Identifying Gaps in OI Research

By Dr. Antonella Forlino, member of OIFE’s Medical Advisory Board

Report from OIF Investigator meeting 2019

It was a great pleasure to be sponsored by OIFE to participate at the 19th Annual OI Foundation (OIF) Scientific Meeting held in Chicago on April 10-12 and co-chaired by Dr Marini and Dr Raggio. The American Scientific Community involved in OI research met to discuss the extremely stimulating topic “Identifying Gaps in OI Research”. Basic, translational and clinical researchers were present. It was a great opportunity to have deep discussions various OI related questions in a friendly and stimulating environment.

Dr. Marini opened the meeting with a brilliant overview on our current understanding of the disease in terms of different OI types, their molecular basis and clinical manifestation.

“The Role of Cellular Metabolism and ER stress”

The first Session on “The Role of Cellular Metabolism and ER stress” moderated by Peter H Byers provided an exciting update on the relevance of cell homeostasis as modulator for OI bone phenotype. The accumulation of mutant collagen type I in many OI types has been demonstrated in several studies and the modulation of its intracellular fate has been pointed out as possible target for novel treatments. To stimulate protein folding using chemical chaperones as well as to enhance protein degradation by favoring autophagy have both been considered valid approaches.

John Bateman presented new data on the effect of autophagy enhancement by rapamycin treatment using the OI murine model Amish carrying a G610C substitution in the α2(I) chain of collagen I. From this study a poor efficacy of autophagy stimulation in ameliorating bone properties emerged, even if positive effect on bone trabecular mass was evident (Bateman JF, et al. J Cell Mol Med. 2019;23(3):1735-1745). Sergey Leikin described a new non-canonical autophagic mechanism for intracellular mutant collagen degradation, identifying a new potential target for therapy (Omari S, et al. Proc Natl Acad Sci U S A. 2018;115(43):E10099-E10108).

Dr Forlino using in vitro and in vivo approaches demonstrated the goodness of the chemical chaperone 4-phenylbutyrate in ameliorating cell homeostasis (Besio R, et. Al. Biochim Biophys Acta Mol Basis Dis. 2018;1864(5 PtA):1642-1652. and Gioia R, et al. Hum Mol Genet. 2017;26(15):2897-2911).

Finally, Dr Phillips illustrated an interesting and novel link between muscle weakness and mitochondrial dysfunction in OI using the oim murine model (Gremminger VL, et al. J Bone Miner Res. 2019).

“OI Type VI and Atypical OI Type VI and the pathway connecting them”

Session 2 “OI Type VI and Atypical OI Type VI and the pathway connecting them” chaired by Dr. Schwarze, was focused on the recessive OI forms type V and VI caused by mutation in IFTIM5 and PEDF genes, coding for the protein BRIL and Pigment Epithelium Derived Factor, respectively. Interestingly, a specific mutation in BRIL (S40L) generates in human a clinical outcome resembling mutation in PEDF, but the biochemical bases are still uncertain. A cross talk between PEDF and TGFβ in modulating PPARγ expression during osteogenic differentiation was proposed by Dr Kang. The role of PEDF in osteoblasts differentiation and the potential use of a PEDF mimetic peptide was presented by Dr. Niyibizi. The very peculiar phenotype associated to overexpression in mice of the protein BRIL carrying the human S40L mutation, responsible for the unusual OI type VI phenotype presented by Dr Moffatt and the new knock-in model carrying the S42L mutation generated by Dr. Guterman-Ram will open new possibility to understand the role of BRIL in osteoblasts function.

“Bone cells and transplant”

In session 3 “Bone cells and transplant” chaired by Dr Nagamani, an update on the potentiality of local transplantation of skeletal progenitor in murine model was provided by Dr Sinder and Dr Morello presented new RNAseq data that will help to dissect the role of osteocytes in the OI disease development.

“Response of Murine Models to therapeutic antibodies”

Session 4 was focused on the “Response of Murine Models to therapeutic antibodies” and chaired by Dr Glorieux. Dr Kozloff presented data on the effect of anti-sclerostin on cranial bone in a murine model of OI, further confirming the goodness of the therapy. A novel system based on the use of patient’ bone chips subcutaneously implanted in nude mice, followed by local antibody injection, has been presented as tool to evaluate the patient specific effect of the drug. Dr Rauch reported interesting data on the limited effect of anti-TGFβ antibody treatment in the severe OI model Col1a1Jrt/+ mice (Tauer JT, et al., J Bone Miner Res. 2019;34(2):207-214).

“Surgical Fractures and healing”

In Session 5 “Surgical Fractures and healing” chaired by Dr. Kruse, Dr. Smith, Dr. Zieba, Dr. Franzone, Dr. Robinson addressed the questions of OI fracture healing using OI murine model and OI patients observation. A better understanding of fracture repair in OI is necessary to improve the treatment of OI fracture, also considering rodding and bisphosphonate treatments.

“Clinical Natural History”

Session 6 focused on the “Clinical Natural History” of OI was chaired by Dr Rush. Dr. Raggio, who suggested cardio-pulmonary screening for all patients, discussed the cardiac and pulmonary complications in adults affected by OI. Dr. Marini presented a standardized chart for growth/BMI in classical OI (Barber LA, et al. Genet Med. 2018). The session closed with an innovative study on the OI cornea presented by Dr. Moroi.

“Updates on Treatment Protocols”

Session 7, chaired by Dr. Rauch was focused on the “Updates on Treatment Protocols”. A preliminary update of the status of the two clinical trials: Mereo trial (Setrusumab, anti-sclerostin antibody) and Fresoluminab trial (Anti-TGFb antibody) was provided by Dr. Nicoal and Dr. Nagamani, respectively.

Current treatment for OI

Dr. Shapiro closed the meeting with a discussion on the current treatment for OI.

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