#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.
A novel de novo KIF1A mutation in a patient with ataxia, intellectual disability and mild foot deformity
KAND is a genetically defined disease – it’s caused by mutations in the KIF1A gene. But genetic sequencing is still a relatively new diagnostic, and many of our community become familiar with symptoms before their diagnosis. Similarly, with each diagnosed patient, we learn more about how KIF1A mutations manifest in KAND. In this week’s article, researchers from the National Center of Neurology and Psychiatry in Tokyo, Japan, describe a KIF1A mutation in a woman with ataxia and foot deformities.
Ataxia is a condition of impaired muscle coordination caused by neurodegeneration of motor regions in the brain, including the cerebellum. The woman also had foot deformities and reduced transmission speed of electrical signals along her legs. With genetic testing, the researchers were able to identify a novel E267Q KIF1A mutation in the motor domain as a likely contributor to these symptoms. Notably, while her movement symptoms had continued to progress, they stabilized for a three year period after participating in an intensive 4-week ataxia-specific rehabilitation program, which consisted of: General conditioning and muscle strengthening, balance and gait exercises, walking, and dual motor tasks such as handling objects.
The KAND family is a small one, which is why we all have so much to gain from a growing recognition of KIF1A mutations, the symptoms they cause, and potential interventions. We’re grateful for the clinicians, researchers, and most of all families, who help us better understand and treat KAND.
RNA interference (RNAi)-based therapeutics for treatment of rare neurologic diseases
Because KIF1A is a genetic disorder, it makes sense that gene therapies – treatments that permanently change the DNA of the KIF1A gene back to normal – are an appealing concept. But gene therapies are permanent and may have off-target effects on the genome. One way to target the specific cause of KAND (a mutant KIF1A) without causing irreversible changes to the genome, is to target RNA.
RNA is an intermediate made from DNA and made into protein. Targeting RNA can prevent the creation of mutant KIF1A protein, and because RNA is continuously produced, it can be targeted with therapeutics that are taken more like a traditional drug than a permanent gene replacement. This means that unlike gene altering approaches, RNA interference therapy doses can be modified over time to benefit each patient.
There are many types of RNA interference (RNAi) therapies being researched; our partners at Ovid, Dr. Noelle Germain and Dr. Patrick Sarmiere, recently spoke to their ASO approaches at our September Community Call. This week, they collaborated with Dr. Wendy Chung to published a review of considerations for RNA interference therapies. This resource provides information on several factors that are important for therapeutic development:
- What types of RNAi are currently being studied, and what are their advantages and disadvantages?
- Small interfering RNAs (siRNAs) can effectively knock down RNA, but must be modified to cross cell membranes and survive the cellular environment.
- Short hairpin RNAs (shRNAs) allow for knockdown of RNA that lasts up to months, and can be tailored to be expressed in specific cells of interest.
- MicroRNAs (miRNAs) can cause long-lasting knockdown of their target, but can impact multiple targets, which isn’t ideal for a monogenic disorder like KAND.
- Antisense oligonucleotides (ASOs), a line of investigation being pursued by Ovid, are highly targeted which is useful for specifically knocking down mutant KIF1A, but require repeated dosing to maintain RNA knockdown.
- What are the best ways to deliver RNA interference therapeutics, especially for disorders of the central nervous system? (For more information check out our past #ScienceSaturday on the subject)
- Adeno associated virus can package an RNA interference therapeutic and cross the cell membrane, but carries some risks of liver toxicity, and can be neutralized by our immune system which recognizes viral components.
- Lipid nanoparticles are molecular capsules that surround the RNA interference therapeutic and can be modified for specific purposes. They are less likely to be suppressed by the immune system, but do not readily cross the blood brain barrier, presenting a challenge for neurological disorders.
- Exosomes are a class of small structures created by many cells in the body. They can be filled with RNA interference therapeutics and can be customized for specific purposes. However their production is currently difficult to scale up for large-scale therapeutic purposes.
- What considerations need to be made for specific disorders like KAND to create and deliver effective RNA interference therapeutics?
- Different KIF1A mutations manifest differently. Some mutations are loss of function (there’s less functional KIF1A than there should be), and some of them are dominant gain of function (mutant KIF1A interferes with healthy KIF1A). Because RNA interference reduces mutant KIF1A, we can learn a lot from what symptoms occur in loss of function patients.
- KAND is a developmental disorder, so the timing of treatment is likely to impact the efficacy of treatment.
Thank you to Wendy, Noelle, and Patrick for their expertise and their #relentless search for the best possible treatments for our KAND community.