Antisense oligonucleotides modulate dopa decarboxylase function in aromatic <scp>l</scp>
-amino acid decarboxylase deficiency

Tsai, Chi-Ren; Lee, Hsiu-Fen; Chi, Ching‐Shiang; Yang, Ming-Te; Hsu, Chia‐Chi

doi:10.1002/humu.23659

Cited by 7 publications

(4 citation statements)

References 63 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We further performed the injection of the AAV9‐IVS‐AAA viral vector in DDC KI mice, and they showed better survival, but the efficiency still needs to be improved (Lee et al, ). Another attempt using antisense oligonucleotides targeting the IVS6 + 4 A > T site on lymphoblastoid cells showed an increase in DDC protein and serotonin levels (Tsai, Lee, Chi, Yang, & Hsu, ).…”

Section: Developing Other Therapeutic Strategiesmentioning

confidence: 99%

A review of aromatic l‐amino acid decarboxylase (AADC) deficiency in Taiwan

Lee

Chien

Hwu

2019

American J of Med Genetics Pt C

View full text Add to dashboard Cite

Aromatic l‐amino acid decarboxylase deficiency (AADCD) is a rare inherited disease prevalent in South East Asia. This disease is due to the founder mutation IVS 6 + 4A > T (c.714 + 4A > T), which accounts for most alleles. Patients with this mutation have severe phenotypes. About 90 % of these patients in South East Asia do not have head control and cannot sit, stand, or speak from birth to the time of observation. In 2012, a gene study to treat these patients with intraputamen injection of adeno‐associated virus2‐human AADC showed prominent motor improvement and an increased PDMS‐2 score 12 months after treatment. In addition, systemic gene therapy in a mouse model of AADCD achieved widespread correction of the Ddc gene. In this article, we review the natural history, clinical course, and treatment effects seen in these clinical and mouse studies. Future studies focusing on noninvasive viral vector delivery or alternative emerging treatments may also benefit patients with AADCD.

show abstract

Section: Developing Other Therapeutic Strategiesmentioning

confidence: 99%

A review of aromatic l‐amino acid decarboxylase (AADC) deficiency in Taiwan

Lee

Chien

Hwu

2019

American J of Med Genetics Pt C

View full text Add to dashboard Cite

show abstract

“…Yet some unexpected novel splice variants were created by the ASOs. To increase efficacy, this group has suggested the combination of ASO-D with suppressor binding blocker ASO-9AA [ 244 ].…”

Section: Splice-modulating Asos Targeting Inborn Errors Of Metabolismmentioning

confidence: 99%

Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases

Chen,

Heendeniya,

et al. 2024

BioDrugs

View full text Add to dashboard Cite

The last decade (2013–2023) has seen unprecedented successes in the clinical translation of therapeutic antisense oligonucleotides (ASOs). Eight such molecules have been granted marketing approval by the United States Food and Drug Administration (US FDA) during the decade, after the first ASO drug, fomivirsen, was approved much earlier, in 1998. Splice-modulating ASOs have also been developed for the therapy of inborn errors of metabolism (IEMs), due to their ability to redirect aberrant splicing caused by mutations, thus recovering the expression of normal transcripts, and correcting the deficiency of functional proteins. The feasibility of treating IEM patients with splice-switching ASOs has been supported by FDA permission (2018) of the first “N-of-1” study of milasen, an investigational ASO drug for Batten disease. Although for IEM, owing to the rarity of individual disease and/or pathogenic mutation, only a low number of patients may be treated by ASOs that specifically suppress the aberrant splicing pattern of mutant precursor mRNA (pre-mRNA), splice-switching ASOs represent superior individualized molecular therapeutics for IEM. In this work, we first summarize the ASO technology with respect to its mechanisms of action, chemical modifications of nucleotides, and rational design of modified oligonucleotides; following that, we precisely provide a review of the current understanding of developing splice-modulating ASO-based therapeutics for IEM. In the concluding section, we suggest potential ways to improve and/or optimize the development of ASOs targeting IEM.

show abstract

“…The desired properties can be generated by chemical modifications of backbone, sugar moiety and/or nucleoside 82,83 . Using a phosphorodiamidate morpholino oligomer (PMO), up to 41% restoration in mRNA level was observed after 72‐h transfection in patient‐derived lymphoblastoid, with significant increase in AADC protein and 5HT levels 81 . However, two new out‐of‐frame isoforms arouse, indicating the need to refine and/or use of combinatory ASOs to ensure appropriate splicing to minimise the risk of off‐target effects.…”

Section: Gene Therapy For Monoamine Nt Disordersmentioning

confidence: 99%

“…Finally, since the founder variant c.714+4A>T results in aberrant splicing and produces a premature stop codon from a pseudoexonic +38 cryptic splice site, 64 an antisense oligonucleotide (ASO) strategy was tested in vitro to restore normal mRNA splicing. 81 ASO binds to target mRNA via Watson‐Crick base pairing, and modulate pre‐mRNA splicing via steric hindrance for the recruitment of splicing factors. 82 , 83 The desired properties can be generated by chemical modifications of backbone, sugar moiety and/or nucleoside.…”

Section: Gene Therapy For Monoamine Nt Disordersmentioning

confidence: 99%

Gene therapy for neurotransmitter‐related disorders

Chu,

Ng,

Waddington

et al. 2024

J of Inher Metab Disea

View full text Add to dashboard Cite

Inborn errors of neurotransmitter (NT) metabolism are a group of rare, heterogenous diseases with predominant neurological features, such as movement disorders, autonomic dysfunction, and developmental delay. Clinical overlap with other disorders has led to delayed diagnosis and treatment, and some conditions are refractory to oral pharmacotherapies. Gene therapies have been developed and translated to clinics for paediatric inborn errors of metabolism, with 38 interventional clinical trials ongoing to date. Furthermore, efforts in restoring dopamine synthesis and neurotransmission through viral gene therapy have been developed for Parkinson's disease. Along with the recent European Medicines Agency (EMA) and Medicines and Healthcare Products Regulatory Agency (MHRA) approval of an AAV2 gene supplementation therapy for AADC deficiency, promising efficacy and safety profiles can be achieved in this group of diseases. In this review, we present preclinical and clinical advances to address NT‐related diseases, and summarise potential challenges that require careful considerations for NT gene therapy studies.

show abstract

Antisense oligonucleotides modulate dopa decarboxylase function in aromatic l -amino acid decarboxylase deficiency

Cited by 7 publications

References 63 publications

A review of aromatic l‐amino acid decarboxylase (AADC) deficiency in Taiwan

A review of aromatic l‐amino acid decarboxylase (AADC) deficiency in Taiwan

Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases

Gene therapy for neurotransmitter‐related disorders

Contact Info

Product

Resources

About