Personalized antisense oligonucleotides (ASOs) are versatile molecules that can be designed to specifically target and modify RNA transcripts, combating the progression of rare genetic diseases. While the use of ASOs in medicine is still relatively limited, researchers at Children’s Mercy Kansas City have achieved a significant advancement in the ASO field, with promising results in preclinical evaluations. Read on for a summary of the groundbreaking study, which is titled “Rapid and scalable personalized ASO screening in patient-derived organoids” and was published in the journal Nature.
New Hope for Patients with Genetic Diseases
To optimize ASOs, researchers generally use cell cultures, such as patient-derived induced pluripotent stem cells, or iPSCs. These stem cells allow researchers to create isogenic cell lines for disease correction in individuals with rare genetic diseases. However, deriving iPSCs can take up to a year, and the process is extremely costly. Given this hurdle to treatment, the team at Children’s Mercy Kansas City set out to find a new method — a method that required fewer patient blood cells and would result in faster, more cost-effective iPSC generation, thus fueling enhanced ASO optimization for patients in urgent need of treatment. The method relied on novel organoids instead of the traditional isogenic cell line approach.
Using Novel Organoids for Genetic Disease Modeling
The team at the Children’s Mercy Genomic Medicine Center began with patient-derived stem cells from three patients enrolled in its Genetic Answers for Kids (GA4K) program with Duchenne muscular dystrophy. The patients were identified as having genetic variants that could be good candidates for ASO treatment.
To optimize ASO treatment, the research team then used patient-derived iPSCs to grow patient-specific organoids: three-dimensional cell models that could recapitulate organ development and function, helping the team gain a more thorough understanding of each patient’s unique disease biology. This was a much faster approach than creating traditional isogenic cell lines using iPSCs. “Instead of waiting more than a year for cell models to be generated before experiments could even begin, a family could go from blood draw to diagnosis and/or treatment recommendation in a month or two,” pointed out Scott Younger, the leader of the Younger Laboratory at Children’s Mercy.
Promising Results from ASO Treatments of Genetic Diseases
The team was ultimately able to restore dystrophin protein expression and function in patient-derived organoids, thanks to an FDA-approved ASO for one patient and customized patient-specific ASOs for the other patients. Steve Leeder, the interim executive director at the Children’s Mercy Research Institute, explained that patient-derived organoids “have the potential to be widely used in creating cellular systems for investigating disorders involving the heart, kidney, liver and other tissues, in addition to identifying which medications are likely to be effective for a specific patient and which ones may not.”
The research team hopes the organoid ASO-optimization method will ultimately provide faster, better care for rare disease patients worldwide. “The methods and protocols generated in this study are accessible and can be implemented in any standard research laboratory without the need for specialized equipment or high-cost reagents,” said Younger. “The widespread ability to generate patient-derived cellular systems will have a substantial effect on the understanding of disease mechanisms as well as potential therapeutic avenues for the treatment of many rare diseases.”
Using patient-derived organoids to optimize ASOs offers new hope for patients with previously untreatable genetic conditions, with faster, more affordable, and personalized care on the horizon for all.
To test ASOs, Scantox Neuro offers various in vitro and in vivo systems of several neurodegenerative and lysosomal storage diseases, including organoids. In vivo models can be treated by various routes. Experiments can be performed up to biosafety level 2.
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