Chapter 7 224 3. Translation of findings towards therapy Considering the absence of curative treatments for 4H, there is still a pressing need for therapy development. In this thesis, we demonstrated a potential role for neuronal deficits in 4H leukodystrophy, possibly mediated through the SHH pathway. Our exploration of SAG, an agonist of Shh, to improve the 4H neuronal phenotype, revealed no significant effects, underscoring the need to investigate alternative targets within this pathway or entirely new pathways. The models and data presented in this thesis establish a critical foundation for these future investigations. However, important validation steps remain necessary to optimize our models and readouts for reliable therapy testing. For development of future therapies, several steps need to be taken. Those include the identification of a therapeutic target and / or measurable phenotypes. Did we identify those? Possibly. With optimization and standardization, the in vitro models displaying interneuron pathology (Chapter 2), could serve as a platform to screen for other drugs modulating the Shh pathway. Additionally, after optimization, FDA-approved drug libraries or CRISPR screens could be used to screen for possible other drugs. These strategies, known as drug repurposing, have the potential to significantly accelerate clinical translation, as Phase II clinical trials may follow logically (Turner et al., 2016), with reduced risk of failure (Rudrapal et al., 2020). How can we analyse drug screens? There is both merit in simple and complex approaches, depending on available expertise and resources. The most established method is highcontent screening of morphology phenotypes (cellomics), as demonstrated in Chapter 2 and 5. With the quick developments in the MEA field, it may soon be feasible to conduct highthroughput screens using MEA platforms, which we have shown to exhibit a strong phenotype already (Chapter 2). When does therapeutic intervention need to take place? Therapeutic timing is critical, especially for neurodevelopmental disorders with prenatal origins. Early interventions may be necessary to prevent or mitigate phenotypes, but strategies targeting later developmental stages could also hold promise for reversing or ameliorating phenotypes postnatally. Determining the optimal therapeutic window for 4H leukodystrophy will require further exploration, likely guided by developmental studies using in vitro and in vivo models.
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