#ScienceSaturday posts share exciting scientific developments and educational resources with the KAND community. Each week, Dr. Dylan Verden of KIF1A.ORG summarizes newly published KIF1A-related research and highlights progress in rare disease research and therapeutic development.

KIF1A-Related Research

A Plant Flavonol Rescues a Pathogenic Mutation Associated with Kinesin in Neurons

We’ve spoken in the past about the power of worms: C. elegans models were used by Dr. Rebecca Shi to teach students about scientific experimentation, and Research Network member Dr. Shinsuke Niwa has answered crucial questions about KIF1A biology by studying KAND-relevant mutations. In this week’s pre-print, researchers in China used the humble worm to study, and improve, a KIF1A mutation.

Studying KIF1A mutations with suppressor screens

This study addressed the R11Q KIF1A mutation and its C. elegans counterpart, R9Q. Worms with this mutation have improper synapse formation and severely impaired movement, which the authors sought to reverse.

To understand why this mutation compromised KIF1A function, the authors leveraged the accessible genetics of C. elegans to perform a suppressor screen. Dr. Niwa has described these screens in a past interview:

“Suppressor screening means we introduce a second mutation into the disease model worm, and look for better suppressor mutants. A suppressor mutant means the disease model worm shows movement defects, however the suppressor shows better movement. [Meaning] that the second mutation makes the symptoms better.”

By introducing random mutations to R9Q worms, the authors were able to screen for 20 other KIF1A mutations that reverse these symptoms.

The point isn’t to introduce secondary mutations to KAND patients – these suppressor mutants are likely to interact with the R9Q, so this gives us a better idea of the structural impact of the R9Q mutation – where is the therapeutic target on the protein?

By identifying suppressors and applying their knowledge of KIF1A structure, the researchers were able to predict why this mutation compromises KIF1A – it prevents the motor from processing ATP, the chemical battery that drives KIF1A steps.

Mutations that helped KIF1A process ATP also rescued synaptic development and movement symptoms. If these mutations change the structure of mutant KIF1A to help it perform better, this begs the question: Can we identify small molecules that fix the structure of mutant R9Q/R11Q KIF1A?

Fisetin alleviates R9Q C. elegans movement and morphological defects

In science, being observant after an accident can be just as useful as having a firm starting hypothesis. The researchers accidentally starved some of their R9Q worms, and surprisingly found that symptoms improved, leading them to investigate nutrient supplements, namely fisetin.

Fisetin is a flavonol, a class of compounds commonly found in plants. In recent years it has been studied in cancer and neurodegeneration research. The authors found that fisetin treatment promoted synaptic and axonal growth, and partially rescued the R9Q worms’ symptoms!

One major limitation of animal studies is that proteins differ between species; this is why R11Q in humans is represented by R9Q in worms. To address these differences, the authors expressed human R11Q KIF1A in worms, and tested fisetin treatments. They were able to confirm that fisetin binds to human KIF1A near the R11Q mutation site, increasing its ability to process ATP and generate force for movement.

This is an exciting study that highlights the strength of “simple” model systems; C. elegans mutants can be quickly generated, their nervous system is accessible, and their behavior can be measured. Applying this model to a disease mutation is a great example of how translational “basic” science can really be.

A note on pre-prints and preclinical research

We’re very excited to discuss this paper, but interpreting the results requires that we review what a pre-print is, and how it fits into the publication process. Here’s a description from BioRxiv:

“Before formal publication in a scholarly journal, scientific and medical articles are traditionally ‘peer reviewed.’ In this process, the journal’s editors take advice from various experts—called ‘referees’ … Because this process can be lengthy, authors use the bioRxiv service to make their manuscripts available as ‘preprints’ before completing peer review and consequent certification by a journal. This allows other scientists to see, discuss, and comment on the findings immediately.”

It’s also worth noting that preclinical research models are limited in scope: This study is an exciting example of structural biology, but there is still a lot we don’t know about fisetin; as the study authors note:

“Caution is crucial when considering the use of fisetin or any other dietary supplement for KAND patients. Safety considerations, including appropriate dosage, potential interactions with other medications or underlying conditions, should be carefully assessed. We strongly recommend consulting with healthcare professionals or experts in the field of neurodevelopmental disorders before initiating any fisetin supplementation regimen for individuals with KAND.”

Chai et al. 2023

Scientific findings need to be validated, replicated, and applied to new systems; this is the reason KIF1A.ORG has invested in our Treatment Accelerator Program. We look forward to leveraging our Research Network of healthcare professionals and neurodevelopmental experts to follow this lead, and others, in our search for KAND treatments.

Rare Roundup

FDA Launches Pilot Program to Develop Better Rare Disease Endpoints

With only two weeks to go before our 2023 KAND Family and Scientific Engagement Conference, we’re incredibly proud to say that we’re on the cusp of having 60 families participate in the KOALA study to establish KAND clinical endpoints.

Endpoints are measurements of a disease. In a clinical trial, treatments are assessed by whether they change endpoints selected before the study. This can a challenge for rare and variable disorders like KAND.

The US Food and Drug Administration (FDA) is taking steps to better accommodate rare disease communities, including the launch of Operation Warp Speed to accelerate drug approval for rare disorders. Earlier this summer the FDA also approved tofersen for ALS, in part by considering spinal fluid and blood biomarkers as endpoints.

The FDA also hopes to establish new clinical endpoints; this month they began accepting applications for drug developers participate in the Rare Disease Endpoint Advancement (RDEA) Program. This project aims to provide additional ways to test treatments for rare disease populations, and integrate patient perspectives to ensure these endpoints are meaningful.

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