Expression and function of four AAV-based constructs for dystrophin restoration in the mdx mouse model of Duchenne muscular dystrophy

被引：0

作者：

Potter, Rachael A. ^{[1
,2
]}

Griffin, Danielle A. ^{[1
,2
]}

Heller, Kristin N. ^{[1
]}

Mendell, Jerry R. ^{[1
,3
]}

Rodino-Klapac, Louise R. ^{[1
,2
,3
]}

机构：

[1] Nationwide Childrens Hosp, Res Inst, Ctr Gene Therapy, Columbus, OH 43205 USA

[2] Sarepta Therapeut Inc, Cambridge, MA 02142 USA

[3] Ohio State Univ, Dept Pediat & Neurol, Columbus, OH 43210 USA

来源：

BIOLOGY OPEN | 2023年 / 12卷 / 09期

关键词：

Adeno-associated virus; Duchenne muscular dystrophy; Dystrophin; Gene therapy; Mdx mouse model; Micro-dystrophin; GENE-TRANSFER; MICRODYSTROPHIN EXPRESSION; MICRO-DYSTROPHIN; SKELETAL-MUSCLES; THERAPY; FIBROSIS; VECTORS; COMPLEX;

D O I：

10.1242/bio.059797

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Robust expression of shortened, functional dystrophin provided impetus to develop adeno-associated virus (AAV)-based constructs for clinical application. Because several cassettes are being tested in clinical trials, this study compared the efficacies of four shortened dystrophin-promoter combinations with implications for outcomes in clinical trials: MHCK7 or MCK promoter with a shortened dystrophin transgene containing the N-terminus and spectrin repeats R1, R2, R3 and R24 (rAAVrh74.MHCK7.micro-dystrophin and rAAVrh74.MCK.micro-dystrophin, respectively); shortened dys-trophin construct containing the neuronal nitric oxide (nNOS) binding site (rAAVrh74.MHCK7.DV.mini-dystrophin); and shortened dys-trophin containing the C-terminus (rAAVrh74.MHCK7.micro-dystro-phin.Cterm). Functional and histological benefit were examined at 4 weeks following intramuscular delivery in mdx mice. rAAVrh74. MHCK7.micro-dystrophin provided the most robust transgene expression and significantly increased specific force output in the tibialis anterior muscle. Muscle environment was normalized (i.e. reductions in central nucleation), indicating functional and histological advantages of rAAVrh74.MHCK7.micro-dystrophin. Thus, promoter choice and transgene design are critical for optimal dystrophin expression/distribution for maximal functional improvement.

引用

页数：10

共 61 条

[1] Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy [J].

Alfano, Lindsay N. ;

Charleston, Jay S. ;

Connolly, Anne M. ;

Cripe, Linda ;

Donoghue, Cas ;

Dracker, Robert ;

Dworzak, Johannes ;

Eliopoulos, Helen ;

Frank, Diane E. ;

Lewis, Sarah ;

Lucas, Karin ;

Lynch, Jessie ;

Milici, A. J. ;

Flynt, Amy ;

Naughton, Emily ;

Rodino-Klapac, Louise R. ;

Sahenk, Zarife ;

Schnell, Frederick J. ;

Young, G. David ;

Mendell, Jerry R. ;

Lowes, Linda P. .

MEDICINE, 2019, 98 (26) :e15858

[2] The Polyproline Site in Hinge 2 Influences the Functional Capacity of Truncated Dystrophins [J].

Banks, Glen B. ;

Judge, Luke M. ;

Allen, James M. ;

Chamberlain, Jeffrey S. .

PLOS GENETICS, 2010, 6 (05) :12

[3] Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan [J].

Birnkrant, David J. ;

Bushby, Katharine ;

Bann, Carla M. ;

Apkon, Susan D. ;

Blackwell, Angela ;

Colvin, Mary K. ;

Cripe, Linda ;

Herron, Adrienne R. ;

Kennedy, Annie ;

Kinnett, Kathi ;

Naprawa, James ;

Noritz, Garey ;

Poysky, James ;

Street, Natalie ;

Trout, Christina J. ;

Weber, David R. ;

Ward, Leanne A. .

LANCET NEUROLOGY, 2018, 17 (05) :445-455

[4] CLINICAL INVESTIGATION IN DUCHENNE DYSTROPHY .2. DETERMINATION OF THE POWER OF THERAPEUTIC TRIALS BASED ON THE NATURAL-HISTORY [J].

BROOKE, MH ;

FENICHEL, GM ;

GRIGGS, RC ;

MENDELL, JR ;

MOXLEY, R ;

MILLER, JP ;

PROVINCE, MA .

MUSCLE & NERVE, 1983, 6 (02) :91-103

[5] Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management [J].

Bushby, Katharine ;

Finkel, Richard ;

Birnkrant, David J. ;

Case, Laura E. ;

Clemens, Paula R. ;

Cripe, Linda ;

Kaul, Ajay ;

Kinnett, Kathi ;

McDonald, Craig ;

Pandya, Shree ;

Poysky, James ;

Shapiro, Frederic ;

Tomezsko, Jean ;

Constantin, Carolyn .

LANCET NEUROLOGY, 2010, 9 (01) :77-93

[6] Plasmapheresis Eliminates the Negative Impact of AAV Antibodies on Microdystrophin Gene Expression Following Vascular Delivery [J].

Chicoine, L. G. ;

Montgomery, C. L. ;

Bremer, W. G. ;

Shontz, K. M. ;

Griffin, D. A. ;

Heller, K. N. ;

Lewis, S. ;

Malik, V. ;

Grose, W. E. ;

Shilling, C. J. ;

Campbell, K. J. ;

Preston, T. J. ;

Coley, B. D. ;

Martin, P. T. ;

Walker, C. M. ;

Clark, K. R. ;

Sahenk, Z. ;

Mendell, J. R. ;

Rodino-Klapac, L. R. .

MOLECULAR THERAPY, 2014, 22 (02) :338-347

[7] Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study [J].

Cirak, Sebahattin ;

Arechavala-Gomeza, Virginia ;

Guglieri, Michela ;

Feng, Lucy ;

Torelli, Silvia ;

Anthony, Karen ;

Abbs, Stephen ;

Garralda, Maria Elena ;

Bourke, John ;

Wells, Dominic J. ;

Dickson, George ;

Wood, Matthew J. A. ;

Wilton, Steve D. ;

Straub, Volker ;

Kole, Ryszard ;

Shrewsbury, Stephen B. ;

Sewry, Caroline ;

Morgan, Jennifer E. ;

Bushby, Kate ;

Muntoni, Francesco .

LANCET, 2011, 378 (9791) :595-605

[8] Highly purified recombinant adeno-associated virus vectors are biologically active and free of detectable helper and wild-type viruses [J].

Clark, KR ;

Liu, XL ;

McGrath, JP ;

Johnson, PR .

HUMAN GENE THERAPY, 1999, 10 (06) :1031-1039

[9] Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy [J].

Clemens, Paula R. ;

Rao, Vamshi K. ;

Connolly, Anne M. ;

Harper, Amy D. ;

Mah, Jean K. ;

McDonald, Craig M. ;

Smith, Edward C. ;

Zaidman, Craig M. ;

Nakagawa, Tomoyuki ;

Hoffman, Eric P. .

JOURNAL OF NEUROMUSCULAR DISEASES, 2022, 9 (04) :493-501

[10] Safety, Tolerability, and Efficacy of Viltolarsen in Boys With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping A Phase 2 Randomized Clinical Trial [J].

Clemens, Paula R. ;

Rao, Vamshi K. ;

Connolly, Anne M. ;

Harper, Amy D. ;

Mah, Jean K. ;

Smith, Edward C. ;

McDonald, Craig M. ;

Zaidman, Craig M. ;

Morgenroth, Lauren P. ;

Osaki, Hironori ;

Satou, Youhei ;

Yamashita, Taishi ;

Hoffman, Eric P. .

JAMA NEUROLOGY, 2020, 77 (08) :982-991

← 1 2 3 4 5 6 7 →