RESUMEN
Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs. In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.
Asunto(s)
Neovascularización Coroidal , Degeneración Macular Húmeda , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Neovascularización Coroidal/tratamiento farmacológico , Humanos , Inyecciones Intravítreas , Ratones , Factor A de Crecimiento Endotelial Vascular , Agudeza VisualRESUMEN
INTRODUCTION: Over 37 million people worldwide are living with Heart Failure (HF). Advancements in medical therapy have improved mortality primarily by slowing the progression of left ventricular dysfunction and debilitating symptoms. Ultimately, heart transplantation, durable mechanical circulatory support (MCS), or palliative care are the only options for patients with end-stage HF. Regenerative therapies offer an innovative approach, focused on reversing myocardial dysfunction and restoring healthy myocardial tissue. Initial clinical trials using autologous (self-donated) bone marrow mononuclear cells (BMMCs) demonstrated excellent safety, but only modest efficacy. Challenges with autologous stem cells include reduced quality and efficacy with increased patient age. The use of allogeneic mesenchymal precursor cells (MPCs) offers an "off the shelf" therapy, with consistent potency and less variability than autologous cells. AREAS COVERED: Preclinical and initial clinical trials with allogeneic MPCs have been encouraging, providing the support for a large ongoing Phase III trial-DREAM-HF. We provide a comprehensive review of preclinical and clinical data supporting MPCs as a therapeutic option for HF patients. EXPERT OPINION: The current data suggest allogeneic MPCs are a promising therapy for HF patients. The results of DREAM-HF will determine whether allogeneic MPCs can decrease major adverse clinical events (MACE) in advanced HF patients.
Asunto(s)
Progresión de la Enfermedad , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/fisiología , Animales , Ensayos Clínicos como Asunto/métodos , Insuficiencia Cardíaca/fisiopatología , Humanos , Trasplante de Células Madre Mesenquimatosas/tendencias , Regeneración/fisiología , Trasplante Homólogo/métodos , Trasplante Homólogo/tendencias , Resultado del TratamientoRESUMEN
OBJECTIVE Disc degeneration and associated low-back pain are major causes of suffering and disability. The authors examined the potential of mesenchymal precursor cells (MPCs), when formulated with pentosan polysulfate (PPS), to ameliorate disc degeneration in an ovine model. METHODS Twenty-four sheep had annular incisions made at L2-3, L3-4, and L4-5 to induce degeneration. Twelve weeks after injury, the nucleus pulposus of a degenerated disc in each animal was injected with ProFreeze and PPS formulated with either a low dose (0.1 million MPCs) or a high dose (0.5 million MPCs) of cells. The 2 adjacent injured discs in each spine were either injected with PPS and ProFreeze (PPS control) or not injected (nil-injected control). The adjacent noninjured L1-2 and L5-6 discs served as noninjured control discs. Disc height indices (DHIs) were obtained at baseline, before injection, and at planned death. After necropsy, 24 weeks after injection, the spines were subjected to MRI and morphological, histological, and biochemical analyses. RESULTS Twelve weeks after the annular injury, all the injured discs exhibited a significant reduction in mean DHI (low-dose group 17.19%; high-dose group 18.01% [p < 0.01]). Twenty-four weeks after injections, the discs injected with the low-dose MPC+PPS formulation recovered disc height, and their mean DHI was significantly greater than the DHI of PPS- and nil-injected discs (p < 0.001). Although the mean Pfirrmann MRI disc degeneration score for the low-dose MPC+PPS-injected discs was lower than that for the nil- and PPS-injected discs, the differences were not significant. The disc morphology scores for the nil- and PPS-injected discs were significantly higher than the normal control disc scores (p < 0.005), whereas the low-dose MPC+PPS-injected disc scores were not significantly different from those of the normal controls. The mean glycosaminoglycan content of the nuclei pulposus of the low-dose MPC+PPS-injected discs was significantly higher than that of the PPS-injected controls (p < 0.05) but was not significantly different from the normal control disc glycosaminoglycan levels. Histopathology degeneration frequency scores for the low-dose MPC+PPS-injected discs were lower than those for the PPS- and Nil-injected discs. The corresponding high-dose MPC+PPS-injected discs failed to show significant improvements in any outcome measure relative to the controls. CONCLUSIONS Intradiscal injections of a formulation composed of 0.1 million MPCs combined with PPS resulted in positive effects in reducing the progression of disc degeneration in an ovine model, as assessed by improvements in DHI and morphological, biochemical, and histopathological scores.
Asunto(s)
Degeneración del Disco Intervertebral/patología , Disco Intervertebral/patología , Células Madre Mesenquimatosas , Poliéster Pentosan Sulfúrico/farmacología , Animales , Modelos Animales de Enfermedad , Disco Intervertebral/efectos de los fármacos , Masculino , OvinosRESUMEN
PURPOSE: To investigate the effect of human joint fluid media on the survival and proliferation of bone marrow derived precusor cell, and to provide the basic data of the intraarticular injection with scaffold-free progenitor cell in advanced degenerative osteoarthritis (OA). MATERIALS AND METHODS: We obtained the joint fluid and bone marrow from 15 patients who had total knee arthroplasty due to degenerative OA, and isolated the mesenchymal progenitor cells (MPCs) from bone marrow by washing and ten times subculture. We devided the control and experiment groups according to the addition of joint fluid at various ratios (1/100, 1/10, 1, 10, 100, 1000 microliter), and statistically analyzed the numbers of mesenchymal progenitor cell proliferated according to the culture period. RESULTS: The experiments using joint fluid without centrifuge showed the increase of MPCs as the culture poriod was extended and was independent to the existence of fetal bovine serum, the dose dependent pattern in the increase of MPCs in proportion to the dose of joint fluid, and statistically significant increase MPCs in 10, 100, 1000 microliter of serum contained groups, 1000 microliter of serum-free groups (p=0.039, p=0.017, p=0.077, p=0.004). The experiments using joint fluid with centrifuge showed the increase of MPCs as the culture period was extended and was independent of fetal bovine serum, and the dose dependent pattern in the increase of MPCs in proportion to the dose of joint fluid, and statistically significant increase MPCs in 1000 microliter of both serum contained and serum-free groups (p=0.006, p=0.024). CONCLUSION: MSCs not only can survive, but also proliferate in human joint fluid. The rate of proliferaton is increased faster by the adding of joint fluid than only using common media in cell culture. And the experiment shows the dose dependent pattern in the increase of MPCs in proportion to the dose of joint fluid.