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Decoding Vitamin B6 Pathways to Unlock Therapies for Rare Diseases
During my training at MIT, I led genome-wide CRISPR screens in cells exposed to high and low levels of vitamin B6. These screens revealed critical genes and pathways required for survival under B6 scarcity, highlighting the central role of pyridoxal 5'-phosphate (PLP) in neurotransmitter synthesis, heme production, and mitochondrial function.
Our top hit, SLC25A38, emerged as essential for mitochondrial PLP accumulation—a key step in heme biosynthesis and the activity of PLP-dependent enzymes. This discovery directly links vitamin B6 metabolism to Congenital Sideroblastic Anemia (CSA), a rare pediatric disorder. Read more: Pena et al, 2025, Nature Communications.
Now, we’re expanding this work by developing CRISPR screens in patient-derived cells to uncover modifier genes that rescue disease phenotypes and synthetic lethal pathways that reveal hidden vulnerabilities. These insights will pave the way for novel therapeutic strategies in rare genetic diseases.
Animal models for rare pediatric diseases:
Our lab is pioneering the use of zebrafish to model rare pediatric neurometabolic disorders. We recently published the first zebrafish model of Pyridoxine-Dependent Epilepsy (PDE), engineered using CRISPR/Cas9 to disrupt aldh7a1. These larvae display spontaneous convulsive seizures, mirroring the human condition. You can view examples of normal and seizure behavior in our Genetics paper.
We also co-led the clinical and molecular characterization of PLPBP-deficiency—a severe neonatal epilepsy—and developed its first zebrafish model, published in Brain. Zebrafish larvae are ideally suited for high-throughput drug screening, as their small size allows for rapid testing in multiwell plates. Seizures can be triggered pharmacologically or genetically, offering a powerful platform to study disease mechanisms and therapeutic interventions.
Our lab is now expanding this work to generate new zebrafish models of rare neurometabolic diseases using CRISPR/Cas9. We aim to integrate gene therapy and drug discovery tools to explore rescue strategies at both systemic and cell-type-specific levels.
Precision Mitochondrial Profiling in Rare Disease Research
Many of the rare pediatric diseases we study involve mitochondrial dysfunction—either through mutations in mitochondrially-localized proteins or genes that regulate mitochondrial biology. During my postdoctoral work at MIT, I developed a novel technique to isolate mitochondria from specific cell types in vivo (in mice) with exceptional purity. This breakthrough opens the door to answering long-standing questions in disease biochemistry, particularly in tissues where mitochondrial defects drive pathology.
Mitochondrial dysfunction is a hallmark of numerous neurological conditions, including neurodegenerative disorders and rare neurometabolic diseases like Pyridoxine-Dependent Epilepsy (PDE). Our lab is now adapting this technology to profile mitochondria in disease-relevant cell types, with a focus on PDE, Glutaric Acidemia Type I (GA1), and Congenital Sideroblastic Anemias (CSA).
Stay tuned—another exciting paper is on the way!
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