New method with implications for treatment

Scheme showing how antisense oligonucleotides restore FKTN and α-DG protein functions in cell-based experiments

image: RNAi-based treatment restores normal FKTN protein production and alpha-dystroglycan glycosylation in cells derived from Fukuyama muscular dystrophy patients carrying the deep intronic variant
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Credit: Mariko Taniguchi-Ikeda of Fujita Health University

Muscular dystrophy is a debilitating disease that causes progressive weakening and loss of muscles. Fukuyama congenital muscular dystrophy (FCMD), the second most common form of childhood muscular dystrophy in Japan, is a serious neuromuscular disease characterized by generalized muscle weakness, decreased muscle tone, eye abnormalities, brain malformation, cardiomyopathy, epilepsy, and associated seizures to disability.

FCMD is caused by a genetic abnormality in “fukutin” (FKT extension) gene. Japanese researchers led by Dr. Mariko Taniguchi-Ikeda, an Associate Professor in the Department of Clinical Genetics at Fujita Health University Hospital, were recently able to overcome this shortcoming in FKT extension gene and restore its normal biological function. Using an experimental technique called exon skipping using antisense oligonucleotides, the team corrected an error in the FKT extension gene that blocks the chemical glycosylation of a biologically important protein. To this end, the team designed specific antisense oligonucleotides, small pieces of DNA or RNA that can bind to specific RNA molecules. The researchers then conducted experiments on patient-derived cells using these antisense oligonucleotides to validate their hypothesis.

Dr. Taniguchi-Ikeda elaborates, “I have been seeing patients with FCMD for more than 20 years. The goal of our research was to find a cure for this incurable disease. FCMD is the second most frequent type of childhood muscular dystrophy in the Japanese population. Our previous studies show that patients carrying retrotransposal insertion can be treated by introducing antisense oligonucleotides. Clinical trials are currently underway. However, no therapeutic methods are available for patients with a deep intronic heterozygous variant. Our results suggest that exon skipping by antisense oligonucleotides as a treatment for patients with the deep intronic variant has enormous potential.”

The basic premise of the research is based on a physiological mechanism involving FKT extension. The FKT extension gene is responsible for the production of “ribitol-phosphate transferase”, an enzyme that chemically transfers a glycosyl group to alpha-dystroglycan (α-DG). α-DG is a key protein found in the cytoskeleton, a vast network of protein filaments and tubules that gives shape and coherence to living cells. The genetic anomaly in the FKT extension gene prevents it from expressing a fully functional form of ribitol-phosphate transferase. This reduced functionality, in turn, blocks a critical process in the biological relay: the glycosylation of α-DG. Incidentally, glycosylation or attachment of sugar molecules to non-sugar fractions such as lipids and proteins, such as α-DG in this case, is important to ensure the structural stability and functionality of these fractions.

The findings, which were published on Nov. 25, 2022 in the journal Human Molecular Geneticshave immediate implications, given that the specially designed antisense oligonucleotides, when introduced into patient-derived cells via RNAi, were able to skip the affected region of the gene, thus restoring normal production of the FKTN protein and subsequent glycosylation of α – DG.

Radical therapies for some types of neuromuscular disorders have evolved considerably in recent years. Although no effective therapies were available until recently, several therapeutic approaches have moved into the clinical stage in recent years. More specifically, the pharmacological modulation of RNA splicing aimed at modifying RNA processing and function has greatly advanced in recent years.

Co-author Hiroki Kurahashi, a renowned professor at Fujita Health University adds: “Patients with FCMD who carry the abnormal FKTN gene produce non-glycosylated α-DG, which makes them bedridden since adolescence. They also require respiratory support, a feeding tube, and lifelong care from their families. Our initial experiments are therefore of paramount importance.”

Encouraged by them in vitro Results, the research team is now proposing translational work by setting up large-scale clinical trials involving patients with FCMD. Lead author Sarantuya Enkhjargal, a Ph.D. student at Fujita Health University Hospital concludes, “The United States Food and Drug Administration has approved eight antisense oligonucleotides for the treatment of various diseases. Our results are promising at the in vitro level. However, further in vivo efficacy and safety studies in animal models will be required before this approach is used in clinical trials.”

These findings, however, offer a ray of hope for the multitude of patients and their families affected by this serious condition.



DOI: 10.1093/hmg/ddac286

About Fujita Health University
Fujita Health University is a private university located in Toyoake, Aichi, Japan. It was established in 1964 and houses one of the largest university teaching hospitals in Japan in terms of number of beds. With over 900 faculty members, the university is committed to providing various academic opportunities to students internationally. Fujita Health University was ranked eighth among all universities and second among all private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. THE University Impact Rankings 2019 displayed university initiatives for the Sustainable Development Goals (SDGs). For the SDG “good health and well-being”, Fujita Health University was ranked second among all universities and number one among private universities in Japan. The university became the first Japanese university to host ‘THE Asia Universities Summit’ in June 2021. The university’s founding philosophy is ‘Our Creativity for the People (DOKUSOU-ICHIRI)’, reflecting the belief that, as for university alumni and alumnae, current students also unlock their future by harnessing their creativity.


About Associate Professor Mariko Taniguchi-Ikeda of Fujita Health University
Dr. Taniguchi-Ikeda is an Associate Professor in the Department of Clinical Genetics, Fujita Health University Hospital. He has over 80 publications and more than 1,300 citations to his credit. Dr. Taniguchi-Ikeda’s research work focuses primarily on Walker-Warburg syndrome, Fukuyama-type muscular dystrophy, lissencephaly, and X-linked retinal dysplasia. He has published his work in renowned journals such as Nature, PLoS geneticsAnd Journal of Human Genetics.

Financing information
This study was supported by grants from the Japan Agency for Medical Research and Development (18ek0109318h0001 to Mariko Taniguchi-Ikeda; 20ek0109405h0002 to Mariko Taniguchi-Ikeda; 18ek0109249h0002 to Tatsushi Toda, Mariko Taniguchi-Ikeda), Grants-in-Aid for Scientific Research (18K07790 to Mariko Taniguchi-Ikeda), The Naito Foundation (to Mariko Taniguchi-Ikeda), Japan Intractable Disease Foundation (to Mariko Taniguchi-Ikeda), Takeda Science Foundation (to Mariko Taniguchi-Ikeda), Houansya Foundation (to Mariko Taniguchi-Ikeda) ).

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