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WO2013066374A2 - Protection par l'humanine des neurones dopaminergiques - Google Patents

Protection par l'humanine des neurones dopaminergiques Download PDF

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Publication number
WO2013066374A2
WO2013066374A2 PCT/US2012/000535 US2012000535W WO2013066374A2 WO 2013066374 A2 WO2013066374 A2 WO 2013066374A2 US 2012000535 W US2012000535 W US 2012000535W WO 2013066374 A2 WO2013066374 A2 WO 2013066374A2
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humanin
subject
disease
analog
administered
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WO2013066374A3 (fr
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Radhika Muzumdar
Diana Casper
Rukmani LEKHRAJ
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Albert Einstein College of Medicine
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Albert Einstein College of Medicine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Parkinson's disease is a significant health concern, and is second only to
  • AD Alzheimer's disease
  • PD Alzheimer's disease
  • a method is provided of treating Parkinson's disease or of protecting dopaminergic neurons from neurotoxicity in a subject comprising administering to the subject an amount of humanin or an active humanin analog effective to treat Parkinson's disease or protect dopaminergic neurons.
  • Also provided is a method of increasing DJ-1 expression in a neuron of subject or of activating STAT-3 in a neuron of a subject comprising administering to the subject an amount of humanin or an active humanin analog effective to increase DJ-1 expression in a neuron or activate STAT-3 in a neuron.
  • a humanin analog is also provided for treating Parkinson's disease or for protecting dopaminergic neurons from neurotoxicity in a subject.
  • Also provided is a method of identifying a candidate treatment for Parkinson's disease comprising a) modeling in silico the 3-dimensional form of the humanin analog comprising SEQ ID NO:2, b) testing in silico if a compound from a library of small molecule compounds mimics the modeled 3-dimensional form, and c) determining in vitro if the small molecule identified in b) is chemically stable, thereby identifying the candidate treatment.
  • FIG. 1 Rattin and its receptor, CNTFR-a are present in rat midbrain and dopaminergic MN9D cells. Western blot of Fischer/Brown Norway rat midbrain homogenates from 4 to 24 months and MN9D-cell lysates with anti-RN antibody. Note that the intensity of the rattin signal appears to decrease in the 24-month animal.
  • FIG. 2A-2D HNG, a potent analog of humanin, protects dopaminergic MN9D cells from neurotoxicity.
  • Replicate cultures were treated in the following manner: A) Hydrogen peroxide: lh pre-treatment with HNG before and during overnight exposure to H 2 0 2 ; B) serum deprivation: lh pre-treatment with HNG before and during overnight incubation in serum-free medium; C) Rotenone: lh HNG pre-treatment before and during overnight incubation with 250nM rotenone; D) Rotenone: 24h HNG pre-treatment before and during overnight incubation with 250 nM rotenone. Results demonstrate that HNG increased neuronal survival for all three types of toxicity. For rotenone, longer (24-h) pre- treatment of cultures with HNG was required for neuroprotection.
  • FIG. 3A-3B DJ-1 expression is induced by oxidative stress and potentiated by HNG. Expression of DJ-1 was assessed by Western blot (A) and RT-PCR (B) at 4h after treatment with H 2 0 2 . HNG treatment signficantly increased protein levels. RNA levels decreased with H 2 0 2 at 4h, which could result in a subsequent decline in DJ-1 protein at a later time. This decrease was attenuated by HNG (p ⁇ 0.05).
  • Figure 4 HNG potentiates AMPK activation: Incubation for 4h with InM HNG increased AMPK activation over H 2 0 2 alone.
  • Figure 5 Humanin activates STAT-3 in primary hypothalamic neurons. Significant induction (increase in p-STAT-3/totaI STAT-3), was apparent at 2 minutes, peaking at 5 min to 1 h, and remained elevated at 4h.
  • FIG. 6 DJ-1 protein levels remain constant over the lifespan of FBN rats. Representative lanes of a western blot depicting DJ-1 signals. Bars represent the mean ⁇ SEM for groups of 4.
  • Figure 7 HNG potentiates AMPK activation: Incubation for 4h with InM HNG increased AMPK activation over H 2 0 2 alone.
  • treating Parkinson's disease means ameliorating an extant Parksinon's disease, or reducing or preventing progression of Parkinson's disease. Treatment is effected when one or more symptoms of the Parkinson's disease are ameliorated, stabilized, reduced or reversed.
  • Parkinson's disease is a neurodegenerative medical condition well-known in the art in which subjects usually display tremor, rigidity, slowness of movement (bradykinesia), and postural instability. Neuropsychiatric symptoms, such as disturbances of speech, cognition, mood, behaviour and thought may also occur. Parkinson's disease (PD) is usually idiopathic, though some subjects show an apparent genetic component. The main pathological characteristic of PD is cell death in the substantia nigra and, more specifically, in the ventral part of the pars compacta.
  • Pro-dromal symptoms associated with Parkinsons' disease are known, and the treatment methods described herein can be applied to a subject exhibiting a plurality of pro-dromal symptoms associated with Parkinsons' disease, for example a combination of more than one of constipation, loss of smell, executive dysfunction, fluctuating cognition, sleep disturbances, and visuospatial dysfunction.
  • treating the disease means either or both of delaying onset of
  • humanin is a peptide having the sequence:
  • MAPRGFSCLLLLTSE1DLPVKRRA SEQ ID NO: l.
  • An active humanin analog is a peptide or peptidomimetic based on humanin and having equivalent or improved activity thereof with regard to DJ-1 and/or STAT-3 as described hereinbelow. Such activitites are readily determined, for example using the assays described in the experimental section hereinbelow.
  • “humanin analog” and “active humanin ananlog” are used interchangeably.
  • the analog is a peptide.
  • the humanin or humanin active analog is 17-50 amino acids in length.
  • the humanin or humanin active analog is 20-25 amino acids in length.
  • the humanin or active humanin analog is 24 amino acids in length. Analogs of humanin are known in the art (e.g. see
  • the humanin analog is HNG, which has the sequence MAPRGFSCLLLLTGEIDLPVKRRA (SEQ ID NO:2). Analogs of humanin can also be created by substitution of conservative amino acids into humanin.
  • DJ-I is the protein known in the art as product of the DJ-1 gene.
  • the DJ-1 has the sequence set forth in NCBI Reference Sequence NP_009193.2 (human DJ-1).
  • a method is provided of treating Parkinson's disease or of protecting dopaminergic neurons from neurotoxicity in a subject comprising administering to the subject an amount of humanin or an active humanin analog effective to treat Parkinson's disease or protect dopaminergic neurons.
  • the neurotoxicity results from oxidative stress.
  • the neurotoxicity results from metabolic stress.
  • STAT-3 is Signal transducer and activator of transcription 3 also known as STAT3. and is a transcription factor which in humans is encoded by the STAT-3 gene.
  • STAT-3 is encoded by the sequence set forth in GenBank: DQ039079.1.
  • it is advantageous to increase DJ-1 expression because DJ-1 is a known mediator of neuronal survival through its role in receptor-mediated signal transduction.
  • STAT3 signaling is known to promote protection against oxidative stress under various pathophysiological conditions in other systems.
  • the humanin or active humanin analog is administered in an amount and manner effective to treat Parkinson's disease or protect dopaminergic neurons or to treat a subject exhibiting a plurality of pro-dromal symptoms associated with Parkinsons' disease.
  • the humanin or active humanin analog is administered in an amount and manner effective to increase DJ-1 expression in a neuron or activate STAT-3 in a neuron.
  • the neuron is a dopaminergic neuron.
  • the neuron is a substantia nigra neuron.
  • the neuron is a striatal neuron.
  • the humanin or active humanin analog is administered in an amount and manner effective to enter the midbrain of the subject.
  • the humanin or humanin analog is administered parenterally.
  • the humanin or humanin analog is administered into the central nervous system of the subject.
  • the humanin or humanin analog is administered into the cerebrospinal fluid of the subject.
  • the humanin or humanin analog is administered via an implant in the central nervous system of the subject.
  • the implant comprises a polymer matrix.
  • the humanin or humanin analog is administered intraventricularly or intrathecally.
  • the humanin or humanin analog is administered, intranasally. In an embodiment of the methods, the humanin or humanin analog is administered in a manner effective to enter the substantia nigra of the subject and/or the striatum of the subject. In an embodiment of the methods, the humanin or humanin analog is administered directly into the substantia nigra of the subject and/or the striatum of the subject. In an embodiment, the humanin or humanin analog is administered directly into the pars compacta of the subject. Such direct administration can be effected by any method known in the art, including cannulation, catheterization, injection and via an implant in the vicinity or, or within, the substantia nigra and/or striatum.
  • the humanin or humanin analog is administered by gene therapy, e.g. using a suitable vector.
  • a suitable vector for a choice of vector and delivery conditions see Gene Therapy of the Central Nervous System: From Bench to Bedside (Kaplitt et al.), Academic Press, (2005), the contents of which are hereby incorporated by reference.
  • a lentiviral, adenoviral, or adeno-associated viral vector comprising a nucleic acid encoding the humanin or humanin analog can be administered to the subject.
  • a site-specific promoter into the vector such as a mammalian CNS-specific promoter, or a substantia-nigra and/or striatium specific promoter is a preferred embodiment.
  • the vector encodes the humanin analog comprising SEQ ID NO:2.
  • the active humanin analog which is administered, and the humanin analog comprises SEQ ID NO:2.
  • the subject has been identified as suffering from Parkinson's disease. In an embodiment of the methods, the subject has been identified as exhibiting a plurality of pro-dromal symptoms associated with Parkinsons' disease.
  • the methods further comprise identifying the subject as suffering from Parkinson's disease prior to administering the humanin or humanin analog. In embodiments, the methods further comprise identifying the subject as as exhibiting a plurality of pro-dromal symptoms associated with Parkinsons' disease.
  • the patient does not have Alzheimer's disease. In an embodiment the patient is diagnosed as not having Alzheimer's disease.
  • a humanin analog is also provided for treating Parkinson's disease or for protecting dopaminergic neurons from neurotoxicity in a subject.
  • the humanin analog comprises SEQ ID NO:2.
  • the neurotoxicity results from oxidative stress.
  • the neurotoxicity results from metabolic stress.
  • the humanin and active humanin analogs described herein can be administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier used can depend on the route of administration.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, a suspending vehicle, for delivering the instant agents to the animal or human subject.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include, but are not limited to, additive solution-3 (AS-3), saline, phosphate buffered saline, Ringer's solution, lactated Ringer's solution, Locke-Ringer's solution, Krebs Ringer's solution, Hartmann's balanced saline solution, and heparinized sodium citrate acid dextrose solution.
  • AS-3 additive solution-3
  • saline phosphate buffered saline
  • Ringer's solution lactated Ringer's solution
  • Locke-Ringer's solution Lactated Ringer's solution
  • Krebs Ringer's solution Hartmann's balanced saline solution
  • Hartmann's balanced saline solution Hartmann's balanced saline solution
  • heparinized sodium citrate acid dextrose solution heparinized sodium citrate acid dextrose solution.
  • the pharmaceutical carrier is acceptable for administration into the central nervous system of a mammal.
  • inhibitors, active fragments, active analogs of fragments, and agents can be administered together or independently in admixtures with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • Dosing can be any method or regime known in the art. For example, daily, twice daily, weekly, bi-weekly, monthly, as needed, and continuously. Implants are advantageous for continuous administration, but are not the only means of continuous administration.
  • the humanin or humanin analog is conjugated to an entity that improves the half-life and/or stability of the humanin or humanin analog.
  • entity that improves the half-life and/or stability of the humanin or humanin analog.
  • Non-limiting examples include PEG or derivatives thereof.
  • the peptide humanin and peptide humanin analogs can be synthesized by any technique known in the art including solid-phase synthesis, liquid-phase synthesis, and expression of appropriate encoding DNA in a host cell and recovery therefrom.
  • the subject is a mammal.
  • the subject is a human.
  • a pharmaceutical composition comprising humanin or an active analog of humanin for treating Parkinson's disease. Also provided is a pharmaceutical composition comprising humanin or an active analog of humanin for activating STAT-3 in a neuron of a subject or for increasing DJ-1 expression in a neuron of a subject.
  • Also provided is a method of identifying a candidate treatment for Parkinson's disease comprising a) modeling in silico the 3-dimensional form of the humanin analog comprising SEQ ID NO:2, b) testing in silico if a compound from a library of small molecule compounds mimics the modeled 3-dimensional form, and c) determining in vitro if the small molecule identified in b) is chemically stable, thereby identifying the candidate treatment.
  • HN humanin
  • AD Alzheimer's Disease
  • HN and its potent analog HNG have been shown to increase cell survival in response to a variety of insults including serum deprivation, prion induced apoptosis and in an ischemia/reperfusion model of stroke (15-17).
  • HN HN and its analogs influence glucose metabolism by improving insulin sensitivity (18) and, in addition, have shown that HNG improves survival in cardiomyocytes when exposed to ischemia/reperfusion (19), an improvement that occurs through the activation of metabolic pathways involving cAMP-activated protein kinase (AMPK) and attenuation of apoptosis.
  • AMPK cAMP-activated protein kinase
  • HN is at the crossroads of cell survival, metabolism, oxidative stress, and aging. It improves cell survival in response to many stressors related to age, nutritional deprivation, ischemia, and oxidative stress that translate to improved outcomes. Strengthening this link between HN and aging and implicating a role for HN in many age-related diseases is this laboratory's observations that HN levels decline with age in human serum, CSF, and brain tissue, and in rodent and human hypothalamus (18). Results
  • Rattin is present in the rat midbrain and may decline with age. Humanin has been shown to offer protection relevant to a variety of age-related diseases such as Alzheimer's disease, stroke, insulin resistance, and myocardial infarction in addition to other insults such as prion-induced apoptosis and amyotrophic lateral sclerosis (10, 16-19, 21). The common thread among these diseases is the presence of cellular stress in the form of metabolic defects, cellular toxins, ischemia or reactive oxygen species. Although protection has been demonstrated in a variety of cell types, including neurons and PC- 12 cells, effects on midbrain dopaminergic neurons or models of PD have not been reported.
  • age-related diseases such as Alzheimer's disease, stroke, insulin resistance, and myocardial infarction in addition to other insults such as prion-induced apoptosis and amyotrophic lateral sclerosis (10, 16-19, 21).
  • the common thread among these diseases is the presence of cellular stress in the form of metabolic defects, cellular
  • results here from Western blots demonstrate that rattin (RN), the rat homolog of HN, is present in the rat midbrain and in MN9D, a dopaminergic cell line.
  • RN rattin
  • MN9D MN9D
  • CNTFR-a is present in MN9D cells and in rat midbrain and others have shown that it is present in the basal ganglia of primates (22).
  • HN is neuroprotective in a dopaminergic cell line.
  • cultures were challenged by serum withdrawal, 3 ⁇ 4 ⁇ 3 ⁇ 4, a free radical, and rotenone, a specific and potent inhibitor of mitochondrial complex I.
  • MN9D a dopaminergic cell line
  • HNG a potent HN analog with activity in rodents
  • Fig. 2A serum withdrawal
  • Fig. 2B hydrogen peroxide
  • Fig. 2C-D rotenone
  • HNG increased expression of DJ-1 in MN9D cells at the RNA and protein levels after serum deprivation and in response to H 2 0 2 (Fig. 3).
  • DJ-1 is an evolutionary conserved multi-functional transcriptional co-activator and the product of the Park7 gene associated with PD. Oxidative insults induce an up-regulation and redistribution of DJ-1 from the nucleus to mitochondria (23) and DJ-1 protects dopaminergic neurons in response to rotenone, H 2 0 2 , MPTP, and 6-OHDA toxicity (24, 25). DJ-1 is also activated as part of physiological receptor-mediated signal transduction.
  • DJ-1 may also act indirectly, through astrocytes, where it is upregulated in neurodegenerative diseases and in stroke (26).
  • Cells deficient in DJ-1 are extraordinarly sensitive to damage from both rotenone and MPTP in flies and in mice (26).
  • astrocytic DJ-1 has been shown to protect neurons in stroke and inflammation and importantly, DJ-1 knockdown in astrocytes impaired neuroprotection against rotenone (27).
  • levels of DJ-1 are low in cerebrospinal fluid in Parkinson's disease and therefore this protein has been regarded as a biomarker (28).
  • Genetic mutations in PARK7/DJ-1 can cause the rare form of autosomal recessive hereditary Parkinson's disease.
  • DJ-1 regulates redox signaling kinase pathways and acts as a transcriptional regulator of antioxidative gene batteries.
  • DJ-1 enhances the activity of the transcription factor, Nuclear-factor-E2-related factor (Nrf)-2, a master regulator of antioxidant genes and up-regulates response genes such as hemeoxygenase-1 (HO-1), thioredoxin (Trx), thrioredoxin reductase (TrxR), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione S-transferase (GST), and catalase ((29), (30-33)) by binding to the antioxidant responsive element (ARE) found in their promoter (34).
  • ARE antioxidant responsive element
  • DJ-1 increases superoxide dismutase (SOD) activity (35). Predicted stimulation of these enzymes would increase resistance to oxidative stress, resulting in higher resistance to oxidative challenges.
  • HN cAMP- activated protein kinase
  • HN and analogs improve insulin sensitivity and increase glucose uptake (18).
  • AMPK is a metabolic sensor and important for the adaptive responses of energetically stressed cells (36). Activation of AMPK is especially relevant for neurons, which are very metabolically active and have a poor capacity for nutrient storage, rendering them highly sensitive to energy fluctuations.
  • AMPK can be activated by resveratrol, a polyphenol found in red wine, but it can also be activated by metabolic stressors, such as ischemia/hypoxia and glucose deprivation (36-38).
  • metabolic stressors such as ischemia/hypoxia and glucose deprivation (36-38).
  • AMPK activation in rat brain protected neurons after energy deprivation, whereas mutations in the AMPK subunit in Drosophila led to progressive neurodegeneration (39).
  • AMPK links metabolic control and neuronal survival (40).
  • inhibition of AMPK increased MPP+- induced cell death and over-expression increased survival in human neuroblastoma cells (41).
  • AMPK can be activated in dopaminergic MN9D cells in response to HNG.
  • HN can activate Jak/STAT, MAPK, and PI3K/Akt signaling pathways in the hypothalamus, skeletal muscle and liver (42-44) and it is known that HN-mediated protection of non-dopaminergic neurons involves the activation of tyrosine kinases and STAT-3 (13).
  • Western blots were probed with antibodies to total and phosphorylated STAT-3 protein.
  • HNG could activate STAT-3 in these neurons within 5 minutes of treatment (Fig. 5).
  • Other groups have demonstrated HN mediated neuroprotection by other molecules involved in metabolic signaling.
  • HN delayed apoptosis by down-regulating P38 and MAPK (15) and prevented cell death when Jun N-terminal kinase (JNK) was constitutively activated, suggesting that an important mechanism of cell protection could be to interrupt JNK activity (45).
  • JNK can mediate the cytotoxic effects of MPTP (24).
  • the data here data shows that HNG protects dopaminergic neurons from rotenone.
  • ERK1/2 signaling was shown to mitigate neurotoxicity in nigral dopaminergic neurons (46), but it is not known whether HN or AMPK activate ER 1/2 in these cells. Activation of metabolic signaling through AMPK should lead to an increase in cellular glucose uptake, which may influence cell survival. HNG has also been shown to increase Akt phosphorylation and increase survival in primary cortical neurons (16). Akt is also important to survival in dopaminergic neurons (47).
  • cAMP-activated protein kinase is a metabolic sensor important for the adaptive responses of energetically stressed cells (50). Activation of AMPK is especially relevant for neurons, which have high metabolic activity, but low capacity for nutrient storage, rendering them highly sensitive to energy fluctuations. AMPK activation in rat brain can protect neurons after energy deprivation (51), whereas mutations in AMPK led to progressive neurodegeneration in Drosophila (52). Thus AMPK links metabolic control and neuronal survival (53).
  • inhibition of AMPK increased MPP+-toxicity and over-expression increased survival in human neuroblastoma cells (54).
  • AMPK can be activated in dopaminergic MN9D cells in response to HNG (Fig. 7).
  • activation of AMPK will prevent the death of midbrain dopaminergic neurons and influence neuronal vulnerability in PD5.
  • humanin analog HNG can protect against neurotoxicity of dopaminergic neurons, and is a viable therapy for treating Parkinson's disease.
  • AMP-activated protein kinase is activated in Parkinson's disease models mediated by l-methyl-4-phenyl-l , 2,3,6- tetrahydropyridine. Biochem Biophys Res Commun. 391 (1): p. 147-51.
  • Ciliary neurotrophic factor stimulates muscle glucose uptake by a PI3- kinase-dependent pathway that is impaired with obesity. Diabetes, 2009. 58(4): p. 829-39.
  • AMP-activated protein kinase AMPK
  • AMP-activated protein kinase is activated in Parkinson's disease models mediated by l-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine. Biochem Biophys Res Commun. 391, 147-51 (2010).

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Abstract

La présente invention concerne des méthodes de traitement de la maladie de Parkinson, consistant à protéger les neurones dopaminergiques contre la neurotoxicité et à augmenter les niveaux de DJ-1 dans les neurones. L'invention concerne également des méthodes d'identification de traitements d'intérêt potentiel contre la maladie de Parkinson.
PCT/US2012/000535 2011-11-02 2012-11-02 Protection par l'humanine des neurones dopaminergiques Ceased WO2013066374A2 (fr)

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WO2024080440A1 (fr) * 2022-10-12 2024-04-18 동아대학교 산학협력단 Composition pour la prévention ou le traitement de troubles neurodégénératifs, comprenant le peptide humanine utilisé comme principe actif

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AU2003242340A1 (en) * 2002-06-14 2003-12-31 Takeda Pharmaceutical Company Limited Novel screening method
CA2499573A1 (fr) * 2002-09-24 2004-04-15 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Procede portant sur l'amelioration de distribution par convection d'agents therapeutiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024080440A1 (fr) * 2022-10-12 2024-04-18 동아대학교 산학협력단 Composition pour la prévention ou le traitement de troubles neurodégénératifs, comprenant le peptide humanine utilisé comme principe actif

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