The long journey to research discovery is enabled by donors like you. Since 1998, SickKids has benefited from the support of the Schwartz family and the Jacob’s Ladder community. Your generous gifts are helping us advance knowledge about genetic medicine, complex care, and rare neurodegenerative diseases in childhood. Thank you for your longstanding support of research excellence at SickKids.

Personally, I am deeply grateful for the two years of funding from Jacob’s Ladder to investigate the little-known gene called PLA2G6 that lies
behind three related neurodegenerative diseases, each one fatal and without treatment or cure.
Your gift allowed my lab to use our expertise in Drosophila (fruit fly) modelling to learn more about this poorly understood gene and its impact on neurodegeneration, with the long-term goal of identifying targets that could lead to therapies for infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (aNAD), and Dystonia- Parkinsonism (DP).

GENERATING A DISEASE MODEL
In Year 1 of the study, your funding allowed my team to develop a robust Drosophila model and use it to probe the effect of PLA2G6 mutations on neurodegeneration in humans. We discovered that the loss of the fruit fly’s equivalent of PLA2G6 caused deficits in motor movements, motor coordination, and psychomotor learning, the
effects were progressive, and lifespan was severely shortened—key features of neurodegeneration in humans with PLA2G6 mutations. We shared our results with the research community in an article published in February 2018 in the prestigious journal Scientific Reports, with the contribution of Jacob’s Ladder acknowledged.

MODELLING PATIENT-SPECIFIC MUTATIONS
Building on Year 1, the key activity in our second year has been to develop our Drosophila model into patient-specific models for PLA2G6 mutations. We’ve developed models for 7 patients—2 for INAD, 2 for aNAD, 2 for DP, and 1 for a never-before seen mutation in a SickKids patient, found by scientist and staff neurologist Dr. James Dowling. We know that each condition is linked to a mutation in PLA2G6, but the mutations are in different parts

of the gene—and the location and function of the mutation seem to make the difference between a child diagnosed with INAD who lives for less than a year and a child diagnosed with DP who may live into early adulthood.

Up until now, we’ve simply not had good animal models for these ultra-rare diseases of childhood neurodegeneration. Thanks to your support of this study, we’ve filled an important gap in our toolkit.
With robust patient-specific models, we’re able to start to understand the mechanisms behind these mutations—we now have the ability to
explore what’s taking place at the level of cells and molecules.

OUR VISION: INDIVIDUALIZED THERAPY
My hope is that these foundational insights will lead us to compounds for new therapies that could one day treat these devastating childhood diseases. With a biobank of patient-specific stem cells, we’re also now able to develop a drug screening platform to test compounds of potential using patient- specific neurons derived from their stem cells.
These are the first essential steps that may lead to individualized therapies in the future.

By focusing on INAD, aNAD, and DP, we hope to identify common disease pathways or shared underlying defects and possible
therapies that could benefit people living with neurodegeneration across the lifespan, from early infancy to old age. Thank you for helping advance knowledge that we hope will transform lives in the future.

Sincerely yours,

Dr. Gabrielle Boulianne Senior Scientist
Developmental & Stem Cell Biology