A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application

Although growth factors have great therapeutic potential because of their regenerative functions, they often have intrinsic drawbacks, such as low thermal stability and high production cost. Oligonucleotides have recently emerged as promising chemical entities for designing synthetic alternatives to growth factors. However, their applications in vivo have been recognized as a challenge because of their susceptibility to nucleases and limited distribution to a target tissue. Here, we present the first example of oligonucleotide-based growth factor mimetics that exerts therapeutic effects at a target tissue after systemic injection. The aptamer was designed to dimerize a growth factor receptor for its activation and mitigated the progression of Fas-induced fulminant hepatitis in a mouse model. This unprecedented functionality of the aptamer can be reasonably explained by its high nuclease stability and migration to the liver parenchyma. These mechanistic analyses provided insights for the successful application of aptamer-based receptor agonists.

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CDNF Protein Therapy in Parkinson’s Disease

Cell Transplantation ◽

10.1177/0963689719840290 ◽

2019 ◽

Vol 28 (4) ◽

pp. 349-366 ◽

Cited By ~ 19

Author(s):

Henri J. Huttunen ◽

Mart Saarma

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Trials ◽

Growth Factors ◽

Growth Factor ◽

Neurotrophic Factor ◽

Therapeutic Potential ◽

Large Animal ◽

Target Tissue ◽

Large Animal Models

Neurotrophic factors (NTF) are a subgroup of growth factors that promote survival and differentiation of neurons. Due to their neuroprotective and neurorestorative properties, their therapeutic potential has been tested in various neurodegenerative diseases. Bioavailability of NTFs in the target tissue remains a major challenge for NTF-based therapies. Various intracerebral delivery approaches, both protein and gene transfer-based, have been tested with varying outcomes. Three growth factors, glial cell-line derived neurotrophic factor (GDNF), neurturin (NRTN) and platelet-derived growth factor (PDGF-BB) have been tested in clinical trials in Parkinson’s disease (PD) during the past 20 years. A new protein can now be added to this list, as cerebral dopamine neurotrophic factor (CDNF) has recently entered clinical trials. Despite their misleading names, CDNF, together with its closest relative mesencephalic astrocyte-derived neurotrophic factor (MANF), form a novel family of unconventional NTF that are both structurally and mechanistically distinct from other growth factors. CDNF and MANF are localized mainly to the lumen of endoplasmic reticulum (ER) and their primary function appears to be modulation of the unfolded protein response (UPR) pathway. Prolonged ER stress, via the UPR signaling pathways, contributes to the pathogenesis in a number of chronic degenerative diseases, and is an important target for therapeutic modulation. Intraputamenally administered recombinant human CDNF has shown robust neurorestorative effects in a number of small and large animal models of PD, and had a good safety profile in preclinical toxicology studies. Intermittent monthly bilateral intraputamenal infusions of CDNF are currently being tested in a randomized placebo-controlled phase I–II clinical study in moderately advanced PD patients. Here, we review the history of growth factor-based clinical trials in PD, and discuss how CDNF differs from the previously tested growth factors.

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Acceleration of Pelvic Tissue Construction by Overexpression of Basic Fibroblast Growth Factor in the Stem Cells

10.21203/rs.3.rs-70178/v1 ◽

2020 ◽

Author(s):

Xiaotong Wu ◽

Yuanyuan Jia ◽

Shiyan Wang ◽

Jiaqi Wang ◽

Xiuli Sun ◽

...

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Growth Factors ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Therapeutic Potential ◽

Target Tissue ◽

Fibroblast Growth ◽

Seed Cells

Abstract Background Pelvic organ prolapse (POP) is a common debilitating condition affecting about 30–40% of women. The application of stem cells therapy and growth factor has greatly promoted the development of pelvic tissue engineering, which remains a promising approach, but there is no consensus on the therapeutic mechanism of stem cells and the application of growth factors. Stem cells were mainly used as seed cells to differentiate into target tissue cells, fuse with target tissue after transplantation and paracrine effect to play a therapeutic role in pelvic tissue engineering. However, whether stem cells can be differentiated into target tissue cells is still to be a question,in this regard, the contemporary trend is to investigated the effect of adipose-derived stem cells (ADSCs) as the seed cells of pelvic tissue engineering on the repair of POP and the underlying mechanisms.Methods In the present study,we evaluated the therapeutic potential of gene-modified ADSC that overexpress basic fibroblast growth factor（bFGF）and evaluated its effects on paracrine function and directional differentiation ability.Results The results showed that following ADSCs are designed to continuously release controllable levels of growth factors during the control period of repair, taking advantage of the paracrine function of stem cells to accelerate cell growth and extracellular matrix (ECM) reconstruction during the early stage of stem cell implantation, and then stem cells are differentiated into target tissues-fibroblasts to accelerate the reconstruction of pelvic floor tissues.Conclusions We suggest that the observed effects are determined by pleiotropic effects of bFGF, along with the multifactorial paracrine action of ADSC which remain viable and functionally active within the engineered cell construct.Thus, we demonstrated the high therapeutic potential of the utilized approach for pelvic tissue engineering.

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Therapeutic potential of the epidermal growth factor receptor transactivation in hypertension: a convergent signaling pathway of vascular tone, oxidative stress, and hypertrophic growth downstream of vasoactive G-protein-coupled receptors?This paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y06-097 ◽

2007 ◽

Vol 85 (1) ◽

pp. 97-104 ◽

Cited By ~ 30

Author(s):

Carlos Fernandez-Patron

Keyword(s):

Oxidative Stress ◽

Growth Factors ◽

Growth Factor ◽

G Protein ◽

Intracellular Signaling ◽

Vascular Tone ◽

Therapeutic Potential ◽

Growth Factor Receptor ◽

Hypertrophic Growth ◽

G Protein Coupled

The concurrence of enhanced vascular tone, oxidative stress, and hypertrophic growth is a hallmark of hypertension, the condition characterized by sustained elevated blood pressure. However, it is unclear how and why such apparently distinct processes coincide in hypertension. Elevated levels of certain vasoactive G-protein-coupled receptor agonists (such as catecholamines, endothelin-1, and angiotensin II) can explain, at least in part, the development and progression of many hypertensive disorders. Here, we review findings made by other investigators and ourselves suggesting that enhanced vascular tone, oxidative stress, and hypertrophic growth characteristically induced by these agonists involve the transactivation of growth factor receptors. The first step in this transactivation mechanism is agonist-induced activation of metalloproteinase-dependent shedding of growth factors. Shed growth factors then trigger intracellular signaling cascades necessary for growth, production of reactive oxygen species, and maintenance of vascular tone. If this hypothesis is proven generally correct, then transactivation blockers have general therapeutic potential in hypertension regardless of the causative agonist.

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Heparan Sulfate Acts as a Bone Morphogenetic Protein Coreceptor by Facilitating Ligand-induced Receptor Hetero-oligomerization

Molecular Biology of the Cell ◽

10.1091/mbc.e10-04-0348 ◽

2010 ◽

Vol 21 (22) ◽

pp. 4028-4041 ◽

Cited By ~ 75

Author(s):

Wan-Jong Kuo ◽

Michelle A. Digman ◽

Arthur D. Lander

Keyword(s):

Growth Factors ◽

Growth Factor ◽

Cell Surface ◽

Heparan Sulfate ◽

Bone Morphogenetic Proteins ◽

Growth Factor Receptor ◽

In Vivo Studies ◽

Type I ◽

Receptor Complexes

Cell surface heparan sulfate (HS) not only binds several major classes of growth factors but also sometimes potentiates their activities—an effect usually termed “coreception.” A view that coreception is due to the stabilization of growth factor–receptor interactions has emerged primarily from studies of the fibroblast growth factors (FGFs). Recent in vivo studies have strongly suggested that HS also plays an important role in regulating signaling by the bone morphogenetic proteins (BMPs). Here, we provide evidence that the mechanism of coreception for BMPs is markedly different from that established for FGFs. First, we demonstrate a direct, stimulatory role for cell surface HS in the immediate signaling activities of BMP2 and BMP4, and we provide evidence that HS–BMP interactions are required for this effect. Next, using several independent assays of ligand binding and receptor assembly, including coimmunoprecipitation, cross-linking, and fluorescence fluctuation microscopy, we show that HS does not affect BMP binding to type I receptor subunits but instead enhances the subsequent recruitment of type II receptor subunits to BMP-type I receptor complexes. This suggests a view of HS as a catalyst of the formation of signaling complexes, rather than as a stabilizer of growth factor binding.

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Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment

10.5772/intechopen.96552 ◽

2021 ◽

Author(s):

Halyna Kuznietsova ◽

Olexandr Ogloblya

Keyword(s):

Cell Proliferation ◽

Growth Factors ◽

Growth Factor ◽

Liver Fibrosis ◽

Growth Factor Receptor ◽

Growth Factor Receptors ◽

In Vivo Models ◽

Novel Approach

The background of liver fibrous degeneration is excessive cell proliferation including hepatic stellate cells, inflammatory cells, fibroblasts and myofibroblasts. Often it is the consequence of increased growth factors and/or their receptors expression. Key contributors to the liver cell proliferation are EGFR, FGFR, PDGFR, VEGFR, TGFβR, the increased expression of which is indicated on in vitro and in vivo models of liver fibrosis and in patients who experienced fibrosis-accompanied liver diseases. Elimination of growth factors/suppression of their receptors is associated with the weakening/elimination of certain processes responsible for fibrogenesis. This chapter represents the evidences of the efficacy of growth factor receptors signaling downregulation for the suppression of liver fibrosis and cirrhosis and their individual manifestations. The data on established and experimental therapeutics – specific and multikinase growth factor receptor inhibitors which demonstrated antifibrotic and anticirrhotic activity under in vitro and in vivo models, are also presented.

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Growth Factor Therapy for Parkinson’s Disease: Alternative Delivery Systems

Journal of Parkinson s Disease ◽

10.3233/jpd-212662 ◽

2021 ◽

pp. 1-7

Author(s):

Sarah Jarrin ◽

Abrar Hakami ◽

Ben Newland ◽

Eilís Dowd

Keyword(s):

Parkinson’S Disease ◽

Gene Therapy ◽

Parkinson's Disease ◽

Growth Factors ◽

Growth Factor ◽

Ex Vivo ◽

Brain Regions ◽

Delivery Systems ◽

Alternative Delivery

Despite decades of research and billions in global investment, there remains no preventative or curative treatment for any neurodegenerative condition, including Parkinson’s disease (PD). Arguably, the most promising approach for neuroprotection and neurorestoration in PD is using growth factors which can promote the growth and survival of degenerating neurons. However, although neurotrophin therapy may seem like the ideal approach for neurodegenerative disease, the use of growth factors as drugs presents major challenges because of their protein structure which creates serious hurdles related to accessing the brain and specific targeting of affected brain regions. To address these challenges, several different delivery systems have been developed, and two major approaches—direct infusion of the growth factor protein into the target brain region and in vivo gene therapy—have progressed to clinical trials in patients with PD. In addition to these clinically evaluated approaches, a range of other delivery methods are in various degrees of development, each with their own unique potential. This review will give a short overview of some of these alternative delivery systems, with a focus on ex vivo gene therapy and biomaterial-aided protein and gene delivery, and will provide some perspectives on their potential for clinical development and translation.

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Roles of microRNAs in Regulating Cancer Stemness in Head and Neck Cancers

Cancers ◽

10.3390/cancers13071742 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1742

Author(s):

Melysa Fitriana ◽

Wei-Lun Hwang ◽

Pak-Yue Chan ◽

Tai-Yuan Hsueh ◽

Tsai-Tsen Liao

Keyword(s):

Growth Factor ◽

Head And Neck ◽

Cancer Cells ◽

Signaling Pathways ◽

Epithelial To Mesenchymal Transition ◽

Survival Rates ◽

Growth Factor Receptor ◽

Cancer Stemness ◽

Mesenchymal Transition

Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40–50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor initiation, progression, metastasis, immune evasion, chemo-/radioresistance, and recurrence. The acquisition of stem-like properties of cancer cells further provides cellular plasticity for stress adaptation and contributes to therapeutic resistance, resulting in a worse clinical outcome. Thus, targeting cancer stemness is fundamental for cancer treatment. MicroRNAs (miRNAs) are known to regulate stem cell features in the development and tissue regeneration through a miRNA–target interactive network. In HNSCCs, miRNAs act as tumor suppressors and/or oncogenes to modulate cancer stemness and therapeutic efficacy by regulating the CSC-specific tumor microenvironment (TME) and signaling pathways, such as epithelial-to-mesenchymal transition (EMT), Wnt/β-catenin signaling, and epidermal growth factor receptor (EGFR) or insulin-like growth factor 1 receptor (IGF1R) signaling pathways. Owing to a deeper understanding of disease-relevant miRNAs and advances in in vivo delivery systems, the administration of miRNA-based therapeutics is feasible and safe in humans, with encouraging efficacy results in early-phase clinical trials. In this review, we summarize the present findings to better understand the mechanical actions of miRNAs in maintaining CSCs and acquiring the stem-like features of cancer cells during HNSCC pathogenesis.

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