The overall clinical and laboratory interests of the Section (NNDCS) focus on early onset neuromuscular disorders of childhood, on their genetic and molecular pathogenesis, the pathways involved, and on developing preclinical translational models to lead to actual clinical trials. Research in the NNDCS lab further focuses on the molecular pathogenesis of early onset muscle disorders using cellular and newly generated animal models, with the goal of defining opportunities for therapeutic interventions. A particular effort is devoted to gene editing approaches as well as RNA directed therapeutics directed at allele specific knockdown of dominantly acting mutations. We are also determining natural history and outcome measures in giant axonal neuropathy and in this condition have initiated the first intrathecal AAV9 mediated gene transfer trial in human.
PaVe-GT: Plateform Vector Gene Therapy
The Platform Vector Gene Therapy (PaVe-GT) team is studying the use of self-complementary AAV and various vector/expression constructs to target the neuromuscular junction (NMJ) that will then be used to treat established animal models in order to determine if gene therapy is successful at restoring NMJ structure and muscle function. Our focus is initially targeted to mouse models of congenital myasthenic syndromes, including Dok7 and Collagen Q deficiencies. With assistance from NCATS and NHGRI, we plan to demonstrate this platform-based gene therapy approach from conception, preclinical optimization, production, toxicology studies, regulatory filings and interactions, all the way to a clinical trial and make all learnings from this fully available. To find more information, please see https://pave-gt.ncats.nih.gov/.
Contact: Janelle Hauserman, PhD
Collagen VI Therapies
Contact: Veronique Bolduc, PhD
Bolduc V, Foley AR, Solomon-Degefa H, Sarathy A, Donkervoort S, Hu Y, Chen GS, Sizov K, Nalls M, Zhou H, Aguti S, Cummings BB, Lek M, Tukiainen T, Marshall JL, Regev O, Marek-Yagel D, Sarkozy A, Butterfield RJ, Jou C, Jimenez-Mallebrera C, Li Y, Gartioux C, Mamchaoui K, Allamand V, Gualandi F, Ferlini A, Hanssen E, , Wilton SD, Lamandé SR, MacArthur DG, Wagener R, Muntoni F, Bönnemann CG (2019)
A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies.
JCI Insight, 4 PubMed ID: 30895940
Bolduc V, Zou Y, Ko D, Bönnemann CG (2014)
siRNA-mediated Allele-specific Silencing of a COL6A3 Mutation in a Cellular Model of Dominant Ullrich Muscular Dystrophy.
Mol Ther Nucleic Acids, 3:e147. PubMed ID: 24518369
Collagen VI Mechanism
Even though it is clear that collagen VI is essential for normal muscle function, how collagen VI absence or mislocalization in the muscle extracellular matrix results in muscle dysfunction, weakness, and fibrosis remains an area of active investigation. Our focus in these studies is to investigate the mechanistic sequence from the extracellular matrix to myofiber dysfunction using animal and cellular models of collagen VI-related dystrophies. These studies add to our general knowledge about how muscle and extracellular matrix change in diseases such as muscular dystrophy. In addition, they have the potential to identify therapeutic targets and biomarkers of disease progression that can then be used for therapeutic development.
Contact: Payam Mohassel, MD
Contact: Jachinta Rooney, PhD
Contact: P. Brian Uapinyoying, PhD
Marshall KL, Saade D, Ghitani N, Coombs AM, Szczot M, Keller J, Ogata T, Daou I, Stowers LT, Bönnemann CG, Chesler AT, Patapoutian A (2020)
PIEZO2 in sensory neurons and urothelial cells coordinates urination.
Nature, 588:290-295. PubMed ID: 33057202
Foley AR, Zou Y, Dunford JE, Rooney J, Chandra G, Xiong H, Straub V, Voit T, Romero N, Donkervoort S, Hu Y, Markello T, Horn A, Qebibo L, Dastgir J, Meilleur KG, Finkel RS, Fan Y, Mamchaoui K, Duguez S, Nelson I, Laporte J, Santi M, Malfatti E, Maisonobe T, Touraine P, Hirano M, Hughes I, Bushby K, Oppermann U, Böhm J, Jaiswal JK, Stojkovic T, Bönnemann CG (2020)
GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome.
Ann Neurol, 88:332-347. PubMed ID: 32403198
Donkervoort S, Kutzner CE, Hu Y, Lornage X, Rendu J, Stojkovic T, Baets J, Neuhaus SB, Tanboon J, Maroofian R, Bolduc V, Mroczek M, Conijn S, Kuntz NL, Töpf A, Monges S, Lubieniecki F, McCarty RM, Chao KR, Governali S, Böhm J, Boonyapisit K, Malfatti E, Sangruchi T, Horkayne-Szakaly I, Hedberg-Oldfors C, Efthymiou S, Noguchi S, Djeddi S, Iida A, di Rosa G, Fiorillo C, Salpietro V, Darin N, Fauré J, Houlden H, Oldfors A, Nishino I, de Ridder W, Straub V, Pokrzywa W, Laporte J, Foley AR, Romero NB, Ottenheijm C, Hoppe T, Bönnemann CG (2020)
Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores.
Am J Hum Genet, 107:1078-1095. PubMed ID: 33217308