The Rise of Precision Medicine in Pediatric Treatments
Over the past two decades, there has been a significant increase in the availability of therapies explicitly approved by the FDA to treat conditions in children.[1] The proportion of approved cancer therapies with pediatric indications increased more than twofold in the period from 2017 to 2021 compared to the previous five years.[2] Still, there remains a significant unmet need for additional safe, effective medicines for the prevention and treatment of diseases affecting children. Precision medicine involves tailoring medical treatment to the individual characteristics of each patient based on their particular genetic or biomarker profiles, with the goal of improving efficacy and limiting toxicity when a therapy is unlikely to be of benefit. In pediatrics, a precision medicine approach is particularly crucial because children are not simply “small adults” and often display different disease symptoms, responses to medication, and recovery patterns than adults.
In this blog, we explore the potential of precision medicine for pediatrics, with a focus on biomarkers and assay development.
Precision Medicine’s Promise in Pediatric Care
The application of precision medicine in pediatrics has shown encouraging results in oncology, where genetic profiling of tumors can guide the selection of targeted therapies, thus improving outcomes. Precision medicine is also expanding into other pediatric therapeutic areas such as neurology, where genetic insights into epilepsy or autism spectrum disorders are facilitating personalized therapeutic strategies. Respiratory and infectious diseases are yet more fields where precision medicine approaches are being studied to tailor treatments according to patient-specific immune responses and microbiomes.[3]
The Critical Role of Biomarkers in Pediatric Precision Medicine
Biomarkers play a pivotal role in precision medicine by serving as indicators that can be objectively measured and evaluated as signs of normal biological activities, pathogenic processes, or pharmacologic responses to a therapeutic intervention. As biologic surrogates, biomarkers allow for less invasive medical testing and can be used for early diagnosis and risk assessment, treatment personalization, and monitoring of disease progression and response to therapy.
Bridging Biomarkers in Pediatric Studies
Biomarkers also play an integral role in pediatric extrapolation, which uses scientific evidence from adult populations to enable more efficient evaluation of an intervention’s effect in children when there is substantive evidence of biological similarity between adult and pediatric disease processes.[4] To have clinical value, a “bridging biomarker” must capture the effects on the primary causal pathway that influence a measure of the well-being, daily-life functioning, and possibly the survival of the children receiving the intervention. Moreover, the bridging biomarker should be reasonably likely to predict the impact of the intervention on a relevant clinical endpoint.3 A validated bridging biomarker can be extraordinarily useful for minimizing the need to generate new pediatric data or conduct unnecessary studies in children.
Challenges and Considerations in Developing Pediatric Biomarkers
Biomarker assay development is a critical aspect of pediatric precision medicine, playing a pivotal role in the translation of biomarker research into actionable clinical practices. The development process is a stringent and rigorous one, particularly for assays involving pediatric populations. Challenges of pediatric biomarker assay development include:
- Confirming applicability of the biomarker in children. Previous validation of a biomarker in adults is frequently not sufficient for applying that biomarker to children. Disease pathogenesis can be distinctly different in pediatric populations so it may be necessary to develop and validate pediatric-specific biomarkers.
- Finding and enrolling patients. Disease incidence among children may be different, and often lower, than among adults. If the disease of interest is not common in pediatric populations, it can be difficult to populate the studies necessary for validating a biomarker. Typically, multicenter collaborations are needed to enroll sufficiently large numbers of affected children across age groups and gender to establish both discovery and validation datasets.
- Determining appropriate reference ranges. The standard or reference range applied to an adult may not be applicable to a child. Establishing a pediatric-specific reference range requires healthy, age-matched donor samples for comparison or control, and sourcing these samples can be a hurdle. Repositories of pediatric biospecimens are rare, and biobanks that span the spectrum of developmental stages are limited.[5]
- Obtaining samples for biomarker measurement. In pediatrics, the sampling method of choice and allowable sample volume vary by age. Importantly, rules on sample draw volume differ from country to country or even hospital to hospital. In addition to these age-related restrictions on sampling method and sample volume, it can be difficult to draw biofluids from children.
Innovative Approaches to Sample Collection and Analysis
Both the development and application of biomarker assays, in clinical trials and clinical practice, require samples. There are two main approaches to blood sampling, which differ in invasiveness and resulting blood volume:
- Venipuncture results in larger volumes but can be difficult in children since they have a layer of protective subcutaneous fat that effectively buries their veins.
- Capillary blood collection yields small volumes but is more appropriate for repeat sampling if it can deliver sufficient volumes for analysis.
Ultimately, the clinical use will determine the sample volume required. While basic clinical parameters such as metabolic panels can be performed on small volumes, immune cell monitoring of several cell types by flow cytometry typically requires larger volumes. In such cases, assay technologies that allow accurate and precise biomarker or cell type monitoring with very small blood volumes offer a helpful tool.
One example for such a technology is Epiontis ID®, an immunophenotyping technology that measures cell type-specific epigenetic markers which identify uniquely demethylated regions on genomic DNA to quantify immune cell populations using quantitative polymerase chain reaction (qPCR)-based assays. A significant advantage of epigenetic immune cell quantification is that it can be applied to fresh, frozen, or paper-spotted dried blood and other bodily fluids or tissues, eliminating the need for real-time assays and making it possible to perform additional testing later.
Case study: Using dried blood spots for immune cell quantification in primary immune deficiency
Flow cytometry remains the most widely used analytical approach for immune cell quantification but its application is intrinsically limited by the requirement for fresh or well-preserved blood samples. Given this limitation, flow cytometry is not applicable in newborn screening for primary immune deficiency (PID), which is routinely performed on dried blood spots (DBS).
To address this challenge, researchers developed an epigenetic real-time qPCR assay for analysis of human leukocyte subpopulations. This assay was applied to DBS collected by heel prick from 250 healthy newborns and 24 newborns with PID to measure CD3 T cells, natural killer (NK) cells, and B cells. It was shown that epigenetic immune cell quantification can be used to identify newborns with various primary immunodeficiencies with high sensitivity and specificity (see Figure 1).[6]
Figure 1. Epigenetic qPCR on DBS from newborns. DBS from healthy newborns (n=250; gray circles) estimate reference ranges for each assay, as defined by 99% confidence region (red ellipse) and 99.9% confidence region (dashed and gray ellipse). DBS from 24 newborns diagnosed with PID are shown as colored circles. (A) Unmethylated CD3G/D, indicating T cells. (B) MVD, indicating NK cells. (C) LRP5, indicating B cells.
Conclusion: Shaping the Future of Pediatric Healthcare
The pediatric population is not only distinct from the adult population, but also heterogeneous due to physiologic and developmental differences. Thus, the success of pediatric precision medicine relies on both an understanding of this heterogeneity and availability of validated biomarkers and assays. As pediatric biomarker research and development advances, precision medicine holds the potential to revolutionize pediatric healthcare by making it more preventative, predictive, and personalized.
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References
[1]Shah P, Siver M. The latest FDA approvals for children’s medications. Contemporary Pediatrics, 2023:40(1):12-15.
[2] Zettler ME. A decade of FDA approvals for pediatric cancer indications: What have we learned? EJC Paediatric Oncology. 2023;1.
[3] Skogstrand K, et al. Editorial: Biomarkers to predict, prevent and find the appropriate treatments of disorders in childhood. Front Pediatr. 2022:10.
[4] Fleming TR, et al. Innovations in Pediatric Therapeutics Development: Principles for the Use of Bridging Biomarkers in Pediatric Extrapolation. Ther Innov Regul Sci. 2023;57(1):109-120.
[5] Shores DR, Everett AD. Children as Biomarker Orphans: Progress in the Field of Pediatric Biomarkers. J Pediatr. 2018;183:14-20.
[6] Baron U, et al. Epigenetic immune cell counting in human blood samples for immunodiagnostics. Sci Transl Med. 2018;10(452):eean3508.
