Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration

Sellers, Drew L.; Bergen, Jamie M.; Johnson, Russell; Back, Heidi; Ravits, John; Horner, Philip J.; Pun, Suzie H.

doi:10.1073/pnas.1515526113

Cited by 34 publications

(34 citation statements)

References 41 publications

(42 reference statements)

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“…Sellers et al identified a different peptide, the targeted axonal import (TAxI) peptide, which enriched recombinant bacteriophage accumulation and delivered an active enzyme into spinal cord motor neurons in the aftermath of an intramuscular injection in mice [155]. According to the authors, the TAxI peptide showed great potential for clinics, since it can also interact with human spinal cord motor neurons.…”

Section: Peptidesmentioning

confidence: 99%

Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System

et al. 2020

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Central nervous system (CNS) disorders encompass a vast spectrum of pathological conditions and represent a growing concern worldwide. Despite the high social and clinical interest in trying to solve these pathologies, there are many challenges to bridge in order to achieve an effective therapy. One of the main obstacles to advancements in this field that has hampered many of the therapeutic strategies proposed to date is the presence of the CNS barriers that restrict the access to the brain. However, adequate brain biodistribution and neuronal cells specific accumulation in the targeted site also represent major hurdles to the attainment of a successful CNS treatment. Over the last few years, nanotechnology has taken a step forward towards the development of therapeutics in neurologic diseases and different approaches have been developed to surpass these obstacles. The versatility of the designed nanocarriers in terms of physical and chemical properties, and the possibility to functionalize them with specific moieties, have resulted in improved neurotargeted delivery profiles. With the concomitant progress in biology research, many of these strategies have been inspired by nature and have taken advantage of physiological processes to achieve brain delivery. Here, the different nanosystems and targeting moieties used to achieve a neuronal delivery reported in the open literature are comprehensively reviewed and critically discussed, with emphasis on the most recent bioinspired advances in the field. Finally, we express our view on the paramount challenges in targeted neuronal delivery that need to be overcome for these promising therapeutics to move from the bench to the bedside.

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Section: Peptidesmentioning

confidence: 99%

Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System

et al. 2020

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“…Regenerative medicine intended vascular homing peptides have been described towards specific clinical situations, such as targeting blood clots that form after an acute, traumatic tissue injury [33] or towards angiogenetic blood vessels at early [34] and late stage of wound healing when granulation tissue matures to scar tissue [26]. In addition to these, homing peptide targeting tissue factor after blood vessel rupture has been used to deliver amphiphile nanofibers to control hemorrhage [35], targeted axonal import peptide delivered therapeutic recombinant proteins to transected nerves after spinal cord injury [36]. Homing peptides that seek out burn injury in intestine [37,38] or deliver diagnostic or therapeutic nanoparticle to brain injury after a traumatic breakage of the blood-brain barrier [39,40] have been described.…”

Section: Ligands Targeting Injured Tissuesmentioning

confidence: 99%

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

Järvinen

Pemmari

2020

Nanomaterials

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Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic blood vessels in the regenerating tissues have a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an appealing opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives to a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine.

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“…can be applied to all injuries, such as identifying peptides capable of binding to the angiogenic or inflammatory blood vessels forming at the injured tissues [24] , or peptides binding to the extracellular matrix (ECM) collagen exposed in inflammatory conditions [30] . Additional targeting peptides have been described towards more specific clinical molecular targets such as blood clots after an injury [31] , angiogenetic blood vessels at early [32] and late stage of wound healing when granulation tissue matures to scar tissue [24] , ruptured blood vessels [33] , transected nerves [34] , intestine with burn injury [35,36] , brain injury after a traumatic breakage of the blood-brain barrier [37,38] , bone tissue [39][40][41] , bacterial infections [42] or simply illuminating neural structures during surgery [43,44] (Table 1).…”

Section: Ligands Targeting Injured Tissuesmentioning

confidence: 99%

Systemically Administered, Target-specific, Multi-functional Therapeutic Recombinant Proteins in Regenerative Medicine

Järvinen

Pemmari

2019

Preprint

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Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic vasculature forming in the regenerating tissues has a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine

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Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration

Cited by 34 publications

References 41 publications

Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System

Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

Systemically Administered, Target-specific, Multi-functional Therapeutic Recombinant Proteins in Regenerative Medicine

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