US20140322252A1 - Peptides for Treating Alzheimers's Disease and Related Conditions - Google Patents
Peptides for Treating Alzheimers's Disease and Related Conditions Download PDFInfo
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- US20140322252A1 US20140322252A1 US14/263,560 US201414263560A US2014322252A1 US 20140322252 A1 US20140322252 A1 US 20140322252A1 US 201414263560 A US201414263560 A US 201414263560A US 2014322252 A1 US2014322252 A1 US 2014322252A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- the present invention relates, broadly to the treatment or prevention of loss of brain neurons, loss of memory, dementia's, loss of motor or any other normal function due to neurodegeneration caused or associated with aging or brain inflammation, whether caused by injury, trauma, concussive blasts, sports via head contact, bacteria, viruses and/or other infective agents, opportunistic infections (which may be consequential to an immunodepressed state, for example resulting from cancer or therapy, particularly immunosuppressive antibodies or cytotoxic drug therapy or radiotherapy), autoimmunity or otherwise.
- FIG. 1 illustrates the activity of Peptide T analogs in chemotaxis of human monocytes.
- FIG. 2 illustrates chemotaxis of human monocytes for several all D pentapeptides.
- FIG. 3 illustrates that D-ala1-STTTNYT-NH2 (DAPTA/RAP-101) and all-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) both inhibit CCR8 function.
- FIG. 4 illustrates cofilin-actin rod stress response is blocked by that all D-ASTTTNYT (SEQ ID NO:1).
- the invention relates to the prevention or treatment of neurodegenerative illnesses which may include Alzheimer's Disease, Huntington's Disease and the synucleinopathies such as Parkinson's Disease, or demyelinating diseases such as HTLV-1-associated myelopathy (HAM), multiple sclerosis (MS), amyotrophic lateral sclerosis and pathological neurological symptoms after injury or trauma, or viral and other encephalopathies which are associated with chronic immune activation that occurs as a result of dysregulated inflammation, some examples of which include cytokine, chemokine, and toll-receptor inflammatory pathways and activation of the microglia or astrocytes.
- the invention also relates to pharmaceutical compositions useful in such treatment and/or prevention and to certain orally active peptides per se.
- Inflammation clearly occurs in pathologically susceptible regions of the Alzheimer's disease (AD) brain. Neurodegeneration and neuroinflammation can result in changes of central nervous system (CNS) proteins (for example, amyloid-beta (A ⁇ ) peptide) or inflammatory mediators (acute-phase proteins and pro-inflammatory cytokines and chemokines) across the blood-brain-barrier (BBB).
- CNS central nervous system
- a ⁇ amyloid-beta
- inflammatory mediators acute-phase proteins and pro-inflammatory cytokines and chemokines
- BBB blood-brain-barrier
- MCP-1 monocyte chemoattractant protein-1
- RANTES and MIP-1 ⁇ chemokine ligands for the CCR5 receptor in response to non-fibrillar beta-amyloid protein.
- cytokines like TNF ⁇ and IL-10 promote reactive microglia and astrocytes causing a cascade of inflammatory factors and neurotoxic-mediators that are associated or co-existing in beta-amyloid plaques.
- the prototype compound DAPTA normalizes the activity of the enzyme Akt (or protein kinase B (PKB)), which is a multifunctional kinase implicated in a broad range of cellular functions, including survival, proliferation, gene expression, and migration of cells of most lineages.
- Akt signaling is newly understood to be involved in the regulation of acute and chronic inflammatory processes, and compounds that normalize, often by antagonizing excess activation of Akt isoforms, are promising drug targets for the modulation of inflammatory and autoimmune disorders including cancer and cardiovascular diseases as well as neurodegenerative illnesses.
- a proposed mechanism of action of DAPTA and the related subject compounds may include normalization of excessive inflammatory signaling via MAP kinase second messenger pathways.
- IL-1 ⁇ , IL-6, and tumor necrosis factor- ⁇ are known to be among the major cytokines up-regulated during CNS stress and injury.
- TNF ⁇ and other inflammatory cytokines exacerbates the activation of glial cells and promotes gliosis, inhibiting astrocytic glutamate uptake and inducing apoptosis, particularly in oligodendrocytes thereby contributing to damaging demyelination, as occurs in multiple sclerosis (MS).
- MS multiple sclerosis
- the ability to inhibit the action of TNF ⁇ and other inflammatory activators in the early phases of CNS illnesses may yield a salutary clinical outcome in diverse neurological diseases, including but not limited to multiple sclerosis and Alzheimers Disease.
- the compounds here described would also have significant patient benefit in the immune reconstitution inflammatory syndrome (IRIS)—a paradoxical deterioration of a preexisting condition, often an infection, related to the recovery of the immune system. If immune function improves rapidly following the commencement of a medical intervention or therapy, systemic or local inflammatory reactions may occur. This restoration of immunity may result in immunopathological reactions. In brain neurological symptoms can worsen and do not always spontaneously resolve, and may be life-threatening.
- IRIS immune reconstitution inflammatory syndrome
- DAPTA D-Ala 1 -Peptide T-NH2
- Rosi ⁇ Rosi ⁇ conducted a study of inflammatory effects in TLR4 stimulated (LPS-infused) rats treated with vehicle or the prototype peptide D-ala 1 -peptide T-NH2 (DAPTA) (0.01 mg/kg, s.c., for 14 days).
- DAPTA dramatically reduced the number of activated microglia and astrocytes, as compared with rats treated with vehicle.
- DAPTA treatment also reduced the number of immunoreactive cells expressing nuclear factor k binding protein (NfKb), a prominent component of the proinflammatory cytokine signaling pathway.
- NfKb nuclear factor k binding protein
- the prototype compound DAPTA thus has actions consistent with benefit in neuroinflammatory conditions, and those putative patient benefits therefore can be extended to other related peptides.
- NBM nucleus basalis
- DAPTA prevents nucleus basalis (NBM)-induced degenerative changes in the parietal neocortex of aged rats (33).
- NBM lesioned animals had: 1) a significant 17% decrease in overall cortical thickness, 2) significant decreases of 13-29% in the thickness of cortical layers II-IV, V, and VI, and 3) significant neuronal and glial cell loss in layer V.
- DAPTA treatment prevented or attenuated these lesion-induced decreases in cortical thickness and attenuated the accompanying loss of large neurons in layer V.
- DAPTA spares neuron loss after NBM lesion, via anti-inflammatory actions.
- An unexpected and non-obvious aspect of the present invention is the use of all-D amino-acid derivatives of the mostly L-amino-acid peptides so far described in the creation of novel orally active therapeutic peptides.
- Those results are unexpected and non-obvious in view of Pert, 1986 FIGS. 3 and 4 ⁇ Pert et al., 1986, #35987 ⁇ , which shows that that D for L substitutions in linear peptide ASTTTNYT (SEQ ID NO:1) (Peptide T) can cause great loss of potency.
- FIG. 1 An example is provided in FIG. 1 .
- DAPTA all-D-amino acid peptide analogs of DAPTA, such as all-D-ASTTTNYT-NH2 (RAP-107), all-D-Peptide ASTTTNYT (SEQ ID NO:1) (RAP-310), and the shorter pentapeptide All-D-TTNYT (SEQ ID NO:2) (RAP-103) that contains the core bioactive moiety of Peptide T ⁇ Ruff, Hallberg, Hill, Pert, 1987 ⁇ .
- RAPs all-D amino acid derivatives
- Peptide T all-L-ASTTTNYT (SEQ ID NO:1)
- MCP-1 CCL2
- Triplicate determinations were made and results are expressed as the mean plus or minus SEM.
- the experiment shown is a direct comparison among all RAPs.
- Statistical analysis was by unpaired t-test, with significance set at the p ⁇ 0.01 (*) level for difference from CCL2 only chemotaxis.
- FIG. 1 illustrates the activity of all-D compared to mostly L-form peptides of formula I. It is shown that three related peptides of general formula I, that have identical primary sequence or that share partial sequence, differing only in enantiomeric form, block CCL2 chemotaxis. The results are unexpected in view of ⁇ Brenneman; Ruff; Smith, ruff ⁇ which show that most L to D substitutions show reduced activity, and some cause complete loss of biopotency.
- RAP-101 is the monomeric form of DAPTA (U.S. Pat. No. 7,390,788) and shows greater potency.
- FIG. 2 We broadened ( FIG. 2 ) the list of efficacious all-D-peptides to include eight more unique examples (SSTYR (SEQ ID NO:3), TTSYT (SEQ ID NO:4), NTRYR (SEQ ID NO:5), IDNYT (SEQ ID NO:6), NTSYR (SEQ ID NO:7), IDNYT (SEQ ID NO:8), NTSYG (SEQ ID NO:9), ETWYS (SEQ ID NO:10)) of HIV envelope gp160 and more commonly gp120-V2 region, near the bridging sheet, at approximately amino-acid 185 in the V2-loop of the envelope protein, depending on HIV env isolate.
- SSTYR SEQ ID NO:3
- TTSYT SEQ ID NO:4
- NTRYR SEQ ID NO:5
- IDNYT SEQ ID NO:6
- NTSYR SEQ ID NO:7
- IDNYT SEQ ID NO:8
- NTSYG
- the synthetic derived all-D-pentapeptides with a tyrosine in the fourth position, and Ser, Thr, or Asp in the second position, that potently block CCR2/CCR5 chemotaxis are broad spectrum chemokine receptor antagonists useful as potential orally active peptide therapeutics.
- the difficulty of development of orally active peptides has greatly impeded their development as therapies.
- FIG. 2 we show that all-D-pentapeptides inhibit CCR2 (MCP-1) elicited chemotaxis of human monocytes.
- Purified human monocytes were treated with 20 ⁇ M of All-D-pentapeptides for 30 minutes prior to chemotaxis against human MCP-1 (0.6 nM) for 2 hours.
- the chemotactic index (ratio of migration for CCR2/buffer) for MCP-1 was 3-4.
- a representative experiment is shown comprising triplicate determinations and is presented as relative fluorescence units, Mean ⁇ SEM.
- the activity of All-D-pentapeptide TTNYT (SEQ ID NO:2) (RAP-103) to block MCP-1 human monocyte chemotaxis has been published, ⁇ Padi, 2012 ⁇ .
- the peptides share activity to block diverse chemokine receptors.
- DAPTA the prototype octapeptide (D-ala1-STTTNYT-NH2) blocks chemokine receptor 8 (CCR8) and the all-D-ASTTTNYT (SEQ ID NO:1) analog also blocks CCR8, with comparable potency.
- CCR8 chemokine receptor 8
- SEQ ID NO:1 the all-D-ASTTTNYT
- FIG. 3 we show D-ala 1 -STTTNYT-NH2 (DAPTA/RAP-101) and all-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) both Inhibit CCR8 Function.
- RAP-101 and RAP-310 Both Inhibit CCL1 (1-309) mediated chemotaxis of human monocytes.
- Human monocytes isolated by Ficoll-Percoll gradient were cultured in complete growth medium (RPMI1640, supplemented with 10% FBS and 4 mM L-glutamine) in presence of M-CSF for 48 hours.
- M2 type macrophages Migration of type M2 monocyte derived macrophages toward CCL1 (I-309, 1 nM) were tested in presence or absence of D-ala 1 -STTTNYT-NH2 (DAPTA/RAP-101) and all-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) at the indicated drug concentrations. The data represent the mean of triplicate determinations of a representative experiment.
- All-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) Blocks A ⁇ and TNF ⁇ induced cofilin rod formation, an early AD pathology.
- a ⁇ or Abeta denotes peptides of 36-43 amino acids that are crucially involved in AD as the main component of the amyloid plaques found in the brains of Alzheimer patients. The peptides result from the amyloid precursor protein (APP), which is being cut by certain enzymes to yield A ⁇ . It is believed that certain misfolded oligomers (known as “seeds”) can induce other A ⁇ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The seeds or the resulting amyloid plaques are toxic to nerve cells.
- FIG. 4 all-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) (the oral active form of Peptide T (ASTTTNYT (SEQ ID NO:1)), same sequence but all-L amino acids) to block A ⁇ , and TNF ⁇ formation of cofilin rods in cultured mouse hippocampal neurons, a very early event in neurodegeneration observed in AD patients. Formation of cofilin-actin rods precedes neuronal death.
- Peptide T or its analog DAPTA protects neurons from toxic effects of activated microglia such as secreted free radicals or cytokines, and so may be beneficial in neurodegenerative illnesses, like AD.
- activated microglia such as secreted free radicals or cytokines
- the Cofilin-Actin Rod Stress Response is blocked by RAP-310, EC50 about 0.1 pM.
- RAP-310 blocks A ⁇ dimer/trimer induced cofilin rods, so may protect to synaptic loss.
- TNF ⁇ also causes the cofilin-actin rod stress response and is comparably blocked by RAP-310 (not shown).
- the ability to substitute a D for an L amino acid and retain biopotency creates the possibility to make peptides orally deliverable drug compounds. Stability of peptides in biological fluids, such as plasma, or digestive enzymes has limited their utility as drugs.
- the ability to create all-D peptides that retain potency is an unexpected general method of creating oral peptides of General Formula I, and likely is useful for other peptides of five to twenty amino-acids, and perhaps larger, which may be stabilized to proteolysis, while retaining biopotency, so a therapeutic may be administered to people via oral dosing or otherwise enjoy benefit from longer bioavailability in the body necessitating fewer doses or reduced amount of active peptide.
- a pharmacokinetic study of all-D-TTNYT (SEQ ID NO:2) (RAP-103) following intravenous and oral administration was conducted at a target dose level of 1 mg/kg in the male Sprague Dawley rat.
- the concentration of RAP-103 in each plasma and brain sample was measured using a suitable LC-MS/MS assay.
- the assay used was a research grade assay (RGA-1) which was established by assessing the accuracy, precision and the linearity of the method. Plasma concentrations generated were used to evaluate the pharmacokinetic parameters of all-D-TTNYT (SEQ ID NO:2) (RAP-103).
- the dose formulation was administered intravenously to some animals as a slow bolus over ca 30 s via the tail vein and to a different group of animals orally via gastric gavage at a target dose volume of 1 mL/kg, to achieve a target dose level of 1 mg/kg.
- the dose volume administered was calculated according to the bodyweight of the animal on the day of dosing. The weight of administered dose was recorded. All dose administrations were well tolerated and no adverse effects from the treatments were observed. Results of the study show oral boavailibity of the all-D-peptide was achieved, results are in Table 1
- mice There is a marked inflammatory component in the mice and amyloid plaques and insoluble amyloid are detectable in mice at 9 months of age. Also while neuronal loss is not commonly observed in APPSw mice or many other mouse models of amyloid deposition thinning of the CA3 region of the hippocampus and the dentate gyrus is readily observed in APPSw/NOS2 ⁇ / ⁇ mice compared to APPSw mice.
- mice Both Transgenic (CVN) and wild-type (WT) mice were used: WT mice were treated orally (p.o.) with vehicle; while CVN mice treated p.o. with either vehicle or treated p.o. with RAP-310, 0.4 mg/kg. At the age of 4.5 to 5 months the mice were subjected to once-a-day oral vehicle or RAP-310. After 1 month of treatment, starting at the age of 6 months, the mice were subjected to radial arm water maze testing. At 9 months of age, the CVN RAP-310 orally treated mice made 50% less errors in block 5 and 30% less errors in sum scores for Day 1 compared to CVN vehicle treated mice.
- the peptides can be used in pharmaceutical compositions and compositions of matter for treating and preventing any disease or condition caused by an organism, compound or immune dysfunction that results in an inflammatory reaction of the immune system.
- the peptides or peptide formulations may be used alone or in combination with any other pharmaceutically active compound, such as an anti-infective agent, for example an antibiotic and/or antiviral agent and/or antifungal agent, or another pharmaceutically active compound, such as an antineoplastic agent.
- the peptides may be administered orally, bucally, parenterally, topically, rectally, vaginally, by intranasal inhalation spray, by intrapulmonary inhalation or in other ways.
- the peptides according to the invention may be formulated for topical use, for inhalation with spray or powder, for injection (for example subcutaneous, intramuscular, intravenous, intra-articular or intra-cisternal injection), for infusion or for oral administration, a preferred embodiment, and may be presented in unit dose form in ampoules or tablets or in multidose vials or other containers with an added preservative.
- compositions may take such forms as suspensions, solutions, or emulsions or gels in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
- the active ingredient may be in powder and/or lyophilised form for direct administration or for constitution with a suitable vehicle (e.g. sterile, pyrogen-free water, normal saline or dextrose or mannose) before use.
- a suitable vehicle e.g. sterile, pyrogen-free water, normal saline or dextrose or mannose
- the pharmaceutical compositions containing peptides(s) may also contain other active ingredients such as antimicrobial agents, or preservatives.
- compositions may contain from 0.001-99% (w/v or, preferably, w/w) of the active material.
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Abstract
A method of treating loss of memory or motor function due to brain neurodegenerative condition, such as Alzheimer's Disease and others, comprising the steps of:
-
- preparing a composition comprising a D peptide and a pharmaceutically acceptable carrier,
- said D peptide further comprises the general structure: A-B-C-D-E-F-G-H
- in which:
- A is Ala, or absent,
- B is Ser, Thr or absent,
- C is Ser, Thr or absent,
- D is Ser, Thr, Asn, Glu, Arg, Ile, Leu,
- E is Ser, Thr, Asp, Asn,
- F is Thr, Ser, Asn, Arg, Gln, Lys, Trp,
- G is Tyr, and
- H is Thr, Ser, Arg, Gly,
- and wherein all amino acids are the D stereoisomeric configuration.
- said D peptide further comprises the general structure: A-B-C-D-E-F-G-H
- preparing a composition comprising a D peptide and a pharmaceutically acceptable carrier,
The composition is administered to the patient in a therapeutically effective dose and acts to treat the condition in the patient.
Description
- This application claims the benefit of U.S. Provisional Application Ser. No. 61/816,565, filed Apr. 26, 2013.
- The present invention relates, broadly to the treatment or prevention of loss of brain neurons, loss of memory, dementia's, loss of motor or any other normal function due to neurodegeneration caused or associated with aging or brain inflammation, whether caused by injury, trauma, concussive blasts, sports via head contact, bacteria, viruses and/or other infective agents, opportunistic infections (which may be consequential to an immunodepressed state, for example resulting from cancer or therapy, particularly immunosuppressive antibodies or cytotoxic drug therapy or radiotherapy), autoimmunity or otherwise.
-
FIG. 1 illustrates the activity of Peptide T analogs in chemotaxis of human monocytes. -
FIG. 2 illustrates chemotaxis of human monocytes for several all D pentapeptides. -
FIG. 3 illustrates that D-ala1-STTTNYT-NH2 (DAPTA/RAP-101) and all-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) both inhibit CCR8 function. -
FIG. 4 illustrates cofilin-actin rod stress response is blocked by that all D-ASTTTNYT (SEQ ID NO:1). - In particular embodiments, the invention relates to the prevention or treatment of neurodegenerative illnesses which may include Alzheimer's Disease, Huntington's Disease and the synucleinopathies such as Parkinson's Disease, or demyelinating diseases such as HTLV-1-associated myelopathy (HAM), multiple sclerosis (MS), amyotrophic lateral sclerosis and pathological neurological symptoms after injury or trauma, or viral and other encephalopathies which are associated with chronic immune activation that occurs as a result of dysregulated inflammation, some examples of which include cytokine, chemokine, and toll-receptor inflammatory pathways and activation of the microglia or astrocytes. The invention also relates to pharmaceutical compositions useful in such treatment and/or prevention and to certain orally active peptides per se.
- Inflammation clearly occurs in pathologically susceptible regions of the Alzheimer's disease (AD) brain. Neurodegeneration and neuroinflammation can result in changes of central nervous system (CNS) proteins (for example, amyloid-beta (Aβ) peptide) or inflammatory mediators (acute-phase proteins and pro-inflammatory cytokines and chemokines) across the blood-brain-barrier (BBB). These CNS-derived proteins and mediators induce both systemic and local in the brain immune reactions and/or recruit immune cells into the CNS. The cells responsible for the local inflammatory reaction in CNS are activated microglia and astrocytes. The hypothesis is that Aβ plaques and tangles stimulate a chronic inflammatory reaction. In addition to CNS resident cells, blood-derived cells can also be implicated in the inflammatory response and seem to both accumulate and activate in the AD brain due to the expression of chemokine receptors.
- Human monocytes and brain microglia express monocyte chemoattractant protein-1 (MCP-1), the chemokine ligand for the CCR2 receptor, and RANTES and MIP-1β, chemokine ligands for the CCR5 receptor in response to non-fibrillar beta-amyloid protein. These, and other actions, e.g, the release of cytokines like TNFα and IL-10 promote reactive microglia and astrocytes causing a cascade of inflammatory factors and neurotoxic-mediators that are associated or co-existing in beta-amyloid plaques.
- In order to overcome limitations of single-chemokine receptor targeted drugs, we have developed modified short peptide antagonists of multiple chemokine receptors CCR8/CCR5/CCR2/CX3CR1/CCR3 and TLR4, which are important innate immune targets in inflammatory conditions like AD. Because of the complexity and redundancies of innate defense pathways, new compounds that block multiple receptor targets, such as we have created, may prove to be better therapeutics.
- Further, the prototype compound DAPTA normalizes the activity of the enzyme Akt (or protein kinase B (PKB)), which is a multifunctional kinase implicated in a broad range of cellular functions, including survival, proliferation, gene expression, and migration of cells of most lineages. Akt signaling is newly understood to be involved in the regulation of acute and chronic inflammatory processes, and compounds that normalize, often by antagonizing excess activation of Akt isoforms, are promising drug targets for the modulation of inflammatory and autoimmune disorders including cancer and cardiovascular diseases as well as neurodegenerative illnesses. Thus a proposed mechanism of action of DAPTA and the related subject compounds may include normalization of excessive inflammatory signaling via MAP kinase second messenger pathways.
- IL-1β, IL-6, and tumor necrosis factor-α (TNFα) are known to be among the major cytokines up-regulated during CNS stress and injury. The release of TNFα and other inflammatory cytokines exacerbates the activation of glial cells and promotes gliosis, inhibiting astrocytic glutamate uptake and inducing apoptosis, particularly in oligodendrocytes thereby contributing to damaging demyelination, as occurs in multiple sclerosis (MS). The ability to inhibit the action of TNFα and other inflammatory activators in the early phases of CNS illnesses may yield a salutary clinical outcome in diverse neurological diseases, including but not limited to multiple sclerosis and Alzheimers Disease.
- In particular the compounds here described would also have significant patient benefit in the immune reconstitution inflammatory syndrome (IRIS)—a paradoxical deterioration of a preexisting condition, often an infection, related to the recovery of the immune system. If immune function improves rapidly following the commencement of a medical intervention or therapy, systemic or local inflammatory reactions may occur. This restoration of immunity may result in immunopathological reactions. In brain neurological symptoms can worsen and do not always spontaneously resolve, and may be life-threatening.
- In Vivo Model of Brain Inflammation Blocked by RAP101.
- Rosi {Rosi} conducted a study of inflammatory effects in TLR4 stimulated (LPS-infused) rats treated with vehicle or the prototype peptide D-ala1-peptide T-NH2 (DAPTA) (0.01 mg/kg, s.c., for 14 days). DAPTA dramatically reduced the number of activated microglia and astrocytes, as compared with rats treated with vehicle. DAPTA treatment also reduced the number of immunoreactive cells expressing nuclear factor k binding protein (NfKb), a prominent component of the proinflammatory cytokine signaling pathway. The prototype compound DAPTA thus has actions consistent with benefit in neuroinflammatory conditions, and those putative patient benefits therefore can be extended to other related peptides.
- In Vivo Model of Cortical Atrophy in Aged Rats is Blocked by D-Ala1-Peptide T-NH2 (DAPTA).
- Loss of the basal neurons, as occurs in aging, results in large reductions of cholinergic markers in cortex, a feature of AD clinical disease that has led to cholinergic therapies in AD. The loss of cortical neurons in aging can be experimentally induced by chemically induced lesions of nucleus basalis (NBM).
- DAPTA prevents nucleus basalis (NBM)-induced degenerative changes in the parietal neocortex of aged rats (33). Aged (20-21 months old) Sprague-Dawley rats were given bilateral neurotoxic lesions of the NBM, and injected daily with PT (1 mg, IP) or vehicle solution for 5 months. NBM lesioned animals had: 1) a significant 17% decrease in overall cortical thickness, 2) significant decreases of 13-29% in the thickness of cortical layers II-IV, V, and VI, and 3) significant neuronal and glial cell loss in layer V. DAPTA treatment prevented or attenuated these lesion-induced decreases in cortical thickness and attenuated the accompanying loss of large neurons in layer V. DAPTA spares neuron loss after NBM lesion, via anti-inflammatory actions.
- Although the animal experiments provide evidence of clinical utility, an unmet medical need is oral dosing of peptides as peptides rarely, if ever, can be administered orally without special measures to prevent proteolysis in the digestive tract. An unexpected and non-obvious aspect of the present invention is the use of all-D amino-acid derivatives of the mostly L-amino-acid peptides so far described in the creation of novel orally active therapeutic peptides. Those results are unexpected and non-obvious in view of Pert, 1986 FIGS. 3 and 4 {Pert et al., 1986, #35987}, which shows that that D for L substitutions in linear peptide ASTTTNYT (SEQ ID NO:1) (Peptide T) can cause great loss of potency.
- Having one D substitution, in the
specific position No 1, (the D-ala) retains potency. Making an additional D substitution, in the specific position No 8 (the D-Thr) results in loss of 99 to 99.9% of the activity. Thus it is shown that introduction of L to D substitutions cannot be made in a general fashion, and that these modifications can, and typically do, destroy biopotency by disrupting the peptide structure required for receptor potency. - This point is further made in Brenneman {Brenneman, 1988}, with specific reference to the peptide TTNYT (SEQ ID NO:2). See
FIG. 2 and Table 1. Upon making the L to D substitution in position 4 (Tyr), the peptide completely loses activity. This directly contradicts Andersen, U.S. Pat. No. 6,265,374 because each of the amino-acids CAN NOT be in the D-form and retain biopotency. The objection stands as Andersen provides no evidence that each amino-acid can be in a D-form. - A detailed study of the peptide TTNYT (SEQ ID NO:2) and L to D substitutions was published in Smith, 1988 {Smith, 1988}. Refer to
FIG. 3 . Introduction of single L to D substitutions in eachposition 1, 2, 3, 4, results in loss of potency, and all of the D form substitutions are substantially less active (50×) to completely inactive. - As such the use of D-substitutions by Andersen in “each” position has not been reduced to practice. The data shows that in no instance does a D for L amino-acid substitution achieve comparable potency to the all-L form, rather D substitutions result in loss of activity, sometimes complete loss of biopotency in a position dependent fashion. In contrast to the repeated findings of numerous authors (op. cit. above) we discovered, while seeking to construct an inactive version of linear peptides ASTTTNYT (SEQ ID NO:1) (“Peptide T”, {Pert et al., 1986, #35987}) or TTNYT (SEQ ID NO:2) by converting them to all-D-amino acids, an unexpected retention of biopotency to block chemokine receptors.
- An example is provided in
FIG. 1 . We synthesized three all-D-amino acid peptide analogs of DAPTA, such as all-D-ASTTTNYT-NH2 (RAP-107), all-D-Peptide ASTTTNYT (SEQ ID NO:1) (RAP-310), and the shorter pentapeptide All-D-TTNYT (SEQ ID NO:2) (RAP-103) that contains the core bioactive moiety of Peptide T {Ruff, Hallberg, Hill, Pert, 1987}. - The results show that all three “all-D” peptides, comprised of all D, no L, amino acids retained nearly full potency. As expected DAPTA, with 7 of 8 amino-acids as L form, was most potent and the other all-D amino-acid peptides were some 2 to 35-fold reduced in potency. The potency reductions will not affect clinical usefulness as all of the compounds are active at sub-nM and pM concentrations to antagonize chemokine receptors.
- Legend: The effect of all-D amino acid derivatives (“RAPs”, generic names) of Peptide T (all-L-ASTTTNYT (SEQ ID NO:1)) (Pert, 1986), the V2 derived antagonist of CCR5/CCR2 mediated HIV infection and inflammation, to block CCL2 (MCP-1) chemotaxis was studied. Triplicate determinations were made and results are expressed as the mean plus or minus SEM. The experiment shown is a direct comparison among all RAPs. Statistical analysis was by unpaired t-test, with significance set at the p<0.01 (*) level for difference from CCL2 only chemotaxis.
- Converting peptides of general formula I (ASTTTNYT (SEQ ID NO:1)) to all-D-amino acids retain similar receptor targets, and similar receptor potencies to block innate immune responses.
FIG. 1 illustrates the activity of all-D compared to mostly L-form peptides of formula I. It is shown that three related peptides of general formula I, that have identical primary sequence or that share partial sequence, differing only in enantiomeric form, block CCL2 chemotaxis. The results are unexpected in view of {Brenneman; Ruff; Smith, ruff} which show that most L to D substitutions show reduced activity, and some cause complete loss of biopotency. The tyrosine moiety is particularly sensitive and the peptides are not active in L-form with a D-tyrosine. RAP-101 is the monomeric form of DAPTA (U.S. Pat. No. 7,390,788) and shows greater potency. - We broadened (
FIG. 2 ) the list of efficacious all-D-peptides to include eight more unique examples (SSTYR (SEQ ID NO:3), TTSYT (SEQ ID NO:4), NTRYR (SEQ ID NO:5), IDNYT (SEQ ID NO:6), NTSYR (SEQ ID NO:7), IDNYT (SEQ ID NO:8), NTSYG (SEQ ID NO:9), ETWYS (SEQ ID NO:10)) of HIV envelope gp160 and more commonly gp120-V2 region, near the bridging sheet, at approximately amino-acid 185 in the V2-loop of the envelope protein, depending on HIV env isolate. The synthetic derived all-D-pentapeptides with a tyrosine in the fourth position, and Ser, Thr, or Asp in the second position, that potently block CCR2/CCR5 chemotaxis are broad spectrum chemokine receptor antagonists useful as potential orally active peptide therapeutics. The difficulty of development of orally active peptides has greatly impeded their development as therapies. Here we suggest a general method to stabilize peptides to proteolytic degradation that preserves biopotency, either as an agonist or as an antagonist of cell surface receptors. - In
FIG. 2 we show that all-D-pentapeptides inhibit CCR2 (MCP-1) elicited chemotaxis of human monocytes. Purified human monocytes were treated with 20 μM of All-D-pentapeptides for 30 minutes prior to chemotaxis against human MCP-1 (0.6 nM) for 2 hours. The chemotactic index (ratio of migration for CCR2/buffer) for MCP-1 was 3-4. A representative experiment is shown comprising triplicate determinations and is presented as relative fluorescence units, Mean±SEM. The activity of All-D-pentapeptide TTNYT (SEQ ID NO:2) (RAP-103) to block MCP-1 human monocyte chemotaxis has been published, {Padi, 2012}. - The peptides share activity to block diverse chemokine receptors. Thus we show that DAPTA, the prototype octapeptide (D-ala1-STTTNYT-NH2) blocks chemokine receptor 8 (CCR8) and the all-D-ASTTTNYT (SEQ ID NO:1) analog also blocks CCR8, with comparable potency. Thus again, with a different receptor target, the all-D peptide performs very similarly to its mostly L-amino acid prototype first described in Pert, 1986. See
FIG. 3 . - In
FIG. 3 we show D-ala1-STTTNYT-NH2 (DAPTA/RAP-101) and all-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) both Inhibit CCR8 Function. RAP-101 and RAP-310 Both Inhibit CCL1 (1-309) mediated chemotaxis of human monocytes. Human monocytes isolated by Ficoll-Percoll gradient were cultured in complete growth medium (RPMI1640, supplemented with 10% FBS and 4 mM L-glutamine) in presence of M-CSF for 48 hours. Resting monocytes, as freshly isolated, were not responsive to CCL1, which required maturation with M-CSF for 48 hrs to up-regulate expression of CCR8, so-called “M2” type macrophages. Migration of type M2 monocyte derived macrophages toward CCL1 (I-309, 1 nM) were tested in presence or absence of D-ala1-STTTNYT-NH2 (DAPTA/RAP-101) and all-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) at the indicated drug concentrations. The data represent the mean of triplicate determinations of a representative experiment. - All-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) Blocks Aβ and TNFα induced cofilin rod formation, an early AD pathology. Aβ or Abeta, denotes peptides of 36-43 amino acids that are crucially involved in AD as the main component of the amyloid plaques found in the brains of Alzheimer patients. The peptides result from the amyloid precursor protein (APP), which is being cut by certain enzymes to yield Aβ. It is believed that certain misfolded oligomers (known as “seeds”) can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The seeds or the resulting amyloid plaques are toxic to nerve cells.
- We tested (
FIG. 4 ) all-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) (the oral active form of Peptide T (ASTTTNYT (SEQ ID NO:1)), same sequence but all-L amino acids) to block Aβ, and TNFα formation of cofilin rods in cultured mouse hippocampal neurons, a very early event in neurodegeneration observed in AD patients. Formation of cofilin-actin rods precedes neuronal death. Our studies show that Peptide T or its analog DAPTA protects neurons from toxic effects of activated microglia such as secreted free radicals or cytokines, and so may be beneficial in neurodegenerative illnesses, like AD. InFIG. 4 , the Cofilin-Actin Rod Stress Response is blocked by RAP-310, EC50 about 0.1 pM. Thus RAP-310 blocks Aβ dimer/trimer induced cofilin rods, so may protect to synaptic loss. TNFα also causes the cofilin-actin rod stress response and is comparably blocked by RAP-310 (not shown). - The ability to substitute a D for an L amino acid and retain biopotency creates the possibility to make peptides orally deliverable drug compounds. Stability of peptides in biological fluids, such as plasma, or digestive enzymes has limited their utility as drugs. The ability to create all-D peptides that retain potency is an unexpected general method of creating oral peptides of General Formula I, and likely is useful for other peptides of five to twenty amino-acids, and perhaps larger, which may be stabilized to proteolysis, while retaining biopotency, so a therapeutic may be administered to people via oral dosing or otherwise enjoy benefit from longer bioavailability in the body necessitating fewer doses or reduced amount of active peptide.
- A pharmacokinetic study of all-D-TTNYT (SEQ ID NO:2) (RAP-103) following intravenous and oral administration was conducted at a target dose level of 1 mg/kg in the male Sprague Dawley rat. The concentration of RAP-103 in each plasma and brain sample was measured using a suitable LC-MS/MS assay. The assay used was a research grade assay (RGA-1) which was established by assessing the accuracy, precision and the linearity of the method. Plasma concentrations generated were used to evaluate the pharmacokinetic parameters of all-D-TTNYT (SEQ ID NO:2) (RAP-103).
- The dose formulation was administered intravenously to some animals as a slow bolus over ca 30 s via the tail vein and to a different group of animals orally via gastric gavage at a target dose volume of 1 mL/kg, to achieve a target dose level of 1 mg/kg. The dose volume administered was calculated according to the bodyweight of the animal on the day of dosing. The weight of administered dose was recorded. All dose administrations were well tolerated and no adverse effects from the treatments were observed. Results of the study show oral boavailibity of the all-D-peptide was achieved, results are in Table 1
-
TABLE 1 CONCENTRATION OF ALL-D-TTNYT (RAP-103) IN MALE RAT PLASMA FOLLOWING INTRAVENOUS ADMINISTRATION AT A TARGET DOSE LEVEL OF 1 MG/KG. RESULTS EXPRESSED AS NG/ML Nominal Time Animal Number (h) 007 M 008 M 009 M 010 M 011 M 012 M 013 M 014 M 015 M 016 M 017 M 0.083 3050 2490 — — — — — — — — — 0.167 — — 2400 2500 — — — — — — — 0.25 — — — — 2050 2270 1860 — — — — 0.5 — — — — — — — 558 561 — — 1 — — — — — — — — — 405 433 - The results show that as quickly as can be determined, 5 minutes (0.083 hrs) after dosing, all-D-TTNYT (SEQ ID NO:2) (RAP-103) is detected in plasma, and continues to be detected at 1 hr. Peak levels occur at 10-15 minutes.
- The biological relevance is shown in the publication by Padi et al., {Padi} that shows oral administration of RAP-103 (0.05-1 mg/kg) for 7 days fully prevents mechanical allodynia and inhibits the development of thermal hyperalgesia after partial ligation of the sciatic nerve in rats. Administered from days 8 to 12, RAP-103 (0.2-1 mg/kg) reverses already established hypersensitivity. RAP-103 relieves behavioral hypersensitivity through either or both CCR2 and CCR5 blockade. Moreover, RAP-103 is able to reduce spinal microglial activation and monocyte infiltration, and to inhibit inflammatory responses evoked by peripheral nerve injury that cause chronic pain. The findings suggest that targeting CCR2/CCR5 should provide greater efficacy than targeting CCR2 or CCR5 alone, and that the dual CCR2/CCR5 antagonist RAP-103 has the potential for broad clinical use in neuropathic pain treatment.
- We tested yet a further all-D-amino acid modified peptide for oral bioavailability and protection to memory losses in an animal AD model. Thus all-D-ASTTTNYT (SEQ ID NO:1) (RAP-310) (the oral active form of Peptide T (ASTTTNYT (SEQ ID NO:1)) on cognitive performance in the Morris Radial Arm Water Maze (RAWM) in the Alzheimer's disease (AD) transgenic mouse (“CVN” model; APPSwDI/NOS2−/−.) {Colton, 2008} was studied. CVN mice (APP with Swedish, Dutch and Iowa mutations crossed with NOS2 knockout) exhibit memory and learning deficits as well as biochemical hallmarks of AD during aging. There is a marked inflammatory component in the mice and amyloid plaques and insoluble amyloid are detectable in mice at 9 months of age. Also while neuronal loss is not commonly observed in APPSw mice or many other mouse models of amyloid deposition thinning of the CA3 region of the hippocampus and the dentate gyrus is readily observed in APPSw/NOS2−/− mice compared to APPSw mice.
- Both Transgenic (CVN) and wild-type (WT) mice were used: WT mice were treated orally (p.o.) with vehicle; while CVN mice treated p.o. with either vehicle or treated p.o. with RAP-310, 0.4 mg/kg. At the age of 4.5 to 5 months the mice were subjected to once-a-day oral vehicle or RAP-310. After 1 month of treatment, starting at the age of 6 months, the mice were subjected to radial arm water maze testing. At 9 months of age, the CVN RAP-310 orally treated mice made 50% less errors in
block 5 and 30% less errors in sum scores forDay 1 compared to CVN vehicle treated mice. These results show that daily treatment with oral RAP-310 (0.4 mg/kg) starting at age 4.5-5 months of age has beneficial effects on RAWM performance at age 9 months in APPSwDI/NOS2−/− transgenic mouse model of Alzheimer's disease. - Treatment Uses in Diseases with Underlying Inflammation
- The peptides can be used in pharmaceutical compositions and compositions of matter for treating and preventing any disease or condition caused by an organism, compound or immune dysfunction that results in an inflammatory reaction of the immune system. The peptides or peptide formulations may be used alone or in combination with any other pharmaceutically active compound, such as an anti-infective agent, for example an antibiotic and/or antiviral agent and/or antifungal agent, or another pharmaceutically active compound, such as an antineoplastic agent.
- The peptides may be administered orally, bucally, parenterally, topically, rectally, vaginally, by intranasal inhalation spray, by intrapulmonary inhalation or in other ways. In particular, the peptides according to the invention may be formulated for topical use, for inhalation with spray or powder, for injection (for example subcutaneous, intramuscular, intravenous, intra-articular or intra-cisternal injection), for infusion or for oral administration, a preferred embodiment, and may be presented in unit dose form in ampoules or tablets or in multidose vials or other containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions or gels in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder and/or lyophilised form for direct administration or for constitution with a suitable vehicle (e.g. sterile, pyrogen-free water, normal saline or dextrose or mannose) before use. The pharmaceutical compositions containing peptides(s) may also contain other active ingredients such as antimicrobial agents, or preservatives.
- The compositions may contain from 0.001-99% (w/v or, preferably, w/w) of the active material.
-
- Brenneman, D. E., J. M. Buzy, M. R. Ruff, and C. B. Pert. 1988. Peptide T sequences prevent neuronal cell death produced by the envelope protein (gp120) of the human immunodeficiency virus. Drug Devel Res. 15:361-369
- Colton, C. A., D. M. Wilcock, D. A. Wink, J. Davis, W. E. Van Nostrand, and M. P. Vitek. 2008. The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. J Alzheimers Dis. 15:571-587
- Padi, S. S., X. Q. Shi, Y. Q. Zhao, M. R. Ruff, N. Baichoo, C. B. Pert, and J. Zhang. 2012. Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation. Pain. 153:95-106. doi:10.1016/j.pain.2011.09.022.
- Pert, C. B., J. M. Hill, M. R. Ruff, R. M. Berman, W. G. Robey, L. O. Arthur, F. W. Ruscetti, and W. L. Farrar. 1986. Octapeptides deduced from the neuropeptide receptor-like pattern of antigen T4 in brain potently inhibit human immunodeficiency virus receptor binding and T-cell infectivity. Proc Natl Acad Sci USA. 83:9254-928.
- Rosi, S., C. B. Pert, M. R. Ruff, K. Gann-Gramling, and G. L. Wenk. 2005. Chemokine receptor 5 antagonist D-Ala-peptide T-amide reduces microglia and astrocyte activation within the hippocampus in a neuroinflammatory rat model of Alzheimer's disease. Neuroscience. 134:671-676
- Ruff, M. R., P. L. Hallberg, J. M. Hill, and C. B. Pert. 1987a. Peptide T[4-8] is core HIV envelope sequence required for CD4 receptor attachment [letter]. Lancet. 2:751
- Ruff, M. R., B. M. Martin, E. I. Ginns, W. L. Farrar, and C. B. Pert. 1987b. CD4 receptor binding peptides that block HIV infectivity cause human monocyte chemotaxis. Relationship to vasoactive intestinal polypeptide. FEBS Lett. 211:17-22
- Smith, C. C., P. L. Hallberg, P. Sacerdote, P. Williams, E. Sternberg, B. Martin, C. Pert, and M. R. Ruff. 1988. Tritiated D-ala1-peptide T binding: A pharmacologic basis for the design of drugs which inhibit HIV receptor binding. Drug Devel Res. 15:371-379
- Socci, D. J., C. B. Pert, M. R. Ruff, and G. W. Arendash. 1996. Peptide T prevents NBM lesion-induced cortical atrophy in aged rats. Peptides. 17:831-837
Claims (11)
1. A method of treating brain neurodegenerative condition in a patient comprising the steps of:
preparing a composition comprising a D peptide and a pharmaceutically acceptable carrier,
said D peptide further comprises the general structure: A-B-C-D-E-F-G-H in which:
A is Ala, or absent,
B is Ser, Thr or absent,
C is Ser, Thr or absent,
D is Ser, Thr, Asn, Glu, Arg, Ile, Leu,
E is Ser, Thr, Asp, Asn,
F is Thr, Ser, Asn, Arg, Gln, Lys, Trp,
G is Tyr, and
H is Thr, Ser, Arg, Gly,
and wherein all amino acids are the D stereoisomeric configuration, and administering said composition to the patient in a therapeutically effective dose,
wherein said composition acts to treat the brain neurodegenerative condition in the patient.
2. The method as defined in claim 1 wherein the brain neurodegenerative condition further comprises loss of memory or motor function.
3. The method as defined in claim 1 wherein said condition is selected from the group consisting of:
Alzheimers's Disease, Huntington's Disease, synucleinopathy, Parkinson's Disease, demyelinating disease, HTLV-1-associated myelopathy (HAM), multiple sclerosis (MS), amyotrophic lateral sclerosis, pathological neurological symptoms after injury or trauma, encephalopathy and viral encephalopathy.
4. The method as defined in claim 1 wherein said administering said composition to the patient is selected from the group consisting of administrating: orally, bucally, parenterally, topically, rectally, vaginally, by intranasal inhalation spray, by intrapulmonary inhalation.
5. The method as defined in claim 1 further comprising,
said D peptide is at most twenty (20) D amino acid residues in length and contains five contiguous D amino acid residues that have a sequence selected from the group consisting of:
6. The method as defined in claim 5 further comprising,
said D peptide derivative is at most twelve (12) D amino acid residues in length.
7. The method as defined in claim 5 further comprising,
said D peptide derivative is at most eight (8) D amino acid residues in length.
8. The method as defined in claim 5 further comprising,
said D peptide is five (5) D amino acid residues in length.
9. A method of treating brain neurodegenerative condition in a patient comprising the steps of:
treating loss of brain function in a patient comprising the steps of:
preparing a composition comprising a peptide analog and a pharmaceutically acceptable carrier,
said peptide analog is [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2 SEQ ID NO:1 in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers and the last amino acid has an amide cap, and
administering said peptide analog to the patient in a therapeutically effective dose,
wherein said composition acts to treat the brain neurodegenerative condition in the patient.
10. The method as defined in claim 9 wherein the brain neurodegenerative condition further comprises loss of memory or motor function.
11. The method as defined in claim 9 wherein said condition is selected from the group consisting of: Alzheimer's Disease, Huntington's Disease, synucleinopathy, Parkinson's Disease, demyelinating disease, HTLV-1-associated myelopathy (HAM), multiple sclerosis (MS), amyotrophic lateral sclerosis, pathological neurological symptoms after injury or trauma, encephalopathy and viral encephalopathy.
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US14/263,519 Abandoned US20140322251A1 (en) | 2013-04-26 | 2014-04-28 | Peptides for Progressive Treating Multi-Focal Leukoencephalopathy and Related Conditions |
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US14/263,347 Active US10501494B2 (en) | 2013-04-26 | 2014-04-28 | Uses of peptides to treat brain injury and disease |
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CN112703008A (en) * | 2017-07-18 | 2021-04-23 | 创新生物肽有限公司 | Oral anti-inflammatory peptides for the treatment of epilepsy, seizures and CNS disorders |
US20210244788A1 (en) * | 2020-02-06 | 2021-08-12 | Creative Bio-Peptides Inc. | Oral peptide antagonists of multiple chemokine receptors for reversing loss of synapses and dendritic spines |
EP4039264A1 (en) * | 2021-02-08 | 2022-08-10 | Creative Bio-Peptides Inc. | Oral peptide antagonists of multiple chemokine receptors for reversing loss of synapses and dendritic spines |
US11510961B2 (en) | 2019-12-19 | 2022-11-29 | Creative Bio-Peptides, Inc. | Methods and compositions for use of a chemokine receptor antagonist peptide to treat addiction, substance abuse disorders or symptoms thereof |
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KR20160030506A (en) | 2013-07-02 | 2016-03-18 | 유스트랄리스 파마슈티칼스 리미티드 (트레이딩 애즈 프레스수라 뉴로) | Method for Preventing and/or Treating Chronic Traumatic Encephalopathy-I |
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US10624944B2 (en) * | 2017-06-19 | 2020-04-21 | Creative Bio-Peptides Inc. | Anti-inflammatory peptides for treating non-alcoholic steatohepatitis (NASH) |
US10624945B2 (en) * | 2017-10-31 | 2020-04-21 | Creative Bio-Peptides Inc. | Use of an all-D-pentapeptide chemokine antagonist to reduce opioid dose in a person with pain |
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US10501494B2 (en) | 2019-12-10 |
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