

38. 1. A method of treating a disease in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the disease, wherein the pharmaceutical composition comprises a peptide, a derivative thereof or a salt thereof, wherein the peptide is i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH ２ (SEQ ID NO: 1) or a derivative thereof, wherein the first amino acid is the D stereoisomer, the remaining amino acids are L stereoisomers, and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 2) or a derivative thereof, wherein the first amino acid is the D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof Including, The disease is selected from the group consisting of postural instability, gait disturbances, balance problems, post-traumatic stress disorder (PTSD), urinary incontinence, Alzheimer's disease with Lewy bodies (LBVAD), Alzheimer's disease-related dementia (ADRD), vascular dementia, and any combination thereof. method.

39. 1. A method of treating mild cognitive impairment or mild dementia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat said mild cognitive impairment or mild dementia, wherein said pharmaceutical composition comprises: I) A peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least 5 consecutive amino acids or derivatives thereof having the general formula: EFGHI; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these. Peptides, derivatives thereof, or salts thereof; and II) Lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these A method comprising:

40. the peptide, the derivative thereof, or the salt thereof comprises at least 8 consecutive amino acids having the general formula ABCEFGHI or a derivative thereof; A is D-Ala, or a derivative thereof; B is D-Ser or D-Thr, or a derivative of either of these; C is D-Ser or D-Thr, or a derivative of either of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these.

40. The method of claim 39.

41. 40. The method of claim 39, wherein the peptide or the salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr and D-Thr, or a salt thereof.

42. 40. The method of claim 39, comprising the derivative of I, wherein I is esterified, glycosylated, or amidated at the C-terminus.

43. 40. The method of claim 39, wherein the mild cognitive impairment or mild dementia is a disease involving amyloid beta (Aβ).

44. 40. The method of claim 39, wherein the mild cognitive impairment or mild dementia is Alzheimer's disease.

45. 40. The method of claim 39, wherein the mild cognitive impairment or mild dementia is mixed dementia.

46. 40. The method of claim 39, wherein the mild cognitive impairment or mild dementia is vascular dementia.

47. 40. The method of claim 39, wherein the pharmaceutical composition is in a unit dose form.

48. 40. The method of claim 39, wherein the pharmaceutical composition further comprises an excipient, a diluent, a carrier, or a combination thereof.

49. 40. The method of claim 39, wherein the mild cognitive impairment or mild dementia comprises deposits of alpha synuclein, tau, or both in the brain.

50. 40. The method of claim 39, wherein the administering step is daily, weekly, or monthly.

51. 40. The method of claim 39, wherein the administering step is once, twice, three times, or four times daily.

52. 40. The method of claim 39, wherein the pharmaceutical composition is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong.

53. 40. The method of claim 39, wherein the pharmaceutical composition comprises the peptide, the derivative thereof, or the salt thereof in an amount of about 0.005 mg to about 1000 mg.

54. 40. The method of claim 39, wherein the pharmaceutical composition is administered by oral, injection, sublingual, buccal, rectal, vaginal, ocular, aural, nasal, internasal, inhalation, dermal, subcutaneous, intramuscular, intravenous, systemic, topical, transdermal route, or any combination thereof.

55. 40. The method of claim 39, wherein the pharmaceutical composition is formulated for oral or intravenous administration.

56. 56. The method of claim 55, wherein the pharmaceutical composition is in the form of a pill or liquid.

57. 40. The method of claim 39, wherein the pharmaceutical composition is in liquid form.

58. 40. The method of claim 39, wherein the subject has been diagnosed with said mild cognitive impairment or said mild dementia prior to said administering.

59. 59. The method of claim 58, wherein the diagnosis comprises an in vitro test, a physical examination, an imaging diagnostic method, or a combination thereof.

60. 40. The method of claim 39, wherein the subject is a mammal.

61. 61. The method of claim 60, wherein the mammal is a human.

62. 1. A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the disease, wherein the pharmaceutical composition comprises: A peptide, a derivative thereof or a salt thereof, wherein the peptide is i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH ２ (SEQ ID NO: 1) or a derivative thereof, wherein the first amino acid is the D stereoisomer, the remaining amino acids are L stereoisomers, and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 2) or a derivative thereof, wherein the first amino acid is the D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof a peptide, a derivative thereof, or a salt thereof, comprising: Lecanemab, its derivatives, its biosimilars, or salts of any of these Including, The disease is mild cognitive impairment or mild dementia. method.

63. I) A peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least 5 consecutive amino acids or derivatives thereof having the general formula: EFGHI; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these. Peptides, derivatives thereof, or salts thereof; and II) Lecanemab, aducanumab, lemternetag, any derivative thereof, any biosimilar thereof, or any salt thereof 10. A pharmaceutical composition comprising:

64. the peptide, the derivative thereof, or the salt thereof comprises at least 8 consecutive amino acids having the general formula ABCEFGHI or a derivative thereof; A is D-Ala, or a derivative thereof; B is D-Ser or D-Thr, or a derivative of either of these; C is D-Ser or D-Thr, or a derivative of either of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these.

64. The pharmaceutical composition of claim 63.

65. 64. The pharmaceutical composition of claim 63, wherein the peptide or the salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr, or a salt thereof.

66. 64. The pharmaceutical composition of claim 63, comprising said derivative of I, wherein I is esterified, glycosylated or amidated at the C-terminus.

67. 64. The pharmaceutical composition of claim 63, further comprising an excipient, diluent, carrier, or a combination thereof.

68. 64. The pharmaceutical composition of claim 63, comprising a pharmaceutical composition comprising said lecanemab, said derivative thereof, said biosimilar thereof, or said salt of any of these.

69. 64. The pharmaceutical composition of claim 63, comprising a pharmaceutical composition comprising aducanumab, its derivative, its biosimilar, or a salt of any of these.

70. 64. The pharmaceutical composition of claim 63, comprising a pharmaceutical composition comprising the remterne tag, its derivative, its biosimilar, or a salt of any of these.

71. 64. The pharmaceutical composition of claim 63, in unit dosage form.

72. 64. The pharmaceutical composition of claim 63, comprising the peptide, the derivative thereof, or the salt thereof in an amount of about 0.005 mg to about 1000 mg.

73. 64. The pharmaceutical composition of claim 63, comprising the lecanemab, the aducanumab, the lemternetag, the derivative thereof, the biosimilar thereof, or the salt of any of these in an amount of about 1 mg to about 500 mg.

74. 64. The pharmaceutical composition of claim 63, comprising the lecanemab, the aducanumab, the lemternetag, the derivative thereof, the biosimilar thereof, or the salt of any of these in an amount of about 10 mg / kg.

75. 64. The pharmaceutical composition of claim 63, formulated for intravenous or oral delivery.

76. 64. The pharmaceutical composition of claim 63, in the form of a pill or liquid.

77. A peptide, a derivative thereof or a salt thereof, wherein the peptide is i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH ２ (SEQ ID NO: 1) or a derivative thereof, wherein the first amino acid is the D stereoisomer, the remaining amino acids are L stereoisomers, and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 2) or a derivative thereof, wherein the first amino acid is the D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof a peptide, a derivative thereof, or a salt thereof, comprising: Lecanemab, aducanumab, lemternetag, any derivative thereof, any biosimilar thereof, or any salt thereof, and optionally an excipient, diluent, carrier, or any combination thereof.

10. A pharmaceutical composition comprising:

78. 64. A kit comprising the pharmaceutical composition of any one of claims 63 and a container.

79. I) a peptide, a derivative thereof, or a salt thereof in a first container, wherein the peptide comprises at least 5 consecutive amino acids or derivatives thereof comprising the general formula: EFGHI; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these. Peptides, derivatives thereof, or salts thereof; and II) one or more of lecanemab, aducanumab, lemternetag, a derivative of any of these, a biosimilar of any of these, or a salt of any of these in a second container Kit including:

80. 1. A method of treating dementia in a subject in need thereof, comprising: I) A peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least 5 consecutive amino acids or derivatives thereof having the general formula: EFGHI; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these. Peptides, derivatives thereof, or salts thereof; and II) Lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these to said subject to treat said dementia.

81. the peptide, the derivative thereof, or the salt thereof comprises at least 8 consecutive amino acids having the general formula ABCEFGHI or a derivative thereof; A is D-Ala, or a derivative thereof; B is D-Ser or D-Thr, or a derivative of either of these; C is D-Ser or D-Thr, or a derivative of either of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg or Gly, or a derivative of any of these.

81. The method of claim 80.

82. 81. The method of claim 80, wherein the peptide, the derivative thereof, or the salt thereof is in unit dose form.

83. 81. The method of claim 80, wherein the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these is in unit dose form.

84. 81. The method of claim 80, wherein the pharmaceutical composition is administered by oral, injection, sublingual, buccal, rectal, vaginal, ocular, aural, nasal, internasal, inhalation, dermal, subcutaneous, intramuscular, intravenous, systemic, topical, transdermal route, or any combination thereof.

85. 81. The method of claim 80, wherein the pharmaceutical composition is formulated for intravenous or oral administration.

86. 81. The method of claim 80, wherein the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of them is in the form of a pill or liquid, and the peptide, the derivative thereof, or the salt thereof is in the form of a pill or liquid.

87. 81. The method of claim 80, wherein the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these is administered concurrently or sequentially with the peptide, the derivative thereof, or the salt thereof.

88. 81. The method of claim 80, wherein the peptide, the derivative thereof, or the salt thereof is in an amount of about 0.005 mg to about 1000 mg.

89. 81. The method of claim 80, wherein the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these is in an amount of about 1 mg to about 500 mg.

90. 81. The method of claim 80, wherein the lecanemab, derivative thereof, biosimilar thereof, or a salt of any of them is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong.

91. 81. The method of claim 80, wherein the peptide, derivative thereof, or salt thereof is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, or lifelong.

92. 81. The method of claim 80, wherein the administration of the peptide, its derivative, or its salt is daily, weekly, or monthly.

93. 81. The method of claim 80, wherein the administration of lecanemab, its derivative, its biosimilar, or the salt of any of these is daily, weekly, or monthly.

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