The expression of microRNAs is commonly dysregulated in human disease. Targeting of microRNAs that are overexpressed and/or replacement of microRNAs whose expression is lost are two distinct approaches to treat diseases whose progression is advanced by microRNA dysregulation. In this review we will discuss recent findings with five specific microRNAs that highlight the opportunity associated with targeting microRNAs in human disease.
Alzheimer's disease is a growing disease burden that affects millions of people worldwide and is expected to double by the year 2030 as the current standard of care only partially treats the symptom. A disease modifying treatment is in urgent need. A major challenge is to demonstrate disease-modification in the clinic, as the current treatment measures monitor mostly pathological biomarkers that are not linearly related to the clinical disease. Since synaptic dysfunction is directly related to cognitive deficits even in early stages of cognitive impairment, attempts are in progress to directly measure synaptic function non-invasively and some of the tools and pharmacological agents to measure synaptic function both in clinic and preclinical models are reviewed here. Finally, we propose measuring synaptic function could be used as an experimental medicine readout while testing disease-modifying agents in the clinic.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by intra- and extracellular deposits of aggregated proteins in the brains of affected individuals. Transgenic mice have been developed to show some of these characteristic histopathological hallmarks of AD in the brain. The availability of transgenic mice with different transgene combinations has given new insights into the pathology of AD and has suggested new approaches and routes to testing disease-modifying treatments.
A greater understanding of disease biology processes, the opportunity to develop targeted drugs leading to further improved patient outcomes and technology advances, as well as increasing pressure on healthcare budgets have led to a shift towards personalised healthcare solutions. Personalised medicine has tremendous potential benefits for patients and healthcare providers, as well as for regulatory agencies and pharmaceutical and diagnostic companies, but the advancement of this innovative therapeutic strategy depends on identifying biomarkers functioning as companion diagnostics for the targeted drug. However, considerable practical, methodological, regulatory and economic issues must be addressed to fully realise the potential of this approach.
Transplanted cells can secrete numerous molecules that may exert a beneficial effect on the host retina and/or choroid even if they do not cure the underlying disease. Ideally, with a single transplant operation, many different pathways can be modified, which may reduce the chance of 'escape' associated with typical pharmacotherapy as well as the need for repeated drug administration. In addition, transplanted cells can replace dead cells (e.g. photoreceptors). Because of their pluripotency and unlimited proliferative capacity, stem cells seem to be a logical choice for starting material because they can be produced en masse safely and they can be induced to differentiate into ocular cells with potential for replacement and rescue therapy. Although preclinical studies demonstrate the feasibility of using embryonic stem cells and induced pluripotent stem cells for treating degenerative retinal diseases associated with abnormalities in the retinal pigment epithelium and/or photoreceptors, some issues may limit the use of stem cells in clinical practice. These issues include: immunogenicity of the cells, stability of cell phenotype (both inherent and environment-induced), the propensity to form tumors in situ, the abnormal microenvironment that can accompany degenerative disease and the synaptic rewiring that accompanies retinal degeneration. In the case of non-exudative age-related macular degeneration, cell transplants might prevent progression of geographic atrophy (through replacement of dysfunctional or dead RPE) and might even bring about some visual improvement in selected cases (through rescue of photoreceptors that are dying but not dead). Cell-based therapy may one day be sight-restoring for patients who are blind due to retinal degeneration of various etiologies. RPE transplantation is an attractive starting point for this sort of therapy as these cells can integrate with the host retina easily.
Progress in antisense technology has identified multiple post hybridization mechanisms that have been successfully exploited to produce pharmacological effects in cells, animals and humans. Advances in understanding the pharmacokinetics and toxicological properties of various types of oligoneucleotides have also been reported. Together these data support optimism that RNA-based therapeutics may bring value. In this very brief review, I focus on the advances in understanding the molecular mechanisms by which antisense drugs work with particular focus on RNase H1 and RISC mediated target reduction.
In the 1990s, the scientific and popular press heralded the emergence of a new paradigm in drug discovery and development called pharmacogenomics (pgmx). As well as capturing the interest of scientists, policymakers and journalists, the field of personalized medicine has also been of immense interest to social scientists who research new innovations in health and biomedicine. This article reviews existing social science research on pgmx. It considers work on mapping industry involvement in pgmx; the dynamics of clinical adoption and the challenges of pgmx testing becoming a standard healthcare service; and patient and public perspectives on pgmx. In conclusion, the article reflects on the future research agenda.
Dry age-related macular degeneration (AMD) is a slowly progressive visual disorder that is a leading cause for severe visual impairment in the elderly population. Clinical options to prevent disease development and progression are very limited at this time. Recently, research on dry AMD has begun to focus on retinal neuroprotection strategies to prevent apoptosis and necrosis, reduce oxidative injury and understand the molecular and cellular response to neuroprotective agents. Here we review the most recent advances in basic and clinical research in neuroprotection as it relates to dry AMD.
The pathological process of Alzheimer's disease (AD) starts years before the appearance of clinical symptoms. The understanding of those mechanisms at the basis of such long phase will permit the development of new drugs to counter neurodegeneration before irreversible neuronal losses occur. Ideally, the development of such drugs should be based on the markers of disease progression homologous in humans and animals. The perfect experimental model recapitulating the main pathological characteristics of AD has yet to be engineered, but available models address a number of pathological AD features allowing to translate human markers to mice. The present paper is an overview of the neuroimaging markers used to map AD-like pathology and its progression in vivo in mice models of amyloidosis. Mice models are widely used to test AD candidate drugs and to predict their effects in human. Therefore, the crucial key is the identification of AD progression imaging markers homologous to those validated in early AD patients.
RNA targeted therapeutics are being developed in a broad array of therapeutic areas, and more recently a growing number of RNA targeted antisense approaches for cardiovascular and metabolic diseases have progressed into clinical development. Cardiovascular and metabolic diseases are growing health issues with significant associated morbidity and mortality. RNA represents a growing and accessible target space that has been shown to be specifically and selectively targeted utilizing short single strand antisense oligonucleotides. Antisense drugs are relatively small synthetic oligonucleotides with predictable safety and pharmacokinetics across a given chemical platform. Once identified, the remaining risk in development as a therapeutic is associated with selection of the right target, sufficient to affect a clinically meaningful change in the course of disease. This review focuses primarily on the translated mRNAs currently being targeted using antisense therapies in cardiovascular and metabolic disease.
The slow progression of non-exudative age-related macular degeneration (dry AMD) presents challenges for drug discovery. The standard endpoint used for ophthalmic clinical trials, best-corrected visual acuity, is insensitive to the early stages and slow progression of dry AMD. Effective drug discovery for dry AMD treatments will therefore require novel applications of more effective visual function endpoints. This review will present candidates for visual function endpoints for dry AMD clinical trials. The promising visual assessments include contrast sensitivity, reading speed, microperimetry, and dark adaptation. Their adoption as exploratory endpoints in future trials will be critical for determining their accuracy, precision, and applicability, and ultimately determine their value for drug discovery.
Transgenic mouse models of Alzheimer's disease (AD) have been used extensively for several years to study the consequences of AD pathology on cortical circuits. Numerous studies have focused on changes in hippocampal function, in particular, memory, synaptic transmission and synaptic plasticity. This review focuses on changes in network activity in mouse models of AD, particularly low gamma (30–80 Hz) frequency oscillations as this rhythm is thought to underlie some of the cognitive functions that are impaired in AD.
As scientific knowledge about gene-environment interactions and the role of epigenetic factors in gene expression grows, new possibilities for personalized medicine may be opened up. In particular, the associations that have been demonstrated between epigenetic markers and certain diseases are an exciting development for personalized medicine. These advances also create new ethical challenges, regarding causal and moral responsibility, due to unique characteristics of how epigenetic effects regulate gene expression, are established and may change over the course of a person's life. This article examines the ethical implications of integrating epigenetic knowledge into personalized medicine.
Alzheimer's disease (AD) induces a widespread pathological extracellular accumulation of beta-amyloid (Aβ) peptides that affects cortical networks underpinning cognitive functions. This is related to abnormal functional and effective brain connectivity as revealed by graph markers of resting-state eyes-closed electroencephalographic (EEG) rhythms. Here we revised EEG studies in mild cognitive impairment and AD subjects showing that these markers are promising network disease endpoints for basic research and AD drug discovery.
The leading cause of vision loss in industrialized countries is age-related macular degeneration (AMD) and its prevalence is increasing with the ageing of the population. Thus, since dysfunction of the local complement system is associated with AMD, the retinal pigment epithelium–choroid complex is a potential location for the delivery of novel therapeutic agents that target the complement cascade. We present an introduction to the complement cascade and a review of current literature that summarizes the role of current and future drugs that may potentially be available as targets in the management of AMD.
•Antisense-induced exon skipping is an investigational, molecular, mutation-specific therapy for Duchenne muscular dystrophy (DMD).•Two clinical drug candidates, drisapersen and eteplirsen, address mutations found in 13% of patients with DMD.•Additional oligonucleotides need to be developed for subsequent, smaller subpopulations of mutations.•This will require a nonstandard, orphan drug-tailored design of the (clinical) development program.•To achieve this, extrapolation between clinical study data on antisense oligonucleotides and patient groups will be essential.
By contrast to other therapeutic approaches, the druggable universe is not limited with antisense technology as these inhibitors can be rationally designed based on sequence information alone. Recent clinical data have demonstrated proof of mechanism and clinical benefit for antisense drugs in many disease areas including cancer. Together with recent advances in antisense chemistry these findings suggest that this technology is now poised to emerge as a key therapeutic modality to bridge the ever growing pharmacogenomic divide in cancer drug discovery.
Cerebrospinal fluid, imaging and blood based biomarkers can provide critical information for dose selection, patient enrichment and supplementary evidence of disease modification in current clinical trials testing experimental therapeutics for Alzheimer's disease (AD). The current treatise provides examples of biomarker strategies utilized in AD clinical trial practice and highlights recent advances towards the identification of non-invasive approaches for enrichment and diagnosis.
