Journal of Personalized Medicine — Open Access Journal

Multiple genes and mechanisms of pathophysiology have been implicated in amyotrophic lateral sclerosis (ALS), suggesting it is a complex systemic disease. With this in mind, applying personalized medicine (PM) approaches to tailor treatment pipelines for ALS patients may be necessary. The modelling and analysis of molecular interaction networks could represent valuable resources in defining ALS-associated pathways and discovering novel therapeutic targets. Here we review existing omics datasets and analytical approaches, in order to consider how molecular interaction networks could improve our understanding of the molecular pathophysiology of this fatal neuromuscular disorder. Full article

The 9th traditional biannual conference on Systems Medicine, Personalised Health & Therapy—“The Odyssey from Hope to Practice”, inspired by the Greek mythology, was a call to search for practical solutions in cardio-metabolic diseases and cancer, to resolve and overcome the obstacles in modern medicine by creating more interactions among disciplines, as well as between academic and industrial research, directed towards an effective ‘roadmap’ for personalised health and therapy. The 9th Santorini Conference, under the Presidency of Sofia Siest, the director of the INSERM U1122; IGE-PCV (www.u1122.inserm.fr), University of Lorraine, France, offered a rich and innovative scientific program. It gathered 34 worldwide distinguished speakers, who shared their passion for personalised medicine with 160 attendees in nine specific sessions on the following topics: First day: The Odyssey from hope to practice: Personalised medicine—landmarks and challenges Second day: Diseases to therapeutics—genotype to phenotype an “-OMICS” approach: focus on personalised therapy and precision medicine Third day: Gene-environment interactions and pharmacovigilance: a pharmacogenetics approach for deciphering disease “bench to clinic to reality” Fourth day: Pharmacogenomics to drug discovery: a big data approach and focus on clinical data and clinical practice. In this article we present the topics shared among the participants of the conference and we highlight the key messages. Full article

The organic cation transporter 1 (OCT1, SLC22A1) is strongly expressed in the human liver and facilitates the hepatic uptake of drugs such as morphine, metformin, tropisetron, sumatriptan and fenoterol and of endogenous substances such as thiamine. OCT1 expression is inter-individually highly variable. Here, we analyzed SNPs in the OCT1 promoter concerning their potential contribution to the variability in OCT1 expression. Using electrophoretic mobility shift and luciferase reporter gene assays in HepG2, Hep3B, and Huh7 cell lines, we identified the SNPs −1795G>A (rs6935207) and −201C>G (rs58812592) as having effects on transcription factor binding and/or promoter activity. The A-allele of the −1795G>A SNP showed allele-specific binding of the transcription factor NF-Y leading to 2.5-fold increased enhancer activity of the artificial SV40 promoter. However, the −1795G>A SNP showed no significant effects on the native OCT1 promoter activity. Furthermore, the −1795G>A SNP was not associated with the pharmacokinetics of metformin, fenoterol, sumatriptan and proguanil in healthy individuals or tropisetron efficacy in patients undergoing chemotherapy. Allele-dependent differences in USF1/2 binding and nearly total loss in OCT1 promoter activity were detected for the G-allele of −201C>G, but the SNP is apparently very rare. In conclusion, common OCT1 promoter SNPs have only minor effects on OCT1 expression. Full article

Duchenne muscular dystrophy (DMD), a fatal X-linked recessive disorder, is caused mostly by frame-disrupting, out-of-frame deletions in the dystrophin (DMD) gene. Antisense oligonucleotide-mediated exon skipping is a promising therapy for DMD. Exon skipping aims to convert out-of-frame mRNA to in-frame mRNA and induce the production of internally-deleted dystrophin as seen in the less severe Becker muscular dystrophy. Currently, multiple exon skipping has gained special interest as a new therapeutic modality for this approach. Previous retrospective database studies represented a potential therapeutic application of multiple exon skipping. Since then, public DMD databases have become more useful with an increase in patient registration and advances in molecular diagnosis. Here, we provide an update on DMD genotype-phenotype associations using a global DMD database and further provide the rationale for multiple exon skipping development, particularly for exons 45–55 skipping and an emerging therapeutic concept, exons 3–9 skipping. Importantly, this review highlights the potential of multiple exon skipping for enabling the production of functionally-corrected dystrophin and for treating symptomatic patients not only with out-of-frame deletions but also those with in-frame deletions. We will also discuss prospects and challenges in multiple exon skipping therapy, referring to recent progress in antisense chemistry and design, as well as disease models. Full article

ATP-binding cassette (ABC) transporters are involved in a large number of processes and contribute to various human genetic diseases. Among other functions, ABC proteins are involved in the transport of multiple drugs through cells. Most of the genes coding for these transporters are highly polymorphic and DNA variants in these genes can affect the normal functioning of these proteins, affecting the way drugs are transported, increasing or decreasing drug levels. These changes in the intracellular and extracellular drug levels may be associated with altered drug effectiveness or severe drug-induced adverse events. This review presents a state-of-art of the most pharmacogenetics clinically relevant ABC transporters closed to the clinical implementation. Full article

Personalized tools relevant to an individual patient’s unique characteristics may be an important component of personalized health care. We randomized 97 patients hospitalized with acute decompensated heart failure to receive a printout of an ultrasound image of their inferior vena cava (IVC) with an explanation of how the image is related to their fluid status (n = 50) or to receive no image and only generic heart failure information (n = 47). Adherence to medications, low-sodium diet, and daily weight measurement at baseline and 30 days after discharge were assessed using the Medical Outcomes Study Specific Adherence Scale, modified to a three-item version for heart failure (HF), (MOSSAS-3HF, maximum score = 15, indicating adherence all of the time). The baseline MOSSAS-3HF scores (mean ± standard deviation (SD)) were similar for intervention and control groups (7.4 ± 3.4 vs. 6.4 ± 3.7, p = 0.91). The MOSSAS-3HF scores improved for both groups but were not different at 30 days (11.8 ± 2.8 vs. 11.7 ± 3.0, p = 0.90). Survival without readmission or emergency department (ED) visit at 30 days was similar (82.6% vs. 84.1%, p = 0.85). A personalized HF tool did not affect rates of self-reported HF treatment adherence or survival without readmission or ED visit. Full article

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease prevalent in 1 in 3500 to 5000 males worldwide. As a result of mutations that interrupt the reading frame of the dystrophin gene (DMD), DMD is characterized by a loss of dystrophin protein that leads to decreased muscle membrane integrity, which increases susceptibility to degeneration. CRISPR/Cas9 technology has garnered interest as an avenue for DMD therapy due to its potential for permanent exon skipping, which can restore the disrupted DMD reading frame in DMD and lead to dystrophin restoration. An RNA-guided DNA endonuclease system, CRISPR/Cas9 allows for the targeted editing of specific sequences in the genome. The efficacy and safety of CRISPR/Cas9 as a therapy for DMD has been evaluated by numerous studies in vitro and in vivo, with varying rates of success. Despite the potential of CRISPR/Cas9-mediated gene editing for the long-term treatment of DMD, its translation into the clinic is currently challenged by issues such as off-targeting, immune response activation, and sub-optimal in vivo delivery. Its nature as being mostly a personalized form of therapy also limits applicability to DMD patients, who exhibit a wide spectrum of mutations. This review summarizes the various CRISPR/Cas9 strategies that have been tested in vitro and in vivo for the treatment of DMD. Perspectives on the approach will be provided, and the challenges faced by CRISPR/Cas9 in its road to the clinic will be briefly discussed. Full article

This study aims to investigate the effects of the three potassium channel genes KCNA1, KCNA2, and KCNV2 on increased susceptibility to epilepsy as well as on responsiveness to antiepileptic drugs (AEDs). The pharmacogenetic and case-control cohort (n = 595) consisted of 296 epileptic patients and 299 healthy individuals. Epileptic patients were recruited from the Pediatric Neurology clinic at the Queen Rania Al Abdullah Hospital (QRAH) in Amman, Jordan. A custom platform array search for genetic association in Jordanian-Arab epileptic patients was undertaken. The MassARRAY system (iPLEX GOLD) was used to genotype seven single nucleotide polymorphisms (SNPs) within three candidate genes (KCNA1, KCNA2, and KCNV2). Only one SNP in KCNA2, rs3887820, showed significant association with increased risk of susceptibility to generalized myoclonic seizure (p-value < 0.001). Notably, the rs112561866 polymorphism of the KCNA1 gene was non-polymorphic, but no significant association was found between the KCNA1 (rs2227910, rs112561866, and rs7974459) and KCNV2 (rs7029012, rs10967705, and rs10967728) polymorphisms and disease susceptibility or drug responsiveness among Jordanian patients. This study suggests that a significant association exists between the KCNA2 SNP rs3887820 and increased susceptibility to generalized myoclonic seizure. However, the present findings indicate that the KCNA1 and KCNV2 SNPs do not influence disease susceptibility and drug responsiveness in epileptic patients. Pharmacogenetic and case-control studies involving a multicenter and multiethnic approach are needed to confirm our results. To improve the efficacy and safety of epilepsy treatment, further studies are required to identify other genetic factors that contribute to susceptibility and treatment outcome. Full article

The pricing of targeted medicines continues to be a major area of contention in healthcare economics. This issue is further complicated by redefining the role of molecular testing in precision medicine. Currently, whilst pricing of clinical laboratory diagnostics is cost-based, drug pricing is value-based. The pricing for molecular testing is under pressure to change the traditional business model, for it has a critical subsidiary role in determining the final value of targeted medicines. The market size for drugs is reduced by molecular testing when patients with the same disease are stratified based on their genetics, it is critical to determine the value of this new enhanced drug specificity to realize its full pricing potential. However, these value-based pricing strategies require a careful understanding of changing market conditions, especially, in the context of stratified patient segments made possible by precision medicine. In this article, we discuss the various factors impacting pricing decisions, and consider evolving economic trends in precision medicine. Full article

Familial Hypercholesterolemia (FH) is an inherited disorder associated with increased cardiovascular risk that requires patients to make multiple impactful decisions regarding the management of their condition. Patient decision aids (PDAs) can facilitate shared decision-making (SDM) and enable patients to make choices that are concordant with their goals and values. To inform the development of a PDA for patients with FH, we employed a qualitative inductive approach and focus group discussions with patients, physicians, and genetic counselors. We explored and analyzed the perceptions and understanding of these stakeholders related to a PDA for FH and identified important concepts to include in the PDA. Categories emerging from focus group discussions included: (a) perceptions of a PDA related to FH; (b) discussion about the content of a PDA related to FH; and (c) SDM. In general, stakeholders were in favor of developing tools which can inform and individualize discussion about genetic testing and treatment options for FH. Physicians valued a tool that facilitates knowledge transfer to FH patients. Patients desired a tool to help them understand the genetic aspects of and treatment options related to FH. Genetic counselors emphasized the inclusion of visual aids to support discussion with patients. Potential barriers to and facilitators of PDA implementation were identified. The input of various stakeholders will inform the development of a prototype tool that will be iteratively tested before implementation in the clinical setting. Full article

Atherosclerosis affects millions of people worldwide. However, the wide variety of limitations in the current therapeutic options leaves much to be desired in future lipid-lowering therapies. For example, although statins, which are the first-line treatment for coronary heart disease (CHD), reduce the risk of cardiovascular events in a large percentage of patients, they lead to optimal levels of low density lipoprotein-cholesterol (LDL-C) in only about one-third of patients. A new promising research direction against atherosclerosis aims to improve lipoprotein metabolism. Novel therapeutic approaches are being developed to increase the levels of functional high density lipoprotein (HDL) particles. This review aims to highlight the atheroprotective potential of the in vitro synthesized reconstituted HDL particles containing apolipoprotein E (apoE) as their sole apolipoprotein component (rHDL-apoE). For this purpose, we provide: (1) a summary of the atheroprotective properties of native plasma HDL and its apolipoprotein components, apolipoprotein A-I (apoA-I) and apoE; (2) an overview of the anti-atherogenic functions of rHDL-apoA-I and apoA-I-containing HDL, i.e., natural HDL isolated from transgenic Apoa1^−/− × Apoe^−/− mice overexpressing human apoA-I (HDL-apoA-I); and (3) the latest developments and therapeutic potential of HDL-apoE and rHDL-apoE. Novel rHDL formulations containing apoE could possibly present enhanced biological functions, leading to improved therapeutic efficacy against atherosclerosis. Full article

The field of interventional cardiology has evolved significantly since the first percutaneous transluminal coronary angioplasty was performed 40 years ago. This evolution began with a balloon catheter mounted on a fixed wire and has progressed into bare-metal stents (BMS), first-generation drug-eluting stents (DES), second- and third-generation biodegradable polymer-based DES, and culminates with the advent of bioabsorbable stents, which are currently under development. Each step in technological advancement has improved outcomes, while new persisting challenges arise, caused by the stent scaffolds, the polymers employed, and the non-selective cytostatic and cytotoxic drugs eluted from the stents. Despite the promising technological advances made in stent technology, managing the balance between reductions in target lesion revascularization, stent thrombosis, and bleeding remain highly complex issues. This review summarizes the evolution of percutaneous coronary intervention with a focus on vascular dysfunction triggered by the non-selective drugs eluted from various stents. It also provides an overview of the mechanism of action of the drugs currently used in DES. We also discuss the efforts made in developing novel cell-selective drugs capable of inhibiting vascular smooth muscle cell (VSMC) proliferation, migration, and infiltration of inflammatory cells while allowing for complete reendothelialization. Lastly, in the era of precision medicine, considerations of patients’ genetic variance associated with myocardial infarction and in-stent restenosis are discussed. The combination of personalized medicine and improved stent platform with cell-selective drugs has the potential to solve the remaining challenges and improve the care of coronary artery disease patients. Full article

Recent advances in genomic medicine have led to the availability of genomic tests that have the potential to improve population health, yet the process for obtaining these tests and getting them reimbursed by insurers has not been described. The objective of this study was to describe the process of ordering pharmacogenomic tests by interviewing providers, patients, and laboratories about cancer-related pharmacogenomic tests. We interviewed patients who were prescribed, providers who prescribed medications that should be guided by pharmacogenomic testing, and individuals from diagnostic laboratories. A total of 10 providers, 16 patients, and eight diagnostic laboratories described logistical and insurance issues relating to ordering and receiving pharmacogenomic tests and medications. We found that the process of ordering pharmacogenomic tests is time-consuming, expensive, and complex. Ordering pharmacogenomic tests is quite different across institutions. Even in the same institution, multiple providers can order the test. Once the provider places the order for the pharmacogenomic test, the laboratory receives the request and usually begins testing without knowing how the test will be paid for. Next, the laboratory completes the pharmacogenomic testing and the results of the tests are reported to providers, patients, or placed directly in the medical record. In conclusion, processes related to ordering and obtaining insurance coverage for pharmacogenomic tests varies greatly across institutions and is time-consuming. Full article

In this endeavour, inspired by the Odyssey, we aim to embark with the reader on a journey on a ship from Troy to Ithaca, coursing through the history of the momentous events and achievements that paved the way for personalised medicine. We will set sail amidst important genetic discoveries, beginning with the discovery of the first human genome, and voyage through the projects that contributed to the progress of pharmacogenomic studies. Concurrently, we will propose methods to overcome the obstacles that are slowing the potential full implementation of accumulated knowledge into everyday practice. This journey aims to reflect on the frontiers of current genetic knowledge and the practical use of this knowledge in preventive, diagnostic and pharmacogenomic approaches to directly impact the socio-economic aspects of public health. Full article

Precision medicine seeks to use genomic data to help provide the right treatment to the right patient at the right time. Next-generation sequencing technology allows for the rapid and accurate sequencing of many genes at once. This technology is becoming more common in oncology, though the clinical benefit of incorporating it into precision medicine strategies remains under significant debate. In this manuscript, we discuss the early findings of the impact of next-generation sequencing on cancer patient outcomes. We investigate why not all patients with genomic variants linked to a specific therapy receive that therapy and describe current barriers. Finally, we explore the current state of health insurance coverage for individual genome sequencing and targeted therapies for cancer. Based on our analysis, we recommend increased transparency around the determination of “actionable mutations” and a heightened focus on investigating the variations in health insurance coverage across patients receiving sequencing-matched therapies. Full article

To evaluate whether recovery from complicated malaria follows a common trajectory in terms of immunological mechanism or, rather, is highly individualized for each patient, we performed longitudinal gene expression profiling of whole blood. RNA sequencing (RNAseq) was performed on blood samples obtained from eight patients on four consecutive days between hospital admission and discharge. Six patients were infected with Plasmodium falciparum, and two with Plasmodium vivax; one patient was a pregnant woman infected with P. falciparum, who was hospitalized for several weeks. The characterization of blood transcript modules (BTM) and blood informative transcripts (BIT) revealed that patients’ responses showed little commonality, being dominated by the balance of gene activity relating to lymphocyte function, inflammation, and interferon responses specific to each patient. Only weak correlations with specific complicated malaria symptoms such as jaundice, thrombocytopenia, or anemia were observed. The differential expression of individual genes, including transcripts derived from the human leukocyte antigen (HLA) complex, generally reflected differences in the underlying immune processes. Although the results of this pilot study do not point to any single process that might provide a target for complicated malaria treatment or prevention or personalized medical strategies, larger patient series and more extensive blood sampling may allow the classification of patients according to their type of response in order to develop novel therapeutic approaches. Full article

The optimization of drug therapy according to the personal characteristics of patients is a perspective direction in modern medicine. One of the possible ways to achieve such personalization is through the application of “omics” technologies, including current, promising metabolomics methods. This review demonstrates that the analysis of pre-dose metabolite biofluid profiles allows clinicians to predict the effectiveness of a selected drug treatment for a given individual. In the review, it is also shown that the monitoring of post-dose metabolite profiles could allow clinicians to evaluate drug efficiency, the reaction of the host to the treatment, and the outcome of the therapy. A comparative description of pharmacotherapy personalization (pharmacogenomics, pharmacoproteomics, and therapeutic drug monitoring) and personalization based on the analysis of metabolite profiles for biofluids (pharmacometabolomics) is also provided. Full article

To inform guidelines for screening family members of patients with familial hypercholesterolemia (FH), we designed a clinical trial to compare the yield of cascade screening in FH patients with and without an identifiable pathogenic variant. Participants with hypercholesterolemia (Low-density lipoprotein cholesterol (LDL-C) > 155 mg/dL) underwent sequencing of LDLR, APOB, and PCSK9 and genotyping of six single nucleotide polymorphisms associated with LDL-C followed by calculation of a polygenic score for LDL-C. We identified 24 patients with definite FH (pathogenic variant in one of the three FH genes), 76 patients with probable FH (Dutch lipid clinic network (DLCN) score ≥ 6, no pathogenic variant), and 262 patients with possible FH (DLCN score 3–5, no pathogenic variant). We will enroll 50 patients with definite FH by recruiting an additional 26 from the FH Clinic at Mayo and 50 patients each with probable and possible FH, matching on age and sex. Family members of patients with definite FH will undergo testing for the relevant pathogenic variant using saliva kits and family members of those with probable/possible FH will have a lipid profile checked. We will assess the number of new cases detected (defined as presence of a pathogenic variant in the family member of definite FH patient or LDL-C > 155 mg/dL (>130 mg/dL in children) in family members of probable/possible FH patients, and the cost of detecting a new case. The proposed clinical trial will compare the yield and cost of cascade screening for FH patients with/without an identifiable pathogenic variant, and thereby inform guidelines for cascade screening for FH. Full article

For personalized healthcare, the purpose of this study was to examine the key genes and metabolites in the one-carbon metabolism (OCM) pathway and their interactions as predictors of colorectal cancer (CRC) in multi-ethnic families. In this proof-of-concept study, we included a total of 30 participants, 15 CRC cases and 15 matched family/friends representing major ethnic groups in southern California. Analytics based on supervised machine learning were applied, with the target variable being specified as cancer, including the ensemble method and generalized regression (GR) prediction. Elastic Net with Akaike’s Information Criterion with correction (AICc) and Leave-One-Out cross validation GR methods were used to validate the results for enhanced optimality, prediction, and reproducibility. The results revealed that despite some family members sharing genetic heritage, the CRC group had greater combined gene polymorphism-mutations than the family controls (p < 0.1) for five genes including MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, and DHFR 19bp. Blood metabolites including homocysteine (7 µmol/L), methyl-folate (40 nmol/L) with total gene mutations (≥4); age (51 years) and vegetable intake (2 cups), and interactions of gene mutations and methylmalonic acid (MMA) (400 nmol/L) were significant predictors (all p < 0.0001) using the AICc. The results were validated by a 3% misclassification rate, AICc of 26, and >99% area under the receiver operating characteristic curve. These results point to the important roles of blood metabolites as potential markers in the prevention of CRC. Future intervention studies can be designed to target the ways to mitigate the enzyme-metabolite deficiencies in the OCM pathway to prevent cancer. Full article