#ScienceSaturday posts share relevant and exciting scientific news with the KAND community. This project is a collaboration between KIF1A.ORG’s Research Engagement Team Leader Alejandro Doval, President Kathryn Atchley and Science Communication Director Dr. Dominique Lessard. Send news suggestions to our team at impact@kif1a.org.

Recent KIF1A-Related Research

Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the ‘beyond epilepsy’ project

This recently published study from the Italian Journal of Pediatrics is aiming to reduce the time between diagnosis of childhood epilepsy and time of first seizure onset. While designed around a neurodegenerative condition called late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2), diagnostic delay is a common problem with rare cases of childhood epilepsy. This study was conducted as a part of the “Beyond Paediatric Epilepsy Panel” project that is “focused on the use of Next Generation Sequencing (NGS)-based techniques for early detection of genetic causes underlying childhood epilepsies.” The clinical cohort of this study averaged just over 3 years of age, with the age of seizure onset being about 2.5 years of age. Types of seizures and phenotypic features of this cohort are represented, as well as pathogenic variants identified as a result of sequencing. Importantly, mutation of the KIF1A gene was identified in one member of the cohort. From this study, we learn of the diagnostic capability of the Beyond Paediatric Epilepsy Panel that may be of use to the rare disease community and suggests a “cost- and time-effective diagnostic weapon in the hands of paediatric neurologists and geneticists, especially when clinical features are not strictly suggestive of a specific disorder.”

Rare Disease News

Targeting Huntington’s Disease with Antisense

This week, we are featuring a 20-minute episode of RARECast with Dr. Eric Swayze, the Executive Vice President for Research at Ionis Pharmaceuticals. In this episode, Dr. Swayze discusses many current advances and approaches in ASO technology from the Ionis team. Intriguingly, he details three separate ways in which ASOs can be designed to help tackle diseases and disorders. First, he discusses their work with Huntington’s disease in which they aim to disrupt the production of a certain protein. Second, he discusses Ionis’ LICA Technology, allowing for targeted ASO delivery to specific areas in the body. Lastly, he discusses the power of designing ASOs to up-regulate the production of a protein, which may be helpful in a variety of neurological diseases and disorders. This is a fantastic educational resource on the current state of ASO development at Ionis–have a listen!

Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

In other ASO news, this study has taken a unique ASO approach that has the potential to treat patients with monogenic loss-of-function diseases. This new approach, called TANGO (targeted augmentation of nuclear gene output), is shown to increase the amount of full-length and fully functional protein by specific types of genetic leveraging. Encouragingly, this proof of concept study has shown successful and dose-dependent production of target proteins in mouse brains. TANGO technology has been spearheaded by Stoke Therapeutics, a company that develops antisense oligonucleotide medicines that increase gene expression.

To Let Neurons Talk, Immune Cells Clear Paths Through Brain’s ‘Scaffolding’

Did you know that our brains have their own type of immune cells that are found nowhere else in the body? Like most immune cells, these cells known as microglia play an important role in protecting our brains from infection and facilitate healing after brain injury. On top of this, microglia are known to break down certain materials in our brain. This article covers a new study out of the University of California San Francisco that discovered a new substance that microglia can break down in our brains: the extracellular matrix (ECM). The ECM is a three-dimensional network of molecules that provide structural and functional support to nearby cells; to provide this support, the ECM has a gelatinous consistency making our brain one big jello mold of cells! ECM surrounds the cells in our brain and makes up about 20% of our brain volume. When microglia “chew away” at the ECM in our brains, this makes room for new cellular connections to be formed. From this study we now know that IL-33, an immune molecule secreted from neurons, acts as an activating signal for microglia, telling them to break down ECM so there is more room for synapses between neurons to be formed. Want to learn more about the microglia in our brain? Check out the video below!

Researchers study effects of cellular crowding on the cell’s transport system

When you think of a kinesin motor like KIF1A walking along a microtubule track, what do you see in your head? Often times this process is represented as a single kinesin motor walking along a nice straight microtubule. However, this is far from the reality of this process. The environment surrounding microtubules in the axon is both extremely complex and extremely crowded! So how does this crowded environment (otherwise known as macromolecular crowding) effect kinesin motor function? One group at NYU Abu Dhabi has begun investigating the effects of macromolecular crowding in both a cellular and a molecular environment. From this study we learn that while crowding can slow the transport of teams of motors (multiple kinesin motors attached to one common cargo) working together, it does not slow the transport of individual motors. If we think about it in the context of a traffic jam, it is much easier for one car to try to navigate through traffic than a bunch of cars that are attached to each other. See this video below to learn more about the process of neuronal cargo trafficking!

Gene-editing discovery could point the way toward a ‘holy grail’: cures for mitochondrial diseases

Mitochondria, often referred to as “the powerhouse of the cell,” are cellular components that produce a chemical energy source for our cells known as ATP. Due to the critical importance of mitochondria throughout our bodies, mitochondrial diseases (sometimes resulting from mutations) are often extremely debilitating. In considering the advancements in gene-editing technology over the past 15 years, one may postulate that a mitochondrial mutation could be edited to fix the causative issue. Sadly, mitochondria are historically very resistant to gene-editing techniques and have been researched with minimal success. That is until Dr. David Liu’s lab used a different approach to solve this problem: engineering a bacterial toxin into a gene editing machine! This is just one of many articles that we have featured recently that highlights the advances in gene-editing technology out of Dr. Liu’s lab. Enjoy this article that details the process of this discovery.

“The genome editing revolution has largely passed mitochondria by. CRISPR doesn’t work: The guide RNA it uses like a bloodhound to find its target within a genome can’t penetrate mitochondrial walls. Earlier editors, such as TALENs, can eliminate mutations in mitochondria in cells growing in lab dishes, but only by destroying the DNA. Nothing could fix mutations by changing one DNA letter into another, such as a C to a T or a G to an A. ‘Mitochondria,’ said Liu, ‘are one of the last bastions of DNA that has resisted precision genome editing.'”

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