We are privileged to be working with exceptional, world-class teams from across the globe. We have commissioned an in depth study of the condition, looked at protein complementation, and considered gene editing and gene silencing. Our current focus is an ambitious project centred on gene replacement therapy and drug development.

Laying the Groundwork for NKX6-2 Therapies

Project 1 | 2022 – Current

Over the past three years, researchers at the UCL Institute of Neurology, led by Dr. Viorica Chelban and Professor Henry Houlden, have carried out pioneering studies into NKX6-2 related spastic ataxia and leukodystrophy. This project focused on understanding the condition in greater depth, identifying measurable disease markers, and taking first steps toward potential gene-based therapies. 


The project had three main aims:


  • Understanding the disease better by identifying more individuals worldwide with NKX6-2 mutations and studying how the condition changes over time. 
  • Identifying “biomarkers” – measurable signs of disease - that can help monitor progression and test whether future treatments are working. This included testing known markers like NfL (neurofilament light chain, a marker of nerve cell damage and disease progression) and developing a brand-new test specifically for the NKX6-2 protein. 
  • Exploring the potential of gene therapy in the lab, using patient-derived cells to test whether delivering a healthy copy of the gene could restore protein levels. 


What the project achieved: 


  • Built a collaborative international network and NKX6-2 patient database. 
  • Recruited and studied more than 20 NKX6-2 patients across Europe, Middle East, and Asia. 
  • Developed and validated new biomarker tests, including a specific assay for the NKX6-2 protein. 
  • Completed early experiments showing that gene transfer into patient cells may restore protein function. 
  • Shared valuable clinical, MRI (shows changes in brain structure), and biomarker data to support future research and therapeutic development. 


This work is an important first step. It has laid the groundwork for future clinical trials, deepened understanding of how the disease progresses, and opened the door to potential gene-based therapies. These efforts bring the global NKX6-2 community closer to the possibility of effective, disease-modifying treatments for the estimated 500 to 1,000 patients worldwide.

Prime Editing Therapy NKX6-2 

Project 2 | 2022 – 2024

A second project was awarded to Professor Jacques P. Tremblay at Laval University in Canada to explore a brand-new approach: Prime Editing, a cutting-edge gene-editing technology based on CRISPR/Cas9. His team has a strong record in applying similar techniques to other genetic diseases, including Duchenne muscular dystrophy and Friedreich's ataxia, making his lab well-suited for this project. 


This project focuses on a specific NKX6-2 mutation (c. 121 A>T) that causes Spastic Ataxia-8, a rare leukodystrophy. NKX6-2 is essential for the maturation of oligodendrocytes, the brain cells responsible for making myelin - the protective coating around nerve fibers. The ultimate goal of this research was to explore whether correcting this mutation could prevent or reverse disease symptoms, beginning with early lab studies and eventually moving toward potential patient treatment. 


The research aims: 

  • Test Prime editing in both patient and lab-grown cells (in vitro). 
  • Explore delivery methods, such as viral vectors and nanoparticles, to bring the treatment into brain cells. 


Targeting oligodendrocytes using this technology currently presents significant challenges. However, as scientific understanding and gene-editing technologies continue to advance, there is potential for Prime editing to emerge as a precise and personalized therapeutic approach for individuals with NKX6-2-related Spastic Ataxia-8.

Restoring NKX6-2 Function: A Proof-of-Concept Study  

Project 3 | 2024 – 2025 

This project, led by Dr. Federico Herrera, in Portugal, is exploring an innovative idea: whether protein complementation could restore NKX6-2 function. Protein complementation is a strategy where scientists try to supply a working piece of a protein to replace or “rescue” the part that is missing or defective. In theory, the added protein fragment could bind or interact with the faulty (or truncated protein) to restore some or all of its normal function. This unique approach has been testing in other conditions, including muscular dystrophy, but has not yet been applied to NKX6-2. 


While this idea is creative, expert reviewers noted that it faces many challenges. It is not yet clear whether protein complementation will work for NKX6-2, and there are significant gaps in experimental models and biomarkers. While the concept is innovative, reviewers felt the likelihood of it leading to a therapy for NKX6-2-related Spastic Ataxia-8 is currently very low, and that its value lies more in advancing basic scientific knowledge than an immediate therapeutic development.

Evaluation of Anti-Sense Oligonucleotide (ASO) Technology – Gene Silencng

Project 4 | 2025

In collaboration with n-Lorem Foundation (www.nlorem.org) 


To express a gene, such as NKX6-2, the DNA within a cell is transcribed (copied) into messenger RNA (mRNA), which the cell can then read and translate into a functional protein. In the case of genetic disorders, the DNA sequence is altered, which results in altered mRNA and dysfunctional protein. Anti-sense oligonucleotides (ASOs) are small DNA or RNA molecules that are designed to interact with specific mRNA sequences to treat genetic disorders. This interaction can degrade the mRNA to prevent protein formation, or it can modify the mRNA processing (known as splicing) to correct the resulting protein. 


The n-Lorem Foundation is a non-profit that specializes in developing personalized ASO technology for patients with nano-rare diseases. Their team of experts evaluated the genetics underlying NKX6-2-related disorder and unfortunately found that ASO technology is not amenable to this disease. NKX6-2-related disorder is caused by loss-of-function genetic variants that disrupt the typical DNA-binding function of NKX6-2. The most common variants result in early “stop” signals that cause rapid degradation of the NKX6-2 mRNA. As a result, there is no available mRNA for potential ASOs to interact with, limiting the therapeutic potential of this approach. For other variants, mRNA and protein are still made, although the protein is non-functional. These genetic changes cannot be corrected by splicing modifications, so ASO technology will not be able to restore the protein function.

NKX6-2 Gene Replacement Therapy Drug Development

Project 5 | 2025 – Current

A new two-year research project began in September 2025, led by Dr. Steven Gray and Dr. Xin Chen of University of Texas Southwestern Medical Center. The team are world renowned experts in developing novel therapies for children with rare monogenetic diseases affecting the nervous system. Their team will develop a gene therapy approach to deliver a healthy copy of the NKX6-2 gene directly to oligodendrocytes in the brain. 


This work will include: 

  • Designing and testing a novel NKX6-2 gene replacement therapy and delivery system. 
  • Studying and characterizing disease features in an NKX6-2 knockout mouse model. 
  • Testing safety of the treatment in healthy mice. 
  • Use the NKX6-2 mouse model to test if gene therapy can improve symptoms when given early or later in the disease. 


If successful, this research could set the stage for the first-ever gene therapy trial in NKX6-2 patients. While still early-stage, it represents a hopeful step toward a future treatment for this ultra rare condition.