Restoration of brain dystrophin using tricyclo-DNA ASOs restores neurobehavioral deficits in DMD mice DOI Creative Commons
Muthukumar Karuppasamy, Matthew S. Alexander

Molecular Therapy — Nucleic Acids, Journal Year: 2023, Volume and Issue: 32, P. 841 - 842

Published: May 25, 2023

Duchenne muscular dystrophy (DMD) is a progressive, X-linked neuromuscular disorder that caused by pathogenic variants in the dystrophin gene resulting loss of production functional protein. DMD patients suffer from muscle degeneration, respiratory weakness, ambulation their teenage years, and cardiomyopathy ultimately leading to patient death third decade. Steroid regimens have extended lifespan delayed symptoms, but no cure currently exists. Dystrophin replacement therapies (both micro- mini-dystrophin) along with exon-skipping antisense oligo (ASO) compounds shown promise delaying disease progression.1Mendell J.R. Goemans N. Lowes L.P. Alfano L.N. Berry K. Shao J. Kaye E.M. Mercuri E. Eteplirsen Study Group Telethon Foundation Italian NetworkLongitudinal effect eteplirsen versus historical control on dystrophy.Ann. Neurol. 2016; 79: 257-271https://doi.org/10.1002/ana.24555Crossref PubMed Scopus (378) Google Scholar,2Mendell Sahenk Z. Lehman Nease C. Miller N.F. Iammarino M.A. Nicholl A. Al-Zaidy S. et al.Assessment systemic delivery rAAVrh74.MHCK7.micro-dystrophin children duchenne dystrophy: nonrandomized controlled trial.JAMA 2020; 77: 1122-1131https://doi.org/10.1001/jamaneurol.2020.1484Crossref (131) Scholar,3Mitelman O. Abdel-Hamid H.Z. Byrne B.J. Connolly A.M. Heydemann P. Proud Shieh P.B. Wagner K.R. Dugar Santra Signorovitch al.A combined prospective retrospective comparison long-term outcomes suggests pulmonary decline treatment.J. Neuromuscul. Dis. 2022; 9: 39-52https://doi.org/10.3233/JND-210665Crossref (8) Scholar,4Iff Gerrits Zhong Y. Tuttle Birk Zheng Paul X. Henricson E.K. McDonald C.M. CINRG-DNHS InvestigatorsDelays eteplirsen-treated dystrophy.Muscle Nerve. 66: 262-269https://doi.org/10.1002/mus.27662Crossref (1) Scholar function "skip" over or bypass mutant transcript restore reading frame novel Becker (BMD)-like protein product. Several drugs been approved US Food Drug Administration for DMD; however, these usually low corrected expression.5Charleston J.S. Schnell F.J. Dworzak Donoghue Lewis Chen L. Young G.D. Milici A.J. Voss DeAlwis U. al.Eteplirsen treatment dystrophy.Exon skipping production. 2018; 90: e2146-e2154https://doi.org/10.1212/wnl.0000000000005680Crossref Newer strategies are being developed improve both translation amount biodistribution compounds. The large (human symbol DMD) isoform (Dp427) expressed skeletal cardiac muscle; expression Dp427 multiple smaller isoforms exist brain, some which transcribed via brain-specific promoter. Assessments human revealed key timing requirements role brain impacting cognitive function.6Doorenweerd Mahfouz van Putten M. Kaliyaperumal R. t' Hoen P.A. Hendriksen J.G. Aartsma-Rus Verschuuren J.M. Niks E.H. Reinders M.T. al.Timing localization provide insights into phenotype dystrophy.Sci. Rep. 2017; 7: 12575https://doi.org/10.1038/s41598-017-12981-5Crossref (89) Questions still remain exact nature impact Dp427, Dp140 Dp71 all implicated function. Previous work this group demonstrated safety therapeutic efficacy ability subsequent levels mdx (dystrophin exon 23 nonsense mutation) groups whole heart tissue using 13-mer tricyclo-DNA AON construct following 12 weeks dosing.7Relizani Griffith G. Echevarría Zarrouki F. Facchinetti Vaillend Leumann Garcia Goyenvalle Efficacy profile oligonucleotides mouse model.Mol. Ther. Nucleic Acids. 8: 144-157https://doi.org/10.1016/j.omtn.2017.06.013Abstract Full Text PDF (44) These studies tcDNA constructs cross blood-brain barrier (BBB) penetration low-level correction; extent improvement consequences brain-mediated correction were not extensively evaluated. In current study, al. demonstrate ASOs capable partial restoration mdx52 mice.8Saoudi Barberat le Coz Vacca Doisy Caquant Tensorer T. Sliwinski Muntoni Partial alleviates emotional deficits mice.Mol. 2023; 32: 173-188https://doi.org/10.1016/j.omtn.2023.03.009Abstract (0) has addition defects, mice develop social anxiety, elevated fear responses, impaired associative learning (Figure 1). authors performed single intracerebroventricular administration targeting 51 (tcDNA-Ex51) restored between 5% 15% hippocampus, cerebellum, cortex 7–11 post injection. tcDNA-Ex51 treated showed improved anxiety phenotypes plus maze responses only improvements reactivity light/dark choice test. overall response was also tcDNA-Ex51-treated compared sense cohorts. Close examination auditory-cued conditioning dystrophic cohorts memory recall. Biodistribution profiling homogeneous distribution exon-skipping, different authors' previously reported evaluation (exon 23) model, suggesting unique constraints each individual ASO.9Goyenvalle Babbs El Andaloussi Ezzat Avril Dugovic B. Chaussenot Ferry Voit al.Functional models oligomers.Nat. Med. 2015; 21: 270-275https://doi.org/10.1038/nm.3765Crossref (224) Further modifications BBB toward at substantial may lead higher amounts responses. Additional exploration longevity tcDNA-Ex51-restored aged use other exons cell lines could yield insight future application technology clinical trials. M.K. M.S.A. conceived written commentary. conflict interest declare.

Language: Английский

AAV-Mediated Restoration of Dystrophin-Dp71 in the Brain of Dp71-Null Mice: Molecular, Cellular and Behavioral Outcomes DOI Creative Commons
Ophélie Vacca, Faouzi Zarrouki, Charlotte Izabelle

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(8), P. 718 - 718

Published: April 20, 2024

A deficiency in the shortest dystrophin-gene product, Dp71, is a pivotal aggravating factor for intellectual disabilities Duchenne muscular dystrophy (DMD). Recent advances preclinical research have achieved some success compensating both muscle and brain dysfunctions associated with DMD, notably using exon skipping strategies. However, this has not been studied distal mutations DMD gene leading to Dp71 loss. In study, we aimed restore expression Dp71-null transgenic mouse an adeno-associated virus (AAV) administrated either by intracardiac injections at P4 (ICP4) or bilateral intracerebroventricular (ICV) adults. ICP4 delivery of AAV9-Dp71 vector enabled 2 14% while ICV overexpression hippocampus cortex adult mice, anecdotal cerebellum. The restoration was mostly located glial endfeet that surround capillaries, it partial localization Dp71-associated proteins, α1-syntrophin AQP4 water channels, suggesting proper scaffold proteins involved blood–brain barrier function homeostasis. did result significant improvements behavioral disturbances displayed mice. potential limitations AAV-mediated strategy are discussed. This proof-of-concept study identifies key molecular markers estimate efficiencies rescue strategies opens new avenues enhancing therapy targeting cognitive disorders subgroup severely affected patients.

Language: Английский

Citations

0
Restoration of brain dystrophin using tricyclo-DNA ASOs restores neurobehavioral deficits in DMD mice DOI Creative Commons
Muthukumar Karuppasamy, Matthew S. Alexander

Molecular Therapy — Nucleic Acids, Journal Year: 2023, Volume and Issue: 32, P. 841 - 842

Published: May 25, 2023

Duchenne muscular dystrophy (DMD) is a progressive, X-linked neuromuscular disorder that caused by pathogenic variants in the dystrophin gene resulting loss of production functional protein. DMD patients suffer from muscle degeneration, respiratory weakness, ambulation their teenage years, and cardiomyopathy ultimately leading to patient death third decade. Steroid regimens have extended lifespan delayed symptoms, but no cure currently exists. Dystrophin replacement therapies (both micro- mini-dystrophin) along with exon-skipping antisense oligo (ASO) compounds shown promise delaying disease progression.1Mendell J.R. Goemans N. Lowes L.P. Alfano L.N. Berry K. Shao J. Kaye E.M. Mercuri E. Eteplirsen Study Group Telethon Foundation Italian NetworkLongitudinal effect eteplirsen versus historical control on dystrophy.Ann. Neurol. 2016; 79: 257-271https://doi.org/10.1002/ana.24555Crossref PubMed Scopus (378) Google Scholar,2Mendell Sahenk Z. Lehman Nease C. Miller N.F. Iammarino M.A. Nicholl A. Al-Zaidy S. et al.Assessment systemic delivery rAAVrh74.MHCK7.micro-dystrophin children duchenne dystrophy: nonrandomized controlled trial.JAMA 2020; 77: 1122-1131https://doi.org/10.1001/jamaneurol.2020.1484Crossref (131) Scholar,3Mitelman O. Abdel-Hamid H.Z. Byrne B.J. Connolly A.M. Heydemann P. Proud Shieh P.B. Wagner K.R. Dugar Santra Signorovitch al.A combined prospective retrospective comparison long-term outcomes suggests pulmonary decline treatment.J. Neuromuscul. Dis. 2022; 9: 39-52https://doi.org/10.3233/JND-210665Crossref (8) Scholar,4Iff Gerrits Zhong Y. Tuttle Birk Zheng Paul X. Henricson E.K. McDonald C.M. CINRG-DNHS InvestigatorsDelays eteplirsen-treated dystrophy.Muscle Nerve. 66: 262-269https://doi.org/10.1002/mus.27662Crossref (1) Scholar function "skip" over or bypass mutant transcript restore reading frame novel Becker (BMD)-like protein product. Several drugs been approved US Food Drug Administration for DMD; however, these usually low corrected expression.5Charleston J.S. Schnell F.J. Dworzak Donoghue Lewis Chen L. Young G.D. Milici A.J. Voss DeAlwis U. al.Eteplirsen treatment dystrophy.Exon skipping production. 2018; 90: e2146-e2154https://doi.org/10.1212/wnl.0000000000005680Crossref Newer strategies are being developed improve both translation amount biodistribution compounds. The large (human symbol DMD) isoform (Dp427) expressed skeletal cardiac muscle; expression Dp427 multiple smaller isoforms exist brain, some which transcribed via brain-specific promoter. Assessments human revealed key timing requirements role brain impacting cognitive function.6Doorenweerd Mahfouz van Putten M. Kaliyaperumal R. t' Hoen P.A. Hendriksen J.G. Aartsma-Rus Verschuuren J.M. Niks E.H. Reinders M.T. al.Timing localization provide insights into phenotype dystrophy.Sci. Rep. 2017; 7: 12575https://doi.org/10.1038/s41598-017-12981-5Crossref (89) Questions still remain exact nature impact Dp427, Dp140 Dp71 all implicated function. Previous work this group demonstrated safety therapeutic efficacy ability subsequent levels mdx (dystrophin exon 23 nonsense mutation) groups whole heart tissue using 13-mer tricyclo-DNA AON construct following 12 weeks dosing.7Relizani Griffith G. Echevarría Zarrouki F. Facchinetti Vaillend Leumann Garcia Goyenvalle Efficacy profile oligonucleotides mouse model.Mol. Ther. Nucleic Acids. 8: 144-157https://doi.org/10.1016/j.omtn.2017.06.013Abstract Full Text PDF (44) These studies tcDNA constructs cross blood-brain barrier (BBB) penetration low-level correction; extent improvement consequences brain-mediated correction were not extensively evaluated. In current study, al. demonstrate ASOs capable partial restoration mdx52 mice.8Saoudi Barberat le Coz Vacca Doisy Caquant Tensorer T. Sliwinski Muntoni Partial alleviates emotional deficits mice.Mol. 2023; 32: 173-188https://doi.org/10.1016/j.omtn.2023.03.009Abstract (0) has addition defects, mice develop social anxiety, elevated fear responses, impaired associative learning (Figure 1). authors performed single intracerebroventricular administration targeting 51 (tcDNA-Ex51) restored between 5% 15% hippocampus, cerebellum, cortex 7–11 post injection. tcDNA-Ex51 treated showed improved anxiety phenotypes plus maze responses only improvements reactivity light/dark choice test. overall response was also tcDNA-Ex51-treated compared sense cohorts. Close examination auditory-cued conditioning dystrophic cohorts memory recall. Biodistribution profiling homogeneous distribution exon-skipping, different authors' previously reported evaluation (exon 23) model, suggesting unique constraints each individual ASO.9Goyenvalle Babbs El Andaloussi Ezzat Avril Dugovic B. Chaussenot Ferry Voit al.Functional models oligomers.Nat. Med. 2015; 21: 270-275https://doi.org/10.1038/nm.3765Crossref (224) Further modifications BBB toward at substantial may lead higher amounts responses. Additional exploration longevity tcDNA-Ex51-restored aged use other exons cell lines could yield insight future application technology clinical trials. M.K. M.S.A. conceived written commentary. conflict interest declare.

Language: Английский

Citations

0