Unlock instant, AI-driven research and patent intelligence for your innovation.

Treatment of tlr-4 mediated diseases and conditions with aptamers targeting tlr-4

An aptamer and pathological technology, applied in the field of treating TLR-4-mediated diseases and pathological conditions with an aptamer targeting TLR-4

Pending Publication Date: 2022-01-21
奥普塔目标公司
View PDF6 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few drugs that modulate TLR-4; moreover, generally, drugs currently in development that modulate TLR-4 and treat or prevent TLR-4-mediated mediation are indicated for the treatment of a specific condition or a limited number of conditions

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Treatment of tlr-4 mediated diseases and conditions with aptamers targeting tlr-4
  • Treatment of tlr-4 mediated diseases and conditions with aptamers targeting tlr-4
  • Treatment of tlr-4 mediated diseases and conditions with aptamers targeting tlr-4

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0588] Example 1. Primary pharmacodynamics in vitro

[0589] Antagonism of hTLR-4 activation by aptamers

[0590] hTLR-4 activation assay was performed on HEK-blue-hTLR4 cells. The use of ultrapure LPS (0.1 ng / ml) as an important aspect related to the mechanism of kidney stone formation can also be drawn from these studies.

[0591] A TLR-4 agonist was used to activate cells, and a natural LPS antagonist (LPS-RS, 200 ng / ml) was used as a positive control for antagonistic activity against hTLR-4. hTLR-4 activation was quantified by measuring secreted embryonic alkaline phosphatase (SEAP) 24 hours after addition of ligand to the incubation medium. Poly AG nucleotides (38x) (38x(AG)) were used as control ssDNA (as scrambler). 38x(AG), is an oligonucleotide ssDNA with a fixed sequence, 38 times that of A-G. It was designed in the laboratory so it is a control aptamer that does not have any 3D structure or has a very limited and unstable When an aptamer interacts with a protei...

example 2

[0607] Example 2. Primary pharmacodynamics in vivo. Efficacy in a Rodent Model of Stroke

[0608] The animal model used in the study consisted of the following:

[0609] a) Permanent middle cerebral artery occlusion (pMCAO) by ligation and temporary middle cerebral artery occlusion (tMCAO) by ligation in mice (Chen et al. (1986) Stroke 17(4):738-743 ),

[0610] b) Transient intraluminal middle cerebral artery occlusion (tMCAO) in rats (Justicia et al. (2001) J Cereb Blood Flow Metab 21(9):1097-1104),

[0611] c) Permanent middle cerebral artery occlusion by electrocoagulation in rats and mice (Morancho et al., Neuropathol Appl Neurobiol 2012).

[0612] In all models, unilateral focal ischemic lesions were surgically induced in the cerebral cortex by permanent or temporary middle cerebral artery occlusion (MCAO). Following the recommendations of the STAIR stroke preclinical investigation (STAIR group: Update of the Stroke Therapy Academic Industry Roundtable Preclinical Rec...

example 3

[0640] Example 3. ApTOLL Effects in Humans

[0641] 3.1 Double-blind, placebo-controlled, randomized Phase Ia clinical study of ApTOLL for the treatment of acute ischemic stroke in healthy volunteers to assess tolerability and pharmacokinetics

[0642] Maximum recommended starting dose for humans

[0643] Calculation of the Maximum Recommended Starting Dose (MRSD) to be administered in Healthy Subjects:

[0644] NOAEL (No Observed Adverse Effect Level):

[0645] Rats: No side effects were observed with a higher dose of 50mg / kg / day intravenously injected for 14 days.

[0646] Cynomolgus monkeys: No side effects were observed with a higher dose of 13.9mg / kg / day (intravenous bolus injection) for 14 days.

[0647] The HED (Human Equivalent Dose) is calculated from the NOAEL, taking into account the conversion of animal doses to human equivalent doses based on body surface area. A correction factor of 10 is taken into account:

[0648] Rat: 50mg / kg x 0.162 / 10=0.81mg / kg

[064...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
affinityaaaaaaaaaa
Login to View More

Abstract

The present disclosure related to methods to treat, prevent (e.g., suppress, inhibit or delay), or ameliorate the symptoms of a TLR-4 mediated disease or condition comprising administering an aptamer of the present disclosure to a subject in need thereof, alone or combination with other pharmacological and / or surgical interventions. In a particular aspect, the aptamers of the present disclosure are administered before, during, or after pharmacological and / or surgical interventions (e.g., thrombolysis such as thrombectomy) or any combination thereof, for the treatment of ischemic (e.g., myocardial infarction or ischemic stroke), hemorrhagic (e.g., hemorrhagic stroke or hemorrhagic transformation), or neurodegenerative (e.g., multiple sclerosis) diseases or conditions. The disclosure also provides specific doses and dosage regimes.

Description

technical field [0001] The present disclosure provides methods for treating TLR-4-mediated diseases and conditions comprising administering nucleic acid aptamers that specifically target the extracellular domain of TLR-4. Background technique [0002] Toll-like receptors (TLRs) are a family of pattern recognition receptors originally identified for their role in the activation of innate immunity which may also control the activation of adaptive immune responses. TLR-4 was the first TLR to be characterized in mammals. The most important endogenous TLR-4 ligands are molecules released in response to tissue or cellular injury. Thus, TLR-4 is involved in a variety of very common pathologies associated with cellular damage to tissue, such as stroke. [0003] The involvement of innate immunity, and specifically TLRs, in a variety of pathologies has fueled interest in the development of agonists and antagonists of these receptors as pharmacological targets. However, there are fe...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/711A61P21/00A61P25/28A61P9/10
CPCA61K31/711A61P9/10A61P21/00A61P25/28A61K31/7088A61K47/02
Inventor 大卫·塞加拉·德拉佩纳利萨尔多·博斯卡·戈马尔伊格纳西奥·利索安·赫尔南德斯费尔南德·德卡斯特罗·苏布里埃卡洛斯·萨拉戈萨马卡雷纳·赫尔南德斯·希门尼斯大卫·皮涅罗·德尔里奥贝亚特里斯·费尔南德斯·戈麦斯玛丽亚·安杰利斯·莫罗·桑切斯迭戈·皮尔兹·罗德里格斯玛丽亚·尤金尼亚·萨拉沃索·莱亚尔
Owner 奥普塔目标公司