#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.
KRIBB develops new gene therapy candidate for hereditary spastic paraplegia
This week we’re flipping the format and starting with our Rare Roundup, after families contacted us with this article about a gene therapy candidate for hereditary spastic paraplegia.
KIF1A mutations and KAND overlap with so many diagnoses that when an article comes out discussing potential treatments for one of those disorders, it’s natural to wonder whether they could apply to KAND as well.
Hereditary Spastic Paraplegia (abbreviated HSP) is a group of disorders that spans over 80 different mutated genes. They’re grouped together because many of the symptoms overlap: in this case, HSPs are unified by progressive spasticity and weakness in the legs. But spastic paraplegia subtypes (SPGs) are usually defined by their genetic cause: For example, KIF1A mutations cause SPG30, which is a type of HSP.
Drugs that treat symptoms in other HSP types could inform treatments for similar symptoms in KAND, so we’re always on the lookout for small molecule or technological interventions that work in other SPGs.
Gene therapies are much more specific – this article is titled as a gene therapy candidate for HSP, but it would be more accurate to say this gene therapy candidate has shown benefits in a mouse model of SPG61.
In this study, mice missing both copies of a gene called ARL61P1 exhibit HSP symptoms, including spasticity: the researchers investigated how ARL61P1 loss impacts brain cells and behavior in these mice, and then inserted a copy of ARL61P1 into brain cells by injecting it into the motor cortex of the brain. The study found improved spasticity and movement in mice treated with ARL61P1 gene therapy; it also restored abnormalities observed in the brains of ARL61P1-deficient mice.
This is an exciting study: Inserting the ARL61P1 gene improves , but it isn’t clinically applicable to KAND, because it doesn’t target KIF1A.
So unfortunately this isn’t the treatment we’re looking for, but progress in gene therapies is a rising tide that lifts all ships; the more evidence that gene therapies can be effective for spasticity and motor symptoms, the more hope for our own gene therapy solutions.
KIF1A gene-based therapies investigated by our Research Network
Speaking of other ships, one of our greatest assets as a community is a Research Network that is actively focusing on therapies for KAND. You can learn about some of strategies under investigation below:
- Antisense Oligonucleotides (ASOs) specifically knock down expression of mutant KIF1A. These are applicable for patients with gain-of-function mutations where the mutant KIF1A interferes with the healthy version. ASOs are traditionally mutation-specific, but the Chung Lab is developing a “handle” approach that allows a single ASO to target patients with different mutations. To learn more about ASOs check out Dr. Wendy Chung’s talk from our 2023 conference, and to learn more about the handle approach you can watch Dr. Michael Zuccaro’s talk.
- A KIF1A mini-gene is a smaller version of the KIF1A gene that adds a functional protein to increase healthy KIF1A levels. This aims to treat people with loss-of-function mutations or KIF1A deletions, similarly to the ARL61P1 gene therapy described above. Dr. Simran Kaur’s 2023 conference talk briefly describes the KIF1A mini-gene approach.
- The Jackson Laboratory, who has developed 3 KAND mouse models and 9 KAND cell models, is working on Prime/base gene editing, which replaces large sections of mutant KIF1A DNA with the healthy sequence. This would allow a single gene therapy to replace an area of KIF1A that includes multiple disease-causing mutations, and treat multiple mutations at once. Dr. Markus Terrey described this approach during his conference talk.
Each of these approaches have their own challenges, but we are incredibly fortunate to have researchers at the forefront of multiple innovations in gene-based therapies for KIF1A mutations.
A retrospective review of 18 patients with childhood-onset hereditary spastic paraplegia, nine with novel variants
Sticking to this week’s theme of hereditary spastic paraplegia, we also wanted to highlight a recent study from Turkiye that investigated 18 patients with HSP, looking to better understand genetic subtypes of the disorder.
Each patient in this study experienced progressive spasticity and weakness consistent with HSP. Notably, the average delay between symptom onset and genetic diagnosis was 5.8 years, reflecting the lengthy and difficult diagnostic journey for patients with genetic disorders.
This study also highlights the diversity of HSP types: across 18 patients, researchers identified 15 different spastic paraplegia subtypes. “In our cohort, there were two subjects each with SPG11, SPG46 and SPG50 followed by single subject each with SPG3A, SPG4, SPG7, SPG8, SPG30, SPG35, SPG43, SPG44, SPG57, SPG62, IAHSP, and SPPRS.”
The single case of SPG30 was caused by a novel mutation, W313C, in KIF1A’s motor domain. The mutation caused familiar symptoms including delayed motor milestones, leg spasticity and weakness, ataxia, and atrophy in the cerebellum.
This investigation of broader disease groups is crucial to provide families with more detailed knowledge of their specific HSP case, and increase our awareness of our global community. It also gives clinicians and researchers more information about the complex relationship between KIF1A mutations, KAND, and spastic paraplegia.