Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A

Yu, Di; Thakor, Devang K.; Han, Inbo; Ropper, Alexander E.; Haragopal, Hariprakash; Sidman, Richard L.; Zafonte, Ross; Schachter, Steven C.; Teng, Yang D.

doi:10.1073/pnas.1300083110

Cited by 58 publications

(68 citation statements)

References 53 publications

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“…Furthermore, ICC staining for CD68 (Fig. 5C), a marker of activated microglia and macrophages (35), was significantly decreased in chronic SCI tissue following treatment with scaffolded hMSCs, compared with control groups. Relative to the lesionalone controls, the PLGA scaffold-only implant did not trigger discernibly worsened inflammatory responses in either subacutely or chronically injured spinal cords.…”

Section: Motosensory Recovery After Sci Resulting From Scaffolded Hmscmentioning

confidence: 94%

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Ropper

Thakor

Han

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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Mesenchymal stromal stem cells (MSCs) isolated from adult tissues offer tangible potential for regenerative medicine, given their feasibility for autologous transplantation. MSC research shows encouraging results in experimental stroke, amyotrophic lateral sclerosis, and neurotrauma models. However, further translational progress has been hampered by poor MSC graft survival, jeopardizing cellular and molecular bases for neural repair in vivo. We have devised an adult human bone marrow MSC (hMSC) delivery formula by investigating molecular events involving hMSCs incorporated in a uniquely designed poly(lactic-co-glycolic) acid scaffold, a clinically safe polymer, following inflammatory exposures in a dorsal root ganglion organotypic coculture system. Also, in rat T9-T10 hemisection spinal cord injury (SCI), we demonstrated that the tailored scaffolding maintained hMSC stemness, engraftment, and led to robust motosensory improvement, neuropathic pain and tissue damage mitigation, and myelin preservation. The scaffolded nontransdifferentiated hMSCs exerted multimodal effects of neurotrophism, angiogenesis, neurogenesis, antiautoimmunity, and antiinflammation. Hindlimb locomotion was restored by reestablished integrity of submidbrain circuits of serotonergic reticulospinal innervation at lumbar levels, the propriospinal projection network, neuromuscular junction, and central pattern generator, providing a platform for investigating molecular events underlying the repair impact of nondifferentiated hMSCs. Our approach enabled investigation of recovery neurobiology components for injured adult mammalian spinal cord that are different from those involved in normal neural function. The uncovered neural circuits and their molecular and cellular targets offer a biological underpinning for development of clinical rehabilitation therapies to treat disabilities and complications of SCI.spinal cord injury | recovery neurobiology | mesenchymal stromal stem cell | PLGA | locomotion R epair of neurotrauma, stroke, and neurodegenerative diseases remains an unmet medical demand because of their pathophysiological complexity and the limited spontaneous healing capacity of adult mammalian CNS. Human mesenchymal stromal stem cells (hMSCs) offer autologous transplantation feasibility (1-4) and have been studied both experimentally and clinically for traumatic brain injury (TBI) and spinal cord injury (SCI) (5-8). Although MSCs possess homeostatic and proneurogenic activities (7, 9), studies relying on neural transdifferentiation (i.e., putative differentiations of MSCs into neural cells without reentering the pluripotency phase) did not show long-term functional improvement in SCI models. The poor outcomes were attributed mainly to suboptimal survival of MSCs, leaving key therapeutic mechanisms undetermined (10). We previously established a 3D cell delivery technology by seeding neural stem cells (NSCs) in biodegradable polymer scaffolds that significantly improved donor efficacy and enabled investigation of NSC repair mechanisms in t...

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Section: Motosensory Recovery After Sci Resulting From Scaffolded Hmscmentioning

confidence: 94%

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Ropper

Thakor

Han

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…7C). Because repeated surgery introduces stress and pain that may impact the survival of the experimental animals, we opted for the convection-enhanced delivery (CED) strategy using an Alzet osmotic pump to deliver a continuous supply of the nano RNAi combination at a rate of 6 μL/24 h for 14 d; this strategy had been successful in our previous application in a rodent model of CNS disorders (48). MGG8 was implanted at a dose of 1 × 10 5 cells per mouse; then we implanted the pump (Durect Corp.) delivering 350 μg/kg (total average dose, 7 μg per mouse) through a brain infusion kit (Fig.…”

Section: Contrasting In Vivo Delivery Strategies Resulted In Varying mentioning

confidence: 99%

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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108

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Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood-brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTICtargeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.siRNA | lipopolymeric nanoparticle | glioblastoma transcription factor | brain tumor-initiating cells | convection-enhanced delivery G lioblastoma (GBM) is one of the most challenging tumors to treat (1, 2). Despite decades of research and maximal clinical combination therapy encompassing surgical resection, chemotherapy, and radiation, the median life expectancy of patients has not been extended beyond 2 y after diagnosis (2). Increasing evidence suggests that the genetic, epigenetic, and signaling heterogeneity of GBM underlies the ineffectiveness of currently available therapeutics (1, 2). Additionally, therapeutic schemes devised to challenge brain tumor cells are frequently thwarted by insufficient delivery caused by pharmacokinetics, the blood-brain barrier (BBB), and an altered tumor microenvironment in which tumor-derived signaling recruits immunomodulatory cells and induces extracellular matrix remodeling to build safe harbors of tumorigenic niches (3-5). These obstacles call for tailored therapeutic strategies to counter tumor heterogeneity and overcome roadblocks in delivery. RNAi targeting drivers of tumorigenesis shows strong potential to supplement the development of traditional small-molecule pharmaceutics (6). However, delivery remains a key obstacle for efficient RNAi against tumor drivers (5,7,8). RNA-sequencing analysis of patient tissue combined with histology and in situ hybridization (Ivy Glioblastoma Atlas Pro...

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“…[ 6,7 ] Lycopodium ( L. ) clavatum is one species of the genus Lycopodium which produces spores and which has been identifi ed to contain a range of promising phytochemicals for therapeutic applications ranging from stomach ailments to Alzheimer's disease. [8][9][10] L. clavatum spores provide a robust capsule structure and are commercially available in large quantities across the globe. [ 1 ] L. clavatum spores are used in traditional herbal medicine and have been shown to exhibit a wide range of therapeutic benefi ts including improved osteogenesis, [ 11 ] improved cognitive function, [ 12 ] treatment of gastrointestinal disorders, [ 8 ] hepatoprotective activity, [ 13 ] and antioxidative properties.…”

Section: Introductionmentioning

confidence: 99%

Lycopodium Spores: A Naturally Manufactured, Superrobust Biomaterial for Drug Delivery

Mundargi

Potroz

Park

et al. 2015

Adv Funct Materials

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Herein, the exploration of natural plant‐based “spores” for the encapsulation of macromolecules as a drug delivery platform is reported. Benefits of encapsulation with natural “spores” include highly uniform size distribution and materials encapsulation by relatively economical and simple versatile methods. The natural spores possess unique micromeritic properties and an inner cavity for significant macromolecule loading with retention of therapeutic spore constituents. In addition, these natural spores can be used as advanced materials to encapsulate a wide variety of pharmaceutical drugs, chemicals, cosmetics, and food supplements. Here, for the first time a strategy to utilize natural spores as advanced materials is developed to encapsulate macromolecules by three different microencapsulation techniques including passive, compression, and vacuum loading. The natural spore formulations developed by these techniques are extensively characterized with respect to size uniformity, shape, encapsulation efficiency, and localization of macromolecules in the spores. In vitro release profiles of developed spore formulations in simulated gastric and intestinal fluids have also been studied, and alginate coatings to tune the release profile using vacuum‐loaded spores have been explored. These results provide the basis for further exploration into the encapsulation of a wide range of therapeutic molecules in natural plant spores.

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Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A

Cited by 58 publications

References 53 publications

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Lycopodium Spores: A Naturally Manufactured, Superrobust Biomaterial for Drug Delivery

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