🔬 1. Combination Therapeutic Studies

Focus:
Identify multi-compound approaches capable of improving lysosomal function, complementing Luka’s clinical success on ManNAc.

Recent Progress:

• Launched a multi-compound study using ATP6AP2 HEK and Luka’s fibroblast lines

• Early laboratory results are encouraging and continue to be evaluated

• Confirmed lysosomal pathway defects in HEK, fibroblast, and iPSC models

• Expanded studies into Luka’s NYSCF-derived iPSC lines

• Preparing differentiated cell models (neurons, hepatocytes) to assess key pathways including:

  • lysosomal function

  • autophagy

  • mitochondrial and metabolic signaling

  • calcium and iron regulation

  • cellular stress responses

Next Steps:

• Complete differentiation studies

• Continue expanding the compound screening panel

• Generate data needed to inform preclinical dosing studies in mouse models

🐁 2. Mouse Models

(CHOP / Dr. Andrew Edmondson)

Focus:
Develop ATP6AP2 mouse models to evaluate therapeutic combinations and study systemic effects of the mutation.

Recent Progress:

• Ongoing colony management of the ATP6AP2-Liver KO model

• Preparing for early therapeutic testing informed by iPSC data

• Luka-mutation mouse model generated and initial profiling underway

Next Steps:

• Begin in vivo testing following final iPSC confirmation

• Integrate mitochondrial, lysosomal, and metabolic readouts into model analysis

🧬 3. iPSC Platforms

(NYSCF + ATP6AP2 Splice-Variant Lines)

Focus:
Develop a robust cellular platform for mechanistic studies, drug screening, and comparative phenotyping.

Recent Progress:

• NYSCF delivered Luka’s iPSC line and expansion is complete

• A gene-edited “corrected” iPSC line is in final stages of validation

• Added new ATP6AP2 splice variant patient-derived iPSCs

  • These represent severe CDG presentations with parkinsonian features

  • Enable compare/contrast with Luka’s cells

  • Expand the therapeutic testing panel

Next Steps:

• Differentiate iPSCs into neuronal and hepatic cell types

• Conduct mechanistic profiling across mitochondrial, lysosomal, metabolic, and trafficking pathways

🧫 4. Protein Glycosylation & Golgi Function

(Münster / Dr. Julien Park)

Focus:
Evaluate how multi-compound approaches impact glycosylation and Golgi function in ATP6AP2 patient-derived cells.

Recent Progress:

• Delivered compound panel to Münster

• Treatment of Luka’s cell lines underway

• Assessing effects on protein glycosylation and Golgi structure/function

Next Steps:

• Integrate results with ongoing combination-therapy datasets

• Evaluate glycosylation rescue potential in both Luka and splice-variant cell lines

🔋 5. Mitochondrial Therapeutic Study

(Mt. Sinai / Drs. Eva Morava & Tamas Kozicz)

Focus:
Evaluate a novel mitochondrial-targeting activator in DHDDS patient-derived organoids—another CDG with severe neurological involvement.

Recent Progress:

• Study fully funded by LSF

• Organoid experiments underway

• Targeting mitochondrial function relevant to both DHDDS and ATP6AP2-associated CDGs

Why this matters:

• May identify a new therapeutic avenue for CDGs

• Provides foundational mitochondrial data applicable to ATP6AP2

❤️ Thank You

We remain profoundly grateful for your support as we push toward new therapeutic possibilities for Luka and for children with severe CDGs. We will continue to share updates as data evolve.

6. The Road Ahead

From Luka’s cells to global collaborations, each step brings us closer to viable therapies for ATP6AP2 and related CDGs.

Our upcoming priorities include:

• Finalizing the pathogenic classification of ATP6AP2

• Advancing combination-therapy testing in mouse models

• Publishing multi-center data sets for open collaboration

• Expanding cross-disease research into mitochondrial and lysosomal biology

• Restoring our Natural History Study services through grant renewal