Skip to main content

Development of an innovative gene therapy platform to cure rare hereditary muscle disorders

Periodic Reporting for period 3 - MYOCURE (Development of an innovative gene therapy platform to cure rare hereditary muscle disorders)

Reporting period: 2019-01-01 to 2019-12-31

MYOCURE advances the development of new therapeutic products for patients suffering from rare inherited muscle diseases. The research focuses on myotubular myopathy (MTM) and glycogen storage disorder (GSD) type II. MTM and GSD II are severe, potentially life-threatening rare muscle diseases for which there is no definitive cure and current treatment is suboptimal. These are attractive diseases for gene therapy since they are comprised of a diverse family of rare genetic diseases typically caused by single gene defects that often provoke significant morbidity and mortality. MYOCURE explores strategies to overcome the key bottlenecks that hamper muscle-directed gene therapy. The main objective of MYOCURE is to develop a novel, innovative and clinically-translatable one-treatment gene therapy platform for patients suffering from rare inherited muscle diseases, specifically focusing on myotubular myopathy (MTM) and glycogen storage disorder (GSD) type II.
MYOCURE seeks to overcome the bottlenecks that hamper muscle-directed gene therapy by:
-Boosting gene transfer and expression.
-Minimizing undesirable immune reactions and improving the efficacy and safety.
-Developing a scalable GMP-like manufacturing process.
-Applying for an orphan drug designation for the innovative advanced therapy medicinal product (ATMP) to ultimately justify a Phase I gene therapy clinical Trial
The main impact of MYOCURE is to advance the development of new therapies for patients with rare muscle diseases. MYOCURE will impact directly on an estimated 20,000 people in the EU suffering from MTM or GSD II. MYOCURE aims to exert a direct positive impact on the lives of MTM and GSD II patients by delivering novel treatment option(s) that will: (i) provide a long-term solution to life-threatening muscle disease and severe myopathy; (ii) exclude or significantly diminish the need for repeated sub-optimal medication by enzyme replacement therapy (ERT); (iii) be safer than the state-of the-art gene therapy options. MYOCURE will pave way towards the development of next-generation gene therapies aiming to improve the quality of life (QoL) of the afflicted patients (and their families). This will in turn impact on the health-care costs by aiming to achieve sustainable therapeutic solutions for the afflicted patients.
The partners have taken significant steps towards the realization of the aforementioned objectives by increasing the efficacy of muscle-directed gene delivery using novel engineered adeno-associated viral vectors (AAV) and by boosting muscle-targeted gene expression levels in the desired target tissues using novel transcriptional elements identified by genome-wide data-mining. Successful efforts were made to minimize undesirable immune reactions by inducing immune tolerance to the transgene products. Steps were made towards the (large-scale) manufacturing of the novel AAV vectors towards initial preclinical validation in animal models of Pompe and myotubular myopathy yielding encouraging efficacy and safety data. The seroprevalence of the new AAV capsids had also been investigated and strategies to eliminate circulating antibodies to AAV have been developed. In addition to the research per se , feedback from the regulatory authorities (European Medicine Agency) had also been obtained. Furthermore, the partners have performed active dissemination and communication activities in the form of press releases or participation in relevant events and liaising with various patient organizations. In particular, awareness for the project’s mission and vision within the scientific community has been created in particular by presenting research and networking at international conferences and meetings and dissemination via the MYOCURE website. Some of the main dissemination events were the annual congresses of the European Society for Gene and Cell Therapy and its national meetings, the American Society of Gene and Cell Therapy and various congresses with a strong focus on muscle disorders and lysosomal storage diseases. MYOCURE contributed actively to the organization of these various scientific events and organized workshops on key technological innovations in the AAV field. The dissemination efforts of the MYOCURE partners also facilitated liaising with multiple stakeholders with a specific interest in the MYOCURE program, including scientist, clinicians, regulatory exports, patients, manufacturing experts and industrial stakeholders with implications for exploitation and valorization. Finally, the MYOCURE partners published their work in peer-reviewed journals (e.g. Science Translational Medicine, Nature Communications, Journal of Clinical Investigations, Molecular Therapy, Human Gene Therapy, Gene Therapy, Molecular Therapy Clinical Development etc.). Several publications will be submitted. The realization of these dissemination objectives provides an independent objective quantitative and qualitative measure of the progress made by MYOCURE.
The project has moved significantly beyond the state of the art through the development of next-generation AAV-based gene therapy technologies that result in increased gene expression and/or gene delivery efficiencies in the desired target muscles compared to what could be achieved with state of the art vectors. In particular, potent muscle-specific transcriptional cis-regulatory modules (CRMs), were identified resulting in higher transgene levels than when conventional promoters are used. This multidisciplinary approach has potentially broad implications for augmenting the efficacy and safety of muscle-directed gene therapy. Next-generation AAV capsids were developed, e.g. by semi-rational AAV capsid engineering that outperformed conventional AAV capsids for muscle-directed gene therapy. In parallel, the muscle tropism and activity of another AAV serotype, AAVpo1, was examined showing robust transduction in all major muscle tissues, with nearly complete detargeting from the liver, making it a very attractive and potentially safer option.
In addition, novel insights were obtained in some of the immune mechanisms after AAV gene therapy, defining a possible role for monocyte-derived dendritic cells and natural killer cells in AAV capsid immunity. Synthetic tolerogenic nanoparticles encapsulating rapamycin, co-administered with AAV vectors, prevented the induction of anti-AAV capsid humoral and cell-mediated responses. This allowed for successful vector re-administration in mice and nonhuman primates. AAV gene transfer with tandem promoter design (i.e. muscle and liver) prevented anti-transgene immunity and provided persistent efficacy in neonate Pompe mice. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. These advances opens potential new avenues for the modulation of vector and/or transgene immunogenicity.
Hence, MYOCURE has significantly advanced the development of new therapies for patients with rare muscle diseases which will ultimately directly impact on the patients and their families and with implications beyond MTM and GSD II. MYOCURE has enhanced EU’s expertise and develop innovations meeting the needs of European and global markets in the field of orphan and rare diseases and has fostered the improvement of medical knowledge and competitiveness of Europe in the field of gene therapy technologies which will further strengthen its indirect economic impact.