Santhera Pharmaceuticals announces the signing of two agreements with Rutgers, The State University of New Jersey as part of its program to advance gene therapy research for the treatment of LAMA2-deficient congenital muscular dystrophy (LAMA2 MD or MDC1A). Under the agreements, Santhera gains rights to intellectual property developed at Rutgers on certain gene constructs that will be further studied under a collaboration agreement.

Santhera has entered into a license agreement with Rutgers, The State University of New Jersey and a collaboration with Prof. Peter Yurchenco. These agreements complement the ongoing collaboration of Santhera with Prof. Markus Rüegg from the Biozentrum of the University of Basel. Previous collaborative work by Prof. Rüegg and Prof. Yurchenco has established the potential of this approach in animal models.

 The novel gene therapy strategy uses two linker proteins that are composed of domains derived from extracellular matrix proteins agrin, laminin and nidogen. 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 thus demonstrating strong evidence for disease modifying potential.

The coordinated work of both collaborations will further advance Santhera′s effort to bring this gene therapy approach to patients with LAMA2 MD.

“Gene replacement is a promising therapeutic option for the treatment of LAMA2 MD,” said Peter D. Yurchenco, MD, PhD, Professor at Rutgers Robert Wood Johnson Medical School, USA. “We have been working on continuously optimizing linker proteins engineered from extracellular matrix proteins which will aid in advancing such gene therapy approach towards clinical use.”

“Santhera is excited to extend its collaborative network for this therapeutic approach, now including experts from Rutgers University,” said Kristina Sj?blom Nygren, MD, Chief Medical Officer and Head of Development of Santhera. “This will add value to our gene therapy program for LAMA2 MD and complements the work already under way with the Biozentrum at the University of Basel, which was awarded a grant by Innosuisse in 2019. Both of our collaboration partners have pioneered this field and will work closely with Santhera, clinical experts and the patient community to establish the best way to bring this approach to clinical use.”

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. 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. First results using the AAV technology have been presented by Prof Rüegg.

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