Advances in Therapeutic Strategies for Rare Skeletal Disorders

The endoplasmicreticulum (ER) is an essential organelle for synthesis, folding and trafficking of proteins entering the secretory pathway. Accumulation of misfolded proteins in ER - known as ER stress - leads to cell death (73). Pseudoachondroplasia and metaphysealchondrodysplasia type Schmid are two forms of disproportionate short stature in which ER stress is the core disease mechanism (74). Because of this, pharmacological drugs targeting ER stress are currently investigated.

Pseudoachondroplasia

Pseudoachondroplasia is a form of disproportionate short-limb short stature. Length is generally normal at birth and the growth rate falls below the standard growth curve by approximately age two years (75), with a mean adult height of 116 cm and 120 cm for females and males respectively (76).

The diagnosis is generally evoked at the onset of walking when children present with significant waddling gait and joint pains. Natural history is marked by joint laxity, early-onset osteoarthritis and dysplasia of the spine, epiphysis, and metaphysis (76,77). This autosomal dominant disease is related to heterozygous mutations in the COMP gene, encoding a non-collagenous extracellular matrix glycoprotein (75).

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Its accumulation induces ER stress, leading to inflammation and chondrocyte death (78). Preclinical study in a MT-COMP mice model demonstrated that antioxidant or anti-inflammatory agents, such as aspirin and resveratol, interrupted the lethal chondrocyte pathological process induced by mutant COMP retention, thereby partially restoring chondrocyte proliferation, resulting in significantly increased femur length. A Phase II randomized clinical trial of resveratol in adults (age range between 18 and 70 years) with pseudoachondroplasia is planned to start in 2019 (NCT03866200).

MetaphysealdysplasiaSchmid type

Metaphysealchondrodysplasia type Schmid (MCDS) is a very rare form of disproportionate short stature with bone deformities.

Patients present after 2 years of age with short stature and short limbs, waddling gait, varus or valgus of the knee and coxavara. The major concern is chronic pain caused by bone deformities. Adult height varies between 135 cm and 160 cm. MCDS is caused by heterozygous mutations in the COL10A1 gene (79,80). Abnormal collagen type X produced by chondrocytes (81) is misfolded and retained within the ER, leading to an increase of ER stress in hypertrophicchondrocytes, which is the primary cause of MCDS phenotype (82). Carbamazepine (CBZ) is an autophagy-stimulating drug, already used in epilepsy, bipolar disorder and neuropathic pain. Preclinical studies showed that CBZ stimulated proteolysis of misfolded collagen X by autophagy or proteasomal degradation, leading to a decrease of its accumulation and thus reduced ER stress in vitro and in vivo. Mouse model studies demonstrated increased bone growth and reduced skeletal dysplasia (83). An open label phase I/IIa trial repurposingCarbamazepine in children with MCDS is expected to begin in the next few years.

Enzyme replacement therapy

Inherited metabolic disorders are caused by enzyme deficiency, leading to substrate accumulation, and produce deficiency resulting in various multisystemic conditions. In recent years, enzyme replacement therapies have emerged, consisting of enzyme substitution. Hypophosphatasia and Morquio disease are two metabolic disorders characterized by severe skeletal phenotypes.

Hypophosphatasia

Hypophosphatasia (HPP) is a rare metabolic disorder ranging from a prenatal lethal form with no skeletal mineralization to a mild adult form with late onset presenting with premature exfoliation of teeth without any other symptoms. Vitamin-B6 dependent seizures occur in children with the severe form. This disease is caused by loss-of-function mutations in the alkaline phosphatase bio-mineralization-associated (ALPL) gene encoding the Tissue Nonspecific Alkaline Phosphatase (TNSALP), a central regulator of mineralization. While recessive mutations are associated with severe or benign forms, dominant mutations are responsible for the benign form only. The diagnosis is suggested with clinical and radiologic features and confirmed by biochemical (low alkaline phosphatase (AP) activity in serum) and genetic analysis (84).

Deficient TNSALP activity results in extracellular accumulation of its substrates, inorganic pyrophosphate (PPi) and pyridoxal 5’-phosphate (PLP). PPi prohibits hydroxyapatite crystal formation, and thus disrupts endochondral and intramembranous bone formation (85). PLP is the principal circulating form of vitamin B6. Its dephosphorylation by TNSALP in pyroxal is essential to its intracellular transport (86), explaining B6-dependant seizures observed in severe form of HPP.

Asfotasealfa (Strensiq, Alexion Pharmaceuticals, Boston, MA, USA) is a human, recombinant, TNSALP replacement therapy approved and now available for pediatric-onset HPP. A single intravenous infusion followed by subcutaneous injections three times per week showed a rapid and substantial improvement of bone mineralization and respiratory and motor functions, with an increased survival rate in patients with perinatal or infantile hypophosphatasia over 7 years. Asfotasealfa was generally well tolerated, with minor adverse events of injection site reactions, lipodystrophy, hypercalcemia and hypocalcemia (87).

Likewise, Asfotasealfa treatment in adult and adolescent HPP patients improves skeletal radiographic findings, enhances fracture healing and reduces muscle pain (88,89) with a recovery of bone mineralization (90,91).

Because of the recurrent injections of Asfotasealfa, alternative treatment using cell and gene therapy is currently being investigated. The first studies have shown that genetic correction in two childhood HPP patient-derived induced pluripotent stem cells (iPSCs) recovers enzyme activity and calcification in vitro (92).

Morquio A syndrome

Morquio A syndrome, also called Mucopolysaccharidosis type IVA (MPS IVA), is an autosomal recessive lysosomal storage disease, caused by mutations in the gene encoding the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to glycosaminoglycans (GAGs) accumulation in the lysosomes. This accumulation results in short stature and progressive skeletal dysplasia with bone deformity. The visual, auditory, cardiovascular and respiratory systems can be involved. However, the central nervous system is preserved in MPS IVA. Diagnosis is confirmed by biochemical analysis and genetic testing (93,94).

Elosulfasealfa (recombinant human GALNS, BMN 110) enzyme replacement therapy (ERT) is approved for Morquio A syndrome and recommended in all patients as soon as possible after a confirmed diagnosis (95). This treatment seems to slow down the natural progression of the disease (96). Patients receiving weekly intravenous infusions showed sustained increase improvements in mobility, self-care, and caregiver-assistance over 2 years.

Hematopoietic Stem Cell Transplantation (HSCT) is recommended in MPSIH (Hurler disease) because as the only treatment that has been shown to attenuate the developmental decline (97). Four patients with MPS IV received a successful HSCT with an increase of enzyme activity. Given the mean age at HCST of 10.5 years, it is unclear whether HSCT may be efficient on bone growth for younger children (97). To date, HSCT is not recommended for patients with MPS IVA (95).

Conclusion

The development of genomic technology leads to a dramatic improvement of pathophysiological understanding of rare genetic conditions, including skeletal disorders. This permits the definition of new therapeutic targets such as a cell type, a cell deficiency or a signaling pathway and thus aids the development of new therapeutic strategies with real benefit for patients. Moreover, skeletal dysplasia represents a good model for clinical trials repurposing drugs already in clinical use.

These advances provide real hope of significant positive life changes for patients and their families. Because these very rare conditions have a limited number of patients, the optimal therapy, timing and dosage is still to be documented for most of these treatments. In addition, natural history studies are essential before all clinical trials to evaluate the benefits of each treatment. The next few years represent an exciting time in genetic disease healthcare, with potential for real transformation of prognosis and management through these new treatments.