Breakthrough announced in treatment for ADO2, Albers-Schonberg disease
* Treatment for rare, debilitating condition proved successful in the laboratory
* Now ready for drug safety tests prior to full clinical trials
* Offers therapy and even cure for a disease presently treated only with palliative care
May 13, 2017, SALZBURG, AUSTRIA. Press Dispensary. Patients with a rare genetic condition known as Type II autosomal dominant osteopetrosis (ADO2) or Albers-Schönberg disease, are being offered hope of a treatment and even a possible cure following successful laboratory development. Antonio Maurizi of the University of L'Aquila, Italy, today announced the breakthrough at ECTS 2017, the 44th European Calcified Tissue Society Congress being held in Salzburg, Austria.
ADO2 is a bone disease that particularly affects skeletal areas such as the spine and pelvis, and can be characterised by multiple fractures, osteomyelitis, haematological deficiency and sensory impairments. Onset is usually in late childhood or adolescence. At present there is no treatment on offer other than palliative care, so therapy targeted at alleviating or curing the disease would be revolutionary for patients.
Professor Anna Teti, of the University of L'Aquila, Italy, explained the basis for the proposed treatment: "In 70% of patients, ADO2 is essentially a mutation of the chloride channel 7 gene, so we designed genetic materials which are able to recognise and silence the mutated gene but not the normal one."
The genetic materials in question are siRNAs - a form of RNA molecule able to prevent the production of specific proteins. RNA (ribonucleic acid) is a nucleic acid present in all living cells. One form of RNA acts as a messenger, carrying instructions from DNA for synthesising proteins . siRNAs can 'silence' this RNA breaking down the molecule. siRNAs occur naturally, and synthetic siRNAs can be designed for specific uses.
Professor Teti continued: "Having designed and patented the siRNAs, we performed a systematic study on ADO2 mice to obtain evidence of the siRNAs' effectiveness, accuracy and safety. We used pilot studies to set the best siRNA dosage - which proved to be 4mg/Kg, three times a week, by infusion - and microCT analysis showed that in pre-pubertal mice there were improvements in two weeks and bone restoration in four weeks, and in adult mice there were improvements in four weeks and full bone restoration in twelve weeks.
"We found no evidence of adverse effects in terms of organ damage and also found benefits to the vital body organs."
Professor Teti went on to conclude: "We are at very exciting point. We know the therapy works in the laboratory and we are now ready to proceed to phase I/II clinical trials, subject to regulatory toxicity studies still to be done in other animal models."
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Notes for editors
About the work
The paper titled "Towards preclinical development of siRNA-based therapy of CLCN7-dependent autosomal dominant osteopetrosis type2 (ADO2)" was presented to ECTS 2017 by Antonio Maurizi of the Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy, reflecting the work of Professor Anna Teti, Mattia Capulli, Rajvi Patel, Nadia Rucci and Antonio Maurizi, all of the same department.
The team designed specific siRNAs recognising CLCN7 single-nucleotide changes, proven effective and specific in silencing the mutant, but not the normal, CLCN7. To progress towards preclinical development essential for EMA/FDA approval of phase I/II clinical trials, they secured the intellectual property by patent application PCT/IB2015/053730 and performed a systematic study to obtain evidence of efficacy, specificity and safety in Clcn7G213R/WT ADO2 mice.
Pilot studies set the best posology at 4mg/Kg siRNA, three times a week, by i.p. infusion. MicroCT analysis showed that treatments of pre-pubertal, 10 day-old, mice, induced improvement of trabecular bone morphometric variables in 2 weeks and rescued the bone phenotype in 4 weeks. Treatments of adult, 3 month-old, mice triggered an improvement of the bone phenotype in 4 weeks and its full rescue in 12 weeks. Histopathology and serum biomarkers of organ damage revealed no adverse effects. Furthermore, the treatment failed to increase the pro-inflammatory cytokines, IL-1β and IL-6, and to downregulate the related Clcn3 and Clcn5 transcripts. The treatment rescued the perivascular fibrosis in visceral organs alongside ClC7 mislocalization and lysosomal pH in ADO2 cells. Finally, siRNA efficacy could be monitored by CTX, TRAcP and CTX/TRAcP ratio in sera, and by downregulation of Clcn7G213R transcript in peripheral blood cells of live ADO2 mice.
The team concluded that the results have immense translational impact and open the door for regulatory toxicity studies to progress the therapy towards clinical development.
About ECTS 2017 (http://ects2017.org)
ECTS 2017 is the 44th European Calcified Tissue Society Congress, held from 13 to 16 May 2017 in the Austrian city of Salzburg.
ECTS serves as a forum for researchers and clinicians working in the musculoskeletal field to join forces, discover and discuss the latest advances and controversies in research and in the daily care of patients.
About The European Calcified Tissue Society (http://www.ectsoc.org/)
The European Calcified Tissue Society (ECTS) is the major organisation in Europe for researchers and clinicians working in the field of calcified tissues and related fields. ECTS acts as a forum for the dissemination of high quality research through its annual meeting, the European Symposium on Calcified Tissues, and through training courses and workshops.
Calcified tissues are central to a healthy skeleton and to bone disorders - such as osteoporosis, back pain and fractures - that make life a misery for countless people. Children can inherit some forms of bone diseases causing bone pain, shortness and deformed limbs.
For further information please contact
Roberta Mugnai, ECTS executive director
European Calcified Tissue Society (ECTS)
Tel: + 32 476 520 716
ECTS 2017: http://ects2017.org
Event hashtag: #ECTS2017