Santhera Pharmaceuticals (SIX: SANN) announces its collaboration with the Biozentrum of the University of Basel to advance gene therapy research for the treatment of LAMA2-deficient congenital muscular dystrophy (LAMA2 MD or MDC1A). The program is supported by public funding for innovation in Switzerland through a grant from Innosuisse - the Suisse Innovation Agency. Innosuisse and Santhera will jointly invest CHF 1.2 million into this preclinical research collaboration.
Santhera has entered in a collaboration with Prof. Markus Rüegg from the Biozentrum, University of Basel, who pioneered a novel gene therapy approach for the treatment of LAMA2 MD. The simultaneous transgenic expression of specifically designed small protein domains, so-called linker proteins, helps to overcome structural and functional loss of muscle fibers in a mouse model for LAMA2 MD, demonstrating strong preclinical evidence for disease modifying potential.
This novel gene therapy strategy developed by Prof. Rüegg and coworkers will use two linker proteins that are composed of domains derived from extracellular matrix proteins agrin, laminin and nidogen [1-4]. In animal models for LAMA2 MD this approach has led to restoration of muscle fiber basement membranes, recovery of muscle force and size, increased overall body weight and markedly prolonged survival .
The preclinical research collaboration between Santhera and the University of Basel will explore the feasibility of gene delivery by standard viral vectors as a basis for subsequent clinical work. "LAMA2 MD is a severe form of congenital muscular dystrophy (CMD) which based on its molecular pathology offers the possibility for gene replacement," said Markus Rüegg, PhD, Professor for Neurobiology at the Biozentrum of the University of Basel. "The approach we have optimized over the past years relies on the simultaneous expression of two linker proteins engineered from extracellular matrix proteins. We and others have shown that this approach has a profound beneficial effect in mouse models of the disease. I am looking forward to collaborating with Santhera as our translational research partner to advance our gene therapy approach towards clinical use." "Santhera is committed to advancing its neuromuscular pipeline and building on its leading expertise in drug development for neuromuscular diseases, including CMD," added Thomas Meier, PhD, CEO of Santhera. "We are excited to collaborate with experts from the Biozentrum to advance this novel gene therapy approach to the clinic for the benefit of patients with this devastating disease. We build on our experience with omigapil, which we have recently studied in a Phase I clinical trial in patients with CMD in a collaboration with experts at the National Institutes of Health (USA). From our previous work we anticipate that this novel gene therapy approach and omigapil could act complementary. As before, we will continue working closely with clinical experts and the patient community to establish the best way forward."
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 of the extracellular matrix proteins agrin, laminin and nidogen, could compensate for the lack of laminin-alpha2 and restore the muscle basement membrane [1-4]. 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 . Recently, it was demonstrated that such linker constructs could be applied by standard adeno-associated virus (AAV) vectors [5, 6]. Omigapil is a deprenyl-analog with anti-apoptotic properties. Previous work has demonstrated that omigapil provides benefit to LAMA2-deficient mice  and has additive effects to gene therapy using linker proteins . Santhera obtained an exclusive license for omigapil from Novartis for the development in CMDs. As previously reported, Santhera has completed an ascending multiple dose cohort study (called CALLISTO) with omigapil in patients with two forms of CMD, including LAMA2 MD. CALLISTO met its primary objective to establish the pharmacokinetic profile of omigapil, applied as liquid formulation, and demonstrated that in this study the drug was safe and well tolerated in children and adolescents with CMD. Furthermore, this trial also demonstrated that it is feasible to run clinical studies in LAMA2 MD patients. Omigapil has orphan drug designations for CMD in the US and Europe and was granted fast track designation by the FDA.
 Reinhard et al. (2017). Sci Transl Med 9, eaal4649
 Moll et al. (2001). Nature 413, 302-307
 Meinen et al. (2007) J. Cell Biol. 176, 979-993
 McKee et al. (2017) J. Clin. Invest. 127, 1075-1089
 Qiao et al. (2018) Mol Ther Methods Clin Dev 9, 47-56
 Qiao et al. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 11999-12004
 Erb et al. (2009) J. Pharmacol. Exp. Ther. 331, 787-795
 Meinen et al. (2011) EMBO Mol Med 3, 465-479