382. Osteopetrosis: An Unusual Presentation of a Rare Disease as a Candidate for Gene Therapy

Osteopetrosis refers to a group of genetic disorders characterized by increased bone density due to failure of osteoclastic bone resorption. Infantile malignant osteopetrosis (IMO; MIM 259700) is the most severe form of the disease. It presents in early infancy and can lead to significant morbidity and death if untreated. Osteosclerotic changes lead to progressive blindness and hearing loss, bone marrow failure, hypocalcemic seizures and pathological fractures. The majority of cases of IMO are due to complete loss-of-function mutations in TCIRG1, which codes for a subunit of the osteoclast vacuolar proton pump (V-ATPase). Currently, hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but can be associated with significant morbidity and toxicity and has a varying success rate depending on the donor source.We present a 9 year old boy from Pakistan in whom increased bone mass and x-ray changes typical of osteopetrosis were found incidentally at age 7. His prior medical history was mostly unremarkable, except for strabismus and dentition problems. Sequence analysis of the TCIRG1 gene revealed a homozygous c.630Gu003eA mutation that changes the last nucleotide of exon 6 and is predicted to result in aberrant splicing, possibly creating a hypomorphic allele and explaining his milder phenotype. Detailed phenotypic evaluation of the patient after diagnosis showed normal bone marrow function, but identified visual impairment with impingement of the optic nerves, and hearing loss.Given the patientu0027s milder phenotype, the morbidity and mortality of HSCT and uncertainty about his speed of disease progression we decided to not pursue HSCT at this point. Thus, novel therapeutic options should be contemplated. Given that the mutation likely results in a splicing defect, this patient could potentially benefit from splicemodifying drugs that are under development. Moreover, we suggest that this patientu0027s clinical presentation makes him an ideal candidate for a trial of gene therapy. Indeed, considering the mortality and morbidity of IMO as well as the established role of HSCT as curative treatment, a randomized clinical trial for the severe form of the disease is not ethically acceptable. There have been encouraging steps towards establishing lentiviral-mediated gene transfer of TCIRG1 as a potential treatment of osteopetrosis in humans. Furthermore, considering the point mutation found in our patient, gene editing technologies, such as CRISPR/Cas9 could allow us to correct this defect by ex-vivo editing of affected CD34+ cells and subsequent re-engraftment. Finally, we suggest that patients with a similarly mild phenotype and mutations in TCIRG1 would be ideal candidates for a clinical trial for gene therapy of osteopetrosis and could be gathered through an international consortium.