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( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2021/0023264 A1 CHENG Et Al

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( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2021/0023264 A1 CHENG Et Al US 20210023264A1 IN ( 19 ) United States ( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2021/0023264 A1 CHENG et al . ( 43 ) Pub . Date : Jan. 28 , 2021 ( 54 ) USE OF IMMUNE MODULATORS TO Publication Classification IMPROVE NERVE REGENERATION ( 51 ) Int. Ci . ( 71 ) Applicants: Edward KEEFER , (US ); The Board A61L 27/18 ( 2006.01 ) of Regents of the University of Texas A61K 45/06 ( 2006.01 ) System , Austin , TX (US ) A61K 38/18 ( 2006.01 ) ( 52 ) U.S. CI . ( 72 ) Inventors : Jonathan CHENG , Dallas , TX (US ); CPC A61L 27/18 ( 2013.01 ) ; A61K 45/06 Edward KEEFER , Dallas , TX (US ); ( 2013.01 ) ; A6IL 2430/32 ( 2013.01 ) ; A61K Srikanth VASUDEVAN , Dallas , TX 38/1866 ( 2013.01 ) ; A61K 38/18 ( 2013.01 ) ; ( US ) A61K 38/185 ( 2013.01 ) ( 73 ) Assignees : The Board of Regents of the University of Texas System , Austin , ( 57 ) ABSTRACT TX (US ); Edward KEEFER , Dallas , TX (US ) The present disclosure describes the use of immune modu ( 21 ) Appl. No .: 16 /922,355 lators to promote nerve growth and regeneration , particu ( 22 ) Filed : Jul . 7 , 2020 larly in the context of nerve deficit stemming from trauma and disease . In particular, the disclosure provides for the use Related U.S. Application Data of of CXCR4 antagonsists , STAT3 activators , and an agent ( 60 ) Provisional application No. 62 / 871,552 , filed on Jul . that increase nitric oxide, alone or in combination , to treat 8 , 2019 . nerve deficit conditions. US 2021/0023264 Al Jan. 28 , 2021 1 USE OF IMMUNE MODULATORS TO nitric oxide content and / or said one or more nerve growth IMPROVE NERVE REGENERATION factors may be delivered in a time -dependent release fash ion . PRIORITY CLAIM [ 0006 ] In one embodiment, no physical support structure [ 0001 ] This application claims benefit of priority to U.S. is inserted into said subject, and / or no growth factor is Provisional Application Ser . No. 62 / 871,552 , filed Jul. 8 , administered to said subject. In another embodiment, the 2019 , the entire contents of which are hereby incorporated CXCR4 antagonist is administered prior to both the STAT3 by reference . activator and the nitric oxide - increasing agent. In yet another embodiment, the CXCR4 antagonist is administered after BACKGROUND both the STAT3 activator and the nitric oxide -increasing agent. In still yet another embodiment, the CXCR4 antago 1. Field nist may be administered between the STAT3 activator and the nitric oxide - increasing agent. [ 0002 ] The present disclosure relates generally to the [ 0007 ] The subject may suffer from a peripheral nervous fields of medicine and neurobiology . More particularly , it system deficit, such as a congenital nerve deficit or a nerve concerns compositions and methods for the treatment of deficit due to trauma or an iatrogenic event . Alternatively, nerve deficits and nerve damage . Specifically, it relates to the the peripheral nerve deficit may be due to infection or to use of of CXCR4 antagonsists, STAT3 activators , and nitric autoimmune disease . The subject may suffer from a central oxide increasing agents, alone or in combination, to treat nervous system system deficit, such as where the nerve these conditions. deficit is in the brain or spinal cord . The peripheral nerve deficit may be a nerve deficit in a cranial nerve or a spinal 2. Description of Related Art nerve . The spinal nerve deficit may be congenital or due to [ 0003 ] Peripheral nerve injuries that require surgical inter trauma or an iatrogenic event . The spinal nerve deficit may vention account for -550,000 patients each year in the be due to infection or to autoimmune disease . The spinal United States alone (published by Magellan Medical Tech nerve deficit may be a cervical deficit, a lumbosacral deficit, nology Consultants, Inc. , Minn . ). This enormous clinical or a thoracic deficit. The subject may a non - human animal, need drives peripheral nerve regeneration research ( Yannas such as a bird , a reptile or a mammal. The subject may be et al . , 2007 ) . The PNS has an inherent capacity to regenerate a human . to a certain extent when subjected to injury. Several com [ 0008 ] The method may further comprise treating said mercially available products provide nerve regeneration subject with physical therapy or other nerve deficit therapy using exogenous materials to bridge short nerve defects < 2-3 prior to , at the time of, or post - administration . The admin cm in length . To date , no widely accepted clinical solutions istering results in improved sensory function in said subject, have : surpassed the “ long gap " barrier for manufactured such as nociceptive function and / or mechanoceptive func constructs to bridge nerve gaps longer than 2-3 cm in length ; tion . The administering may result in improved motor con increased the rate of nerve regeneration ; or increased the trol in said subject, such as fine motor control, gross motor quality of nerve regeneration . As such , finding new methods control or autonomic nerve control. of treating nerve injury that can satisfy these high standards [ 0009 ] It is contemplated that any method or composition will greatly enhance the ability to treat patients suffering described herein can be implemented with respect to any from this common and devastating family of conditions . other method or composition described herein . [ 0010 ] The use of the word “ a ” or “ an ” when used in SUMMARY conjunction with the term “ comprising ” in the claims and / or [ 0004 ] Thus, in accordance with the present disclosure, the specification may mean “ one , ” but it is also consistent there is provided a method of enhancing nerve growth , with the meaning of “ one or more , " " at least one ," and " one regrowth or regeneration in a subject comprising adminis or more than one . " tering to said subject a CXCR4 antagonist, a STAT3 acti [ 0011 ] It is contemplated that any embodiment discussed vator, and / or an agent that increases nitric oxide content . The in this specification can be implemented with respect to any method may result in bridging of a critical gap of at least 3 method or composition of the disclosure, and vice versa . cm , such as 3 cm , 3.5 cm , 4 cm , 4.5 cm or 5 cm . Admin Furthermore , compositions and kits of the disclosure can be istering may comprise administering a CXCR4 antagonist used to achieve methods of the disclosure . alone , administering a CXCR4 antagonist with a STAT3 [ 0012 ] Throughout this application , the term “ about ” is activator, administering a CXCR4 antagonist with an agent used to indicate that a value includes the inherent variation that increases nitric oxide content, or administering a of error for the device , the method being employed to CXCR4 antagonist with a STAT3 activator and an agent that determine the value , or the variation that exists among the increases nitric oxide content . study subjects . [ 0005 ] The method may further comprise inserting a [ 0013 ] The terms “ comprise” ( and any form of comprise , physical support structure into the critical gap , such as a such as comprises ” and “ comprising ” ), “ have” ( and any structure composed of poly - lactide acid , polyurethane , form of have , such as " has ” and “ having ” ), “ contain ” ( and polydioxanone, silicone , cellulose, collagen , PLGA , poly any form of contain , such as “ contains ” and “ containing ” ), caprolactone or processed natural extracellular matrix . The and “ include” ( and any form of include , such as “ includes ” method may further comprise administering to said subject and “ including ” ) are open - ended linking verbs . As a result, one or more nerve growth factors, such as a neurotrophic a device or a method that “ comprises , " " has, " " contains , " or (NGF , BDNG , NT- 3 ) , a glial - derived ( GDNF ) and / or a “ includes ” one or more elements possesses those one or pleotropic ( PTN , VEGF ) nerve growth factor . The CXCR4 more elements but is not limited to possessing only those antagonist, said STAT3 activator, said agent that increases one or more elements or steps . Likewise , an element of a US 2021/0023264 A1 Jan. 28 , 2021 2 device or method that “ comprises, " " has , " " contains, " or describe all the many variations of nerve injury . In 1941 , " includes ” one or more features possesses those one or more Seddon introduced a classification of nerve injuries based on features but is not limited to possessing only those one or three main types of nerve fiber injury and whether there is more features. continuity of the nerve . Usually, however, ( peripheral) nerve injury is classified in five stages , based on the extent of DESCRIPTION OF ILLUSTRATIVE damage to both the nerve and the surrounding connective EMBODIMENTS tissue , since supporting glial cells may be involved . Unlike [ 0014 ] Nerve deficits and injuries constitute a major chal in the central nervous system , neuroregeneration in the lenge for health care providers and represent a tremendous peripheral nervous system is possible . The processes that financial strain on insurance companies as well as individu occur in peripheral regeneration can be divided into the als suffering from such injuries. One significant example is following major events : Wallerian degeneration , axon spinal cord injury ( SCI ) , which commonly results in per regeneration / growth , and end - organ reinnervation . The manent paralysis and sensory impairments due to poor events that occur in peripheral regeneration occur with spontaneous nerve regeneration in the central nervous sys respect
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