The MED13L Foundation strategic research plan: a roadmap to the future

Abstract

A strategic research plan (SRP) serves as a compass for the patient advocacy organizations driving the therapeutic options for their rare disorder. The MED13L Foundation commissioned the SRP in 2022 through COMBINEDBrain, a consortium of patient advocacy organizations of rare neurodevelopmental disorders, working toward clinical trial readiness. The MED13L Foundation SRP is an objective evaluation of MED13L literature including clinical and basic science knowledge interwoven with an assessment of preclinical trial readiness tools necessary for achieving therapeutic interventions. Clinical evaluation is conducted through a review of the literature documenting symptoms and variant information for each individual with MED13L syndrome. Data is collated and presented as a summary, providing any unique genotype-phenotype, as applicable. Scientific literature is reviewed in the same manner, identifying areas of opportunity to expand knowledge of MED13L syndrome. Researchers and clinicians responsible for growing the understanding of MED13L syndrome are interviewed and information is shared to create an open and collaborative network. Preclinical trial readiness tools are largely framed through Food and Drug Administration guidelines for the development of therapeutics from bench to bedside. Finally, the Foundation infrastructure and community engagement are assessed providing areas of strengths and opportunities to elevate the bond formed to drive patient-centered research forward. Completed, this SRP becomes a living resource for the MED13L Foundation to set priorities, share with researchers and clinicians, and provide direction to reach their organizational goals, including therapies for their community affected by MED13L syndrome.

Keywords: MED13L; advocacy led research; drug development resources; neurodevelopmental rare disease; patient advocacy organization; research roadmap.

Figure 1.

The MED13L foundation strategic roadmap.^– The roadmap serves as a summary of progress regarding the necessary preclinical trial tools and resources developed as part of the larger SRP. Each forward-moving arrow represents a broad category of needs, from diagnosis to regulatory tasks, essential for optimal clinical trial readiness. Each box above and below the arrows represents a set of tools and resources that align with these categories. The resources may flow across arrows and do not fully represent all that must be achieved to reach clinical trials or therapeutic development. Additionally, tools and resources may apply to many rare disorders or be specific to a particular disorder. An engaged and active community is crucial throughout the entire process. Early and intentional investment in individuals affected by MED13L syndrome is key to developing effective therapeutics. EEG, electroencephalogram; FDA, Food and Drug Administration; ICD-10, International Classification of Diseases, 10th revision; iPSCs, induced pluripotent stem cells; SRP, strategic research plan.

Figure 2.

Proposed mechanism of MED13L compared to MED13L haploinsufficiency (created with BioRender). Left side: Under normal conditions, one of the functions of MED13 is to link the MKM to the Mediator Complex^,; presumably, MED13L has a similar function given that biochemical and mass spectrometry data show Mediator association with MED13 and MED13L.^, MED13L has specifically been shown to regulate Wnt, FGF, and Rb/E2F pathways.^,, Additionally, upon induction of stress or a loss of the nuclear-tethering of MED13L, cyclin C has been shown to exit the nucleus and interact with mitochondrial fission machinery, promoting organelle fragmentation/fission.^– Right side: It is hypothesized that in MED13L Haploinsufficiency Syndrome, the transcriptional process related to the mediator complex interaction with RNA polymerase II may be disrupted. Cyclin C is aberrantly released into the cytoplasm, increasing susceptibility to cell death through mitochondrial fragmentation, decreased oxygen consumption as well as decreased ATP production.^, FGF, fibroblast growth factor; MKM, mediator kinase module; Rb/E2F, retinoblastoma tumor suppressor; Wnt, wingless-type integration type.