Santhera Signs Agreements in Gene Therapy Research for Congenital Muscular Dystrophy with Rutgers University - Seite 2
About LAMA2 MD (CMD Type 1A or MDC1A) and Emerging Therapy Approaches
Congenital muscular dystrophies (CMDs) are inherited neuromuscular diseases characterized by early-onset weakness and hypotonia alongside associated dystrophic findings in muscle biopsy.
Progressive muscle weakness, joint contractures and respiratory insufficiency characterize most CMDs. Laminins are proteins of the extracellular matrix that help maintain muscle fiber stability by
binding to other proteins. LAMA2-related muscular dystrophy (LAMA2 MD, also called MDC1A), is one of the most common forms of CMD. It is caused by mutations in the LAMA2 gene encoding the
alpha2 subunit of laminin-211. Most LAMA2 MD patients show complete absence of laminin-alpha 2, are hypotonic (floppy) at birth, fail to ambulate, and succumb to respiratory complications.
Previous work has demonstrated that two linker proteins, engineered with domains derived from the extracellular matrix proteins agrin, laminin and nidogen, could compensate for the lack of laminin-alpha2 and restore the muscle basement membrane [2-5]. Through simultaneous expression of artificial linkers (“SEAL”), this gene therapy approach aims to overcome the genetic defect by substituting laminin-alpha2 deficiency with small linker proteins containing necessary binding domains to re-establish muscle fiber integrity. In a transgenic mouse model, the linker expression increased the lifespan of LAMA2-deficient mice 5-fold to a median of 81 weeks compared to 15.5 weeks in the disease model without the therapeutic linker expression [2]. Recently, it was demonstrated that such linker constructs could be applied by standard adeno-associated virus (AAV) vectors [6, 7]. First results using the AAV technology have been presented by Prof Rüegg [8].
References
[1] Santhera press release on gene collaboration with Biozentrum Basel (May 21, 2019), accessible here
[2] Reinhard et al. (2017). Sci Transl Med 9, eaal4649
[3] Moll et al. (2001). Nature 413, 302-307.
[4] Meinen et al. (2007) J. Cell Biol. 176, 979-993.
[5] McKee et al. (2017) J. Clin. Invest. 127, 1075-1089.
[6] Qiao et al. (2018) Mol Ther Methods Clin Dev 9, 47-56.
[7] Qiao et al. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 11999-12004.
[8] Reinhard, J. et al. (2019) Neuromuscular Disorders, Volume 29, S164
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Rutgers, The State University of New Jersey, is a leading national research university and the state of New Jersey’s preeminent, comprehensive public institution of higher education. Established in
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