#ScienceSaturday posts share exciting scientific developments and educational resources with the KAND community. Each week, Dr. Dominique Lessard and Dr. Dylan Verden of KIF1A.ORG summarize newly published KIF1A-related research and highlight progress in rare disease research and therapeutic development.
Identification of an in-frame homozygous KIF1A variant causing a mild SPG30 phenotype in a Korean family
In the last five years, our KAND community has grown from a handful of families to over 500. Despite this rapid growth, we still don’t think that we have the full picture. Every year we learn more about the ways KIF1A mutations can manifest thanks to advances in genetic testing and greater accessibility.
In this week’s article, researchers in South Korea worked with a man who started experiencing gait disturbances at 55 years old. The man’s siblings were unaffected, but his father also had gait disturbances that began at 65 years of age, so the researchers performed genetic testing on the family.
Genetic screening is a complex process – the researchers had to use multiple filters to narrow down a list of 160,085 potential variants across the genome down to just 3, including a single KIF1A mutation in a region outside of the motor domain. This mutation, Glu917del, deleted a single amino acid (or structural building block) from KIF1A.
The genetic testing showed that siblings carrying a single copy of the Glu917del mutation were unaffected, indicating this mutation is recessive – two copies of the mutation are necessary to cause disease, meaning the man’s father and mother carried the same mutation and passed it on to their son. Since the father also had symptoms, he likely inherited a copy from each of his parents as well.
This mutation appears relatively mild; affected family members had spasticity, but no epilepsy or brain atrophy. This kind of mild, late-onset progression is more common with mutations outside of KIF1A’s motor domain, and seeing these cases helps us build a fuller picture of symptom progression caused by KIF1A mutations.
Using brain organoids to test gene therapies for a rare disease in children
When scientists find or develop a promising new therapeutic, they can test it in model systems to assess its effectiveness and safety. This is called preclinical testing and it’s a major component of therapeutic development.
Traditionally, preclinical testing has consisted of testing the drug in cells in a dish, and animal models, each of which have benefits and drawbacks:
- Cells in a dish can be used to test therapeutic mechanisms, and can be used relatively quickly and cheaply. But their simplicity means that they may not capture all the effects of a treatment on an organism.
- Animal models can provide more realistic information about a treatment’s effects on an organism’s health, and can be used to test administration routes. But these models can be time consuming and expensive, and the biological differences between humans and other animals present their own challenges.
One emerging system that bridges the gap between these methods are brain organoids, in which cells are grown into a tissue that better represents the 3D architecture of the brain. Organoids grown from patient-derived cells share the genetic makeup of real patients, providing more insight into the potential of a drug without risking human health.
Researchers at the University of Queensland are now using cells from patients with Hereditary Spastic Paraplegia Type 56 to grown brain organoids and test potential gene therapies. The success of this project could better inform our own efforts to develop small molecule and gene therapies to treat spasticity in KAND patients.
And good news, our Research Network already includes an Australian group working on KAND patient-derived organoids! You can learn more from our 2022 interview with Dr. Wendy Gold and Dr. Simran Kaur.