Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - MYOCURE (Development of an innovative gene therapy platform to cure rare hereditary muscle disorders)

Teaser

Hereditary muscle disorders are attractive diseases for gene therapy. They comprise a diverse family of rare genetic diseases typically caused by single gene defects that often provoke significant morbidity and mortality due to skeletal muscle, cardiac and/or diaphragm...

Summary

Hereditary muscle disorders are attractive diseases for gene therapy. They comprise a diverse family of rare genetic diseases typically caused by single gene defects that often provoke significant morbidity and mortality due to skeletal muscle, cardiac and/or diaphragm dysfunction. Eventually, these severe and rare diseases are lacking an effective cure or treatment despite being life-threatening or chronically debilitating, warranting the development of an effective cure by gene therapy.
Therefore, the ultimate goal of the MYOCURE project is to develop an innovative gene therapy platform to cure rare hereditary muscle disorders, specifically focusing on myotubular myopathy (MTM) and glycogen storage disorder (GSD) type II (Pompe disease). MYOCURE focuses specifically on overcoming some of the bottlenecks that hamper muscle-directed gene therapy.

Work performed

During the period 19-36 months of the project, significant progress was achieved towards the realization of MYOCURE’s objectives.
Firstly, to boost muscle-specific gene expression in the desired target tissues, myoderived cis-regulatory transcriptional modules (CRMs) had been identified and were shown to result in robust increase in gene expression in diaphragm, skeletal muscles and/or heart. Next, prototype AAV vectors were constructed that contained optimized therapeutic gene sequence under the control of the most optimal CRM-combination. To increase muscle-specific gene delivery, muscle-tropic AAV capsids were generated. To date, all AAV capsid libraries have been produced, and the most robust myotropic AAV capsids (designated as AAV-MYO) had been selected and myoderived-CRMs expression cassettes have now been combined to maximize delivery and expression of reporter and therapeutic genes in the desired target tissues. In this report, we showed that combining the most robust CRMs with the most optimal AAV-MYO capsid led to a significant increase in gene delivery and mRNA expression levels in the target muscle of both reporter and therapeutic genes (i.e. GAA, MTM1). However, the therapeutic GAA protein, when expressed in the muscle, resulted in the induction of antibodies that curtail long-term efficacy warranting further investigations. The vector manufacturing of these novel AAV-CRM prototypes with these new AAV-MYO capsids had now been optimized for subsequent in vivo validation. The consortium members also generated a new rat model for myotubular myopathy and Pompe disease that mimics the cognate human disease. These rat models will be employed to validate the efficacy and safety of the new therapeutic myotropic AAV vectors. The seroprevalence of the new AAV-MYO capsids had been investigated. Strategies to eliminate circulating antibodies to AAV have been developed.

To obtain an orphan drug designation (ODD) for this innovative advanced therapy medicinal product (ATMP), the Scientific Advice (SA) documents have been compiled and were sent to the Scientific Advice Working Party (SWAP) of the EMA. The related feedback was received recently and pivotal GLP-compliant studies were designed. In addition to the scientific work, the MYOCURE partners have performed dissemination and communication activities in the form of press releases, participation in relevant events and the publication of several scientific papers and many more papers are currently been drafted for submission. The MYOCURE project website (www.myocure.eu) has been online since the beginning of the project.

Final results

One of the unique strengths of MYOCURE is that it combines the latest innovations in gene therapy with the latest insights in immune control to maximize efficacy and safety. MYOCURE is ambitious as it aims to validate these technological and conceptual innovations in two rare disease targets for which no long-term cure is available, with broad implications for other (rare) muscle disorders. The availability of a unique gene therapy platform developed within MYOCURE that is ‘tailor-made’ for muscle-directed gene therapy would greatly enhance the versatility of gene therapy beyond the state of the art. Notwithstanding MYOCURE’s importance for advancing skeletal muscle and heart-directed gene therapy per se, successful gene transfer and expression in the diaphragm would represent an important leap forward, since patients suffering from MTM (and other rare muscle disorders) typically die of respiratory failure due to diaphragm dysfunction. MYOCURE uses a multidisciplinary approach that goes significantly beyond the state of the art by:
i) Improving the expression by the gene therapy vector
ii) Maximizing gene delivery in the affected target tissues
iii) Reducing immune responses
iv) Preventing vector neutralization
v) Vector manufacturing

By impacting directly on an estimated 20,000 people in the EU suffering from MTM or GSD II, MYOCURE will have a noticeable effect on society, economy, medicine and science.
The project aims to exert a direct positive impact on the lives of patients by delivering novel treatment option that (i) will provide a long-term solution to life-threatening muscle disease and severe myopathy; (ii) will exclude or significantly diminish the need for repeated suboptimal medication; (iii) will be safer than the state of the art gene therapy options. Next to the individual patient level, MYOCURE will also have a positive impact at the family level by improving their quality of life through a decreased need for family or relatives to take care for the affected person.
In developing a cure for rare muscular diseases, MYOCURE will help to ensure that the IRDiRC objectives will be met by having 200 new market authorisations given for new (or repurposed) therapies by 2020. MYOCURE will also strengthen the regulatory framework through the pro-active involvement of EMA and patient organisations.
The annual costs for treating GSD II and MTM patients put significant strain on an already over-stretched healthcare system. The gene therapy approach developed in MYOCURE aims at being a one-time treatment and is therefore expected to have a lower overall cost and a better efficacy. This will therefore ultimately lead to a significant reduction in Europe’s healthcare costs. Moreover, the market capacity will expand further, once the MYOCURE technologies have proven their efficacy. Consequently, the gene therapy products developed within MYOCURE represent a multi-million € market either directly (MTM, GSD II) or indirectly by impacting on the treatment of other muscle diseases.
Due to the advances in MYOCURE, the SME partners within the consortium will consolidate themselves further in the emerging market of personalized medicine and gene therapy. By pro-actively liaising with various industrial stakeholders stimulating private investments, which will further maximize the return on investments and create additional economic activity in this field.
Finally, MYOCURE will foster improvement of medical knowledge and competitiveness of Europe in the field of gene therapy technologies.

Website & more info

More info: http://www.myocure.eu.