76 research outputs found
High-Density Lipoprotein in Metabolic Disorders and Beyond: An Exciting NewWorld Full of Challenges and Opportunities
High-density lipoprotein (HDL) is an enigmatic member of the plasma lipid and lipoprotein
transport system, best known for its ability to promote the reverse cholesterol efflux and the
unloading of excess cholesterol from peripheral tissues. More recently, data in experimental mice
and humans suggest that HDL may play important novel roles in other physiological processes
associated with various metabolic disorders. Important parameters in the HDL functions are its
apolipoprotein and lipid content, further reinforcing the principle that HDL structure defines its
functionality. Thus, based on current evidence, low levels of HDL-cholesterol (HDL-C) or dysfunctional
HDL particles contribute to the development of metabolic diseases such as morbid obesity,
type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Interestingly, low levels of HDL-C
and dysfunctional HDL particles are observed in patients with multiple myeloma and other types of
cancer. Therefore, adjusting HDL-C levels within the optimal range and improving HDL particle
functionality is expected to benefit such pathological conditions. The failure of previous clinical
trials testing various HDL-C-raising pharmaceuticals does not preclude a significant role for HDL
in the treatment of atherosclerosis and related metabolic disorders. Those trials were designed on
the principle of “the more the better”, ignoring the U-shape relationship between HDL-C levels
and morbidity and mortality. Thus, many of these pharmaceuticals should be retested in appropriately
designed clinical trials. Novel gene-editing-based pharmaceuticals aiming at altering the
apolipoprotein composition of HDL are expected to revolutionize the treatment strategies, improving
the functionality of dysfunctional HDL
Gene Delivery Technologies for Efficient Genome Editing: Applications in Gene Therapy
Specific nucleases (SNs), including ZFNs, TALENs, and CRISPR (clustered regularly interspaced palindromic repeats), are powerful tools for genome editing (GE). These tools have achieved efficient gene repair and gene disruption of human primary cells. However, their efficiency and safety must be improved before translation into clinic. In particular, one of the main hurdles of GE technology is the delivery of the different components into the nucleus of target cells. Successful gene editing must be able to deliver the SNs and/or the donor DNA into a large number of target cells in order to have a therapeutic benefit. In addition, the delivery must be nontoxic and the SNs must be innocuous to the target cells. In this chapter, we will summarize the different ways to deliver SNs and donor DNA
Preclinical Evidence for the Use of Oral Mesenchymal Stem Cell-Derived Extracellular Vesicles in Bone Regenerative Therapy: A Systematic Review
Tissue engineering is a relatively recent research area aimed at developing artificial tissues that can restore, maintain, or even improve the anatomical and/or functional integrity of injured tissues. Otolaryngology, as a leading surgical specialty in head and neck surgery, is a candidate for the use of these advanced therapies and medicinal products developed. Nevertheless, a knowledge-based analysis of both areas together is still needed. The dataset was retrieved from the Web of Science database from 1900 to 2020. SciMAT software was used to perform the science mapping analysis and the data for the biomedical translation identification was obtained from the iCite platform. Regarding the analysis of the cognitive structure, we find consolidated research lines, such as the generation of cartilage for use as a graft in reconstructive surgery, reconstruction of microtia, or the closure of perforations of the tympanic membrane. This last research area occupies the most relevant clinical translation with the rest of the areas presenting a lower translational level. In conclusion, Tissue engineering is still in an early translational stage in otolaryngology, otology being the field where most advances have been achieved. Therefore, although otolaryngologists should play an active role in translational research in tissue engineering, greater multidisciplinary efforts are required to promote and encourage the translation of potential clinical applications of tissue engineering for routine clinical useUniversidad Peruana
de Ciencias Aplicadas, Lima, Perú (UPC-ExPost-2023-2)The
PECART-0027-2020 (Consejería de Salud y Familias, Junta
de Andalucía, Spain)ProyExcel_00875 (Consejería
de Transformación Económica, Industria, Conocimiento y
Universidades, Junta de Andalucía, Spain)Research Group
#CTS-1028 (MP-M and PG-M, Junta de Andalucía, Spain
Rnd3 Expression is Necessary to Maintain Mitochondrial Homeostasis but Dispensable for Autophagy
Autophagy is a highly conserved process that mediates the targeting and degradation of
intracellular components to lysosomes, contributing to the maintenance of cellular
homeostasis and to obtaining energy, which ensures viability under stress conditions.
Therefore, autophagy defects are common to different neurodegenerative disorders. Rnd3
belongs to the family of Rho GTPases, involved in the regulation of actin cytoskeleton
dynamics and important in the modulation of cellular processes such as migration and
proliferation. Murine models have shown that Rnd3 is relevant for the correct development
and function of the Central Nervous System and lack of its expression produces several
motor alterations and neural development impairment. However, little is known about the
molecular events through which Rnd3 produces these phenotypes. Interestingly we have
observed that Rnd3 deficiency correlates with the appearance of autophagy impairment
profiles and irregular mitochondria. In this work, we have explored the impact of Rnd3 loss
of expression in mitochondrial function and autophagy, using a Rnd3 KO CRISPR cell
model. Rnd3 deficient cells show no alterations in autophagy and mitochondria turnover is
not impaired. However, Rnd3 KO cells have an altered mitochondria oxidative metabolism,
resembling the effect caused by oxidative stress. In fact, lack of Rnd3 expression makes
these cells strictly dependent on glycolysis to obtain energy. Altogether, our results
demonstrate that Rnd3 is relevant to maintain mitochondria function, suggesting a
possible relationship with neurodegenerative diseases.MINECO (SAF 2013-49176-C2-1-
R)Conselleria d’ Educació, Investigació, Cultura i Esport
(AICO/2016/047)FUSP-CEU-UCH (FUSP-PPC-19-
28A751CC)Instituto de Salud Carlos III (ISCIII) (PI18/
00337)WKZ Fonds (R4376)ReumaNederland
(16-1-2-1)Nicolas Monardes regional Ministry of
Health contrac
Externally-Controlled Systems for Immunotherapy: From Bench to Bedside
We thank GENYO Institute and LentiStem Biotech for the
support to compile of the necessary information to write this
review. We also thank Fundación Poco Frecuente (FPF) and
Asociación Española de Enfermos con Glucogenosis (AEEG) for
their kindly support.Immunotherapy is a very promising therapeutic approach against cancer that is
particularly effective when combined with gene therapy. Immuno-gene therapy
approaches have led to the approval of four advanced therapy medicinal products
(ATMPs) for the treatment of p53-deficient tumors (Gendicine and Imlygic), refractory
acute lymphoblastic leukemia (Kymriah) and large B-cell lymphomas (Yescarta). In
spite of these remarkable successes, immunotherapy is still associated with severe
side effects for CD19+ malignancies and is inefficient for solid tumors. Controlling
transgene expression through an externally administered inductor is envisioned as a
potent strategy to improve safety and efficacy of immunotherapy. The aim is to develop
smart immunogene therapy-based-ATMPs, which can be controlled by the addition
of innocuous drugs or agents, allowing the clinicians to manage the intensity and
durability of the therapy. In the present manuscript, we will review the different inducible,
versatile and externally controlled gene delivery systems that have been developed and
their applications to the field of immunotherapy. We will highlight the advantages and
disadvantages of each system and their potential applications in clinics.Spanish ISCIII Health Research FundEuropean Union (EU)
PI12/01097
PI15/02015
PI18/00337
PI18/00330CECEyUCSyF of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) for Andalusia
2016000073391-TRA
2016000073332-TRA
PI-57069
PAIDI-Bio326
PI-0014-2016Nicolas Monardes regional Ministry of Health
0006/2018Spanish Government
FPU16/05467
FPU17/02268MCI
DIN2018-01018
Genome-edited adult stem cells: Next-generation advanced therapy medicinal products
Over recent decades, gene therapy, which has enabled the treatment of several incurable
diseases, has undergone a veritable revolution. Cell therapy has also seen major advances
in the treatment of various diseases, particularly through the use of adult stem cells
(ASCs). The combination of gene and cell therapy (GCT) has opened up new opportunities to improve advanced therapy medicinal products for the treatment of several diseases. Despite the considerable potential of GCT, the use of retroviral vectors has major
limitations with regard to oncogene transactivation and the lack of physiological expression. Recently, gene therapists have focused on genome editing (GE) technologies as an
alternative strategy. In this review, we discuss the potential benefits of using GE technologies to improve GCT approaches based on ASCs. We will begin with a brief summary of
different GE platforms and techniques and will then focus on key therapeutic approaches
that have been successfully used to treat diseases in animal models. Finally, we discuss
whether ASC GE could become a real alternative to retroviral vectors in a GCT setting.European Regional Development Fund
(FEDER), Grant/Award Numbers: PI18/01610,
PI18/00330, PI18/00337, grants PI12/01097;
Spanish ISCIII Health Research Fun
The Rhizophagus irregularis Genome Encodes Two CTR Copper Transporters That Mediate Cu Import Into the Cytosol and a CTR-Like Protein Likely Involved in Copper Tolerance
Arbuscular mycorrhizal fungi increase fitness of their host plants under Cu deficient and toxic conditions. In this study, we have characterized two Cu transporters of the CTR family (RiCTR1 and RiCTR2) and a CTR-like protein (RiCTR3A) of Rhizophagus irregularis. Functional analyses in yeast revealed that RiCTR1 encodes a plasma membrane Cu transporter, RiCTR2 a vacuolar Cu transporter and RiCTR3A a plasma membrane protein involved in Cu tolerance. RiCTR1 was more highly expressed in the extraradical mycelia (ERM) and RiCTR2 in the intraradical mycelia (IRM). In the ERM, RiCTR1 expression was up-regulated by Cu deficiency and down-regulated by Cu toxicity. RiCTR2 expression increased only in the ERM grown under severe Cu-deficient conditions. These data suggest that RiCTR1 is involved in Cu uptake by the ERM and RiCTR2 in mobilization of vacuolar Cu stores. Cu deficiency decreased mycorrhizal colonization and arbuscule frequency, but increased RiCTR1 and RiCTR2 expression in the IRM, which suggest that the IRM has a high Cu demand. The two alternatively spliced products of RiCTR3, RiCTR3A and RiCTR3B, were more highly expressed in the ERM. Up-regulation of RiCTR3A by Cu toxicity and the yeast complementation assays suggest that RiCTR3A might function as a Cu receptor involved in Cu tolerance
Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma
Autologous T cells expressing the Chimeric Antigen Receptor (CAR) have been
approved as advanced therapy medicinal products (ATMPs) against several
hematological malignancies. However, the generation of patient-specific CART
products delays treatment and precludes standardization. Allogeneic off-theshelf
CAR-T cells are an alternative to simplify this complex and timeconsuming
process. Here we investigated safety and efficacy of knocking out
the TCR molecule in ARI-0001 CAR-T cells, a second generation aCD19 CAR
approved by the Spanish Agency of Medicines and Medical Devices (AEMPS)
under the Hospital Exemption for treatment of patients older than 25 years with
Relapsed/Refractory acute B cell lymphoblastic leukemia (B-ALL). We first
analyzed the efficacy and safety issues that arise during disruption of the TCR
gene using CRISPR/Cas9. We have shown that edition of TRAC locus in T cells
using CRISPR as ribonuleorproteins allows a highly efficient TCR disruption
(over 80%) without significant alterations on T cells phenotype and with an
increased percentage of energetic mitochondria. However, we also found that
efficient TCRKO can lead to on-target large and medium size deletions,
indicating a potential safety risk of this procedure that needs monitoring.
Importantly, TCR edition of ARI-0001 efficiently prevented allogeneic
responses and did not detectably alter their phenotype, while maintaining a
similar anti-tumor activity ex vivo and in vivo compared to unedited ARI-0001 CAR-T cells. In summary, we showed here that, although there are still some
risks of genotoxicity due to genome editing, disruption of the TCR is a feasible
strategy for the generation of functional allogeneic ARI-0001 CAR-T cells. We
propose to further validate this protocol for the treatment of patients that do
not fit the requirements for standard autologous CAR-T cells administration.Spanish ISCIII Health Research FundEuropean Commission PI15/02015
PI18/00337
PI21/00298Red TerAv RD21/ 0017/0004
PI18/ 00330
PI17/00672CECEyU and CSyF of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) for Andalusia 2016000073391-TRA
2016000073332-TRA
PI-57069
PAIDIBio326
CARTPI-0001- 201
PECART-0031-2020
PI0014-2016
PEER-0286-2019Spanish Government 00123009/SNEO-20191072
PLEC2021-008094regional Ministry of Health 0006/2018
C2-0002-2019Spanish Government FPU16/05467
FPU17/02268
FPU17/04327Junta de Andalucia PECART-00312020Consejeria de Salud y Familias PECART-0027-2020
MCI DIN2018-010180
DIN2020-01155
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