270,133 research outputs found
The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development
Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD. We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme. To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics. Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community's chances of successfully bringing new rare disease drugs to registration and ultimately to marke
Production of Living Nanoparticles for Blood Cancer Therapy
Current cancer therapies leave much to be desired because they are very harmful to the patient and cause a significant decrease in quality of life. Chimeric Antigen Receptors (CAR) are a promising novel approach for treating specific types of leukemia due to their binding affinity for proteins expressed solely on leukemia B cells. This approach increases specificity of how cells receive treatment, thus allowing for the destruction of cancerous cells while leaving the healthy cells unharmed. In this experiment, we show that production of CAR expressing exosomes (liposome like vesicles produced naturally by human cells) is possible through cell transfection. This finding demonstrates that a new wave of cancer therapeutics, that are more specific and have less harmful side effects, are producible
Recent progress in mitochondria-targeted drug and drug-free agents for cancer therapy
The mitochondrion is a dynamic eukaryotic organelle that controls lethal and vital functions of the cell. Being a critical center of metabolic activities and involved in many diseases, mitochondria have been attracting attention as a potential target for therapeutics, especially for cancer treatment. Structural and functional differences between healthy and cancerous mitochondria, such as membrane potential, respiratory rate, energy production pathway, and gene mutations, could be employed for the design of selective targeting systems for cancer mitochondria. A number of mitochondria-targeting compounds, including mitochondria-directed conventional drugs, mitochondrial proteins/metabolism-inhibiting agents, and mitochondria-targeted photosensitizers, have been discussed. Recently, certain drug-free approaches have been introduced as an alternative to induce selective cancer mitochondria dysfunction, such as intramitochondrial aggregation, self-assembly, and biomineralization. In this review, we discuss the recent progress in mitochondria-targeted cancer therapy from the conventional approach of drug/cytotoxic agent conjugates to advanced drug-free approaches
Packaging biological cargoes in mesoporous materials: Opportunities for drug delivery
Introduction: Confinement of biomolecules in structured nanoporous materials offers several desirable features ranging from chemical and thermal stability, to resistance to degradation from the external environment. A new generation of mesoporous materials presents exciting new possibilities for the formulation and controlled release of biological agents. Such materials address niche applications in enteral and parenteral delivery of biologics, such as peptides, polypeptides, enzymes and proteins for use as therapeutics, imaging agents, biosensors, and adjuvants.Areas covered: Mesoporous silica Santa Barbara Amorphous-15 (SBA-15), with its unique, tunable pore diameter, and easily functionalized surface, provides a representative example of this new generation of materials. Here, we review recent advances in the design and synthesis of nanostructured mesoporous materials, focusing on SBA-15, and highlight opportunities for the delivery of biological agents to various organ and tissue compartments.Expert opinion: The SBA-15 platform provides a delivery carrier that is inherently separated from the active biologic due to distinct intra and extra-particle environments. This permits the SBA-15 platform to not require direct modification of the active biological therapeutic. Additionally, this makes the platform universal and allows for its application independent of the desired methods of discovery and development. The SBA-15 platform also directly addresses issues of targeted delivery and controlled release, although future challenges in the implementation of this platform reside in particle design, biocompatibility, and the tunability of the internal and external material properties. Examples illustrating the flexibility in the application of the SBA-15 platform are also discussed
Novel in vitro and mathematical models for the prediction of chemical toxicity
The
focus
of
much
scientific
and
medical
research
is
directed
towards
understanding
the
disease
process
and
defining
therapeutic
intervention
strategies.
Whilst
the
scientific
basis
of
drug
safety
has
received
relatively
little
attention,
despite
the
fact
that
adverse
drug
reactions
(ADRs)
are
a
major
health
concern
and
a
serious
impediment
to
development
of
new
medicines.
Toxicity
issues
account
for
~21%
drug
attrition
during
drug
development
and
safety
testing
strategies
require
considerable
animal
use.
Mechanistic
relationships
between
drug
plasma
levels
and
molecular/cellular
events
that
culminate
in
whole
organ
toxicity
underpins
development
of
novel
safety
assessment
strategies.
Current
in
vitro
test
systems
are
poorly
predictive
of
toxicity
of
chemicals
entering
the
systemic
circulation,
particularly
to
the
liver.
Such
systems
fall
short
because
of
1)
the
physiological
gap
between
cells
currently
used
&
human
hepatocytes
existing
in
their
native
state,
2)
the
lack
of
physiological
integration
with
other
cells/systems
within
organs,
required
to
amplify
the
initial
toxicological
lesion
into
overt
toxicity,
3)
the
inability
to
assess
how
low
level
cell
damage
induced
by
chemicals
may
develop
into
overt
organ
toxicity
in
a
minority
of
patients,
4)
lack
of
consideration
of
systemic
effects.
Reproduction
of
centrilobular
&
periportal
hepatocyte
phenotypes
in
in
vitro
culture
is
crucial
for
sensitive
detection
of
cellular
stress.
Hepatocyte
metabolism/phenotype
is
dependent
on
cell
position
along
the
liver
lobule,
with
corresponding
differences
in
exposure
to
substrate,
oxygen
&
hormone
gradients.
Application
of
bioartificial
liver
(BAL)
technology
can
encompass
in
vitro
predictive
toxicity
testing
with
enhanced
sensitivity
and
improved
mechanistic
understanding.
Combining
this
technology
with
mechanistic
mathematical
models
describing
intracellular
metabolism,
fluid-‐flow,
substrate,
hormone
and
nutrient
distribution
provides
the
opportunity
to
design
the
BAL
specifically
to
mimic
the
in
vivo
scenario.
Such
mathematical
models
enable
theoretical
hypothesis
testing,
will
inform
the
design
of
in
vitro
experiments,
and
will
enable
both
refinement
and
reduction
of
in
vivo
animal
trials.
In
this
way,
development
of
novel
mathematical
modelling
tools
will
help
to
focus
and
direct
in
vitro
and
in
vivo
research,
and
can
be
used
as
a
framework
for
other
areas
of
drug
safety
science
Dynamic and multi-pharmacophore modeling for designing polo-box domain inhibitors.
The polo-like kinase 1 (Plk1) is a critical regulator of cell division that is overexpressed in many types of tumors. Thus, a strategy in the treatment of cancer has been to target the kinase activity (ATPase domain) or substrate-binding domain (Polo-box Domain, PBD) of Plk1. However, only few synthetic small molecules have been identified that target the Plk1-PBD. Here, we have applied an integrative approach that combines pharmacophore modeling, molecular docking, virtual screening, and in vitro testing to discover novel Plk1-PBD inhibitors. Nine Plk1-PBD crystal structures were used to generate structure-based hypotheses. A common pharmacophore model (Hypo1) composed of five chemical features was selected from the 9 structure-based hypotheses and used for virtual screening of a drug-like database consisting of 159,757 compounds to identify novel Plk1-PBD inhibitors. The virtual screening technique revealed 9,327 compounds with a maximum fit value of 3 or greater, which were selected and subjected to molecular docking analyses. This approach yielded 93 compounds that made good interactions with critical residues within the Plk1-PBD active site. The testing of these 93 compounds in vitro for their ability to inhibit the Plk1-PBD, showed that many of these compounds had Plk1-PBD inhibitory activity and that compound Chemistry_28272 was the most potent Plk1-PBD inhibitor. Thus Chemistry_28272 and the other top compounds are novel Plk1-PBD inhibitors and could be used for the development of cancer therapeutics
Multifunctional nanocarriers for lung drug delivery
Nanocarriers have been increasingly proposed for lung drug delivery applications. The strategy of combining the intrinsic and more general advantages of the nanostructures with specificities that improve the therapeutic outcomes of particular clinical situations is frequent. These include the surface engineering of the carriers by means of altering the material structure (i.e., chemical modifications), the addition of specific ligands so that predefined targets are reached, or even the tuning of the carrier properties to respond to specific stimuli. The devised strategies are mainly directed at three distinct areas of lung drug delivery, encompassing the delivery of proteins and protein-based materials, either for local or systemic application, the delivery of antibiotics, and the delivery of anticancer drugs-the latter two comprising local delivery approaches. This review addresses the applications of nanocarriers aimed at lung drug delivery of active biological and pharmaceutical ingredients, focusing with particular interest on nanocarriers that exhibit multifunctional properties. A final section addresses the expectations regarding the future use of nanocarriers in the area.UID/Multi/04326/2019; PD/BD/137064/2018info:eu-repo/semantics/publishedVersio
Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules
The Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability. Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds
Evaluation of the current knowledge limitations in breast cancer research: a gap analysis
BACKGROUND
A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients.
METHODS
Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action.
RESULTS
Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds).
CONCLUSION
Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care
Unlocking the potential of RNA interference as a therapeutic tool
The existence of an intrinsic biochemical pathway enabling specified regulation of gene expression was unheard of until the final years of the last decade. The identification of ribonucleic acid interference (RNAi) in mammalian cells has nowadays become of extreme importance in the field of functional genomics and translational medicine. The advent of RNAi technology has brought to the scientific research and pharmaceutical communities the ability to regulate expression of any desired gene in a reproducible manner. Consequently, such technology may be utilised in the design of novel therapeutics for clinical conditions having dys-regulated gene expression. Since most RNAi-based therapies in the drug development pipeline of pharmaceutical companies utilise short interfering RNA (siRNA), this review will focus on the role of siRNA in drug development.peer-reviewe
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