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Gene Therapy Consortium Reports on Progress

We are excited to report to the Rett Syndrome community and to everyone who cares about an afflicted family on recent progress made by RSRT’s Gene Therapy Consortium. As you may know, Rett Syndrome is caused by spontaneous mutations in the MECP2 gene that prevents the production of healthy MeCP2 protein. Decades of basic science research have demonstrated that the MeCP2 protein is critical for proper brain functioning and that the symptoms of Rett result from its deficiency. Research efforts have yet to identify any drugs with profound therapeutic benefit in animal models or in people with Rett. In contrast, restoring normal levels of healthy MeCP2 protein in Rett mice dramatically reverses symptoms and disabilities.

The fact that symptoms in adult female mice can be reversed suggests that a diagnosis of Rett need not translate to lifelong disability. The strategy of safely and effectively restoring MeCP2 protein via gene therapy is a particularly attractive therapeutic option that has been a major focus at RSRT.

Scientific advances in gene therapy are proceeding at a rapid pace and many gene therapy treatments are being tested for a variety of diseases. Treating Rett via gene therapy presents several challenges that needed to be addressed before proceeding to the clinic.

1. The gene needs to be broadly delivered to every part of the brain - so choice of viral vector, route of administration and dose is critical.

2. Too much MeCP2 can cause serious symptoms - so optimization of regulatory elements that allow sufficient MeCP2 protein production to improve function yet prevent overproduction is necessary.

To accelerate the pace of progress, RSRT launched the Gene Therapy Consortium, an international collaboration among four laboratories who together bring all the necessary skills to optimize gene therapy for the treatment of Rett Syndrome. We’re delighted to say that the progress made by the Consortium has exceeded our expectations.

Two studies recently by the Consortium report on progress toward overcoming these key challenges with first and second-generation vectors. Specifically, progress has been made in defining the dose, route of administration and critical regulatory elements to ensure correct amount of protein production.

Most importantly, these studies provide the scientific foundation and insights for the development of more effective third-generation vectors that are already being tested and appear to produce therapeutic benefit at lower doses while simultaneously increasing tolerability. These results will be shared in a future publication.

We believe the broader therapeutic window achieved with the Consortium’s next-generation vector will provide sufficient efficacy, safety and delivery characteristics to support advancement into human clinical trials. We look forward to keeping the community updated on this very promising progress.

*Gadalla KKE, Vudhironarit T, Hector RD, Sinnett S, Bahey NG, Bailey MES, Gray SJ, Cobb SR
Development of a novel AAV gene therapy cassette with improved safety features and efficacy in a mouse model of Rett syndrome
Molecular Therapy: Methods & Clinical Development

(2017), doi: 10.1016/j.omtm.2017.04.007

*Sinnett SE, Hector RD, Gadalla KKE, Heindel C, Chen D, Zaric V, Bailey MES, Cobb SR, Gray SJ
Improved MECP2 gene therapy extends the survival of MeCP2-null mice without apparent toxicity after intracisternal delivery
Molecular Therapy: Methods & Clinical Development

(2017), doi: 10.1016/j.omtm.2017.04.006