Farber disease (acid ceramidase deficiency): Data from an ongoing natural history study

15th Annual Research Meeting of the WORLDSymposium(TM) -- FEB 04-07, 2019 -- Orlando, FLWOS: 000457351700338…WORLDSymposiu

Dose Responsive Effects of Subcutaneous Pentosan Polysulfate Injection in Mucopolysaccharidosis Type VI Rats and Comparison to Oral Treatment

<div><p>Background</p><p>We previously demonstrated the benefits of daily, oral pentosan polysulfate (PPS) treatment in a rat model of mucopolysaccharidosis (MPS) type VI. Herein we compare these effects to once weekly, subcutaneous (sc) injection. The bioavailability of injected PPS is greater than oral, suggesting better delivery to difficult tissues such as bone and cartilage. Injected PPS also effectively treats osteoarthritis in animals, and has shown success in osteoarthritis patients.</p><p>Methodology/Principal Findings</p><p>One-month-old MPS VI rats were given once weekly sc injections of PPS (1, 2 and 4 mg/kg, human equivalent dose (HED)), or daily oral PPS (4 mg/kg HED) for 6 months. Serum inflammatory markers and total glycosaminoglycans (GAGs) were measured, as were several histological, morphological and functional endpoints. Overall, weekly sc PPS injections led to similar or greater therapeutic effects as daily oral administration. Common findings between the two treatment approaches included reduced serum inflammatory markers, improved dentition and skull lengths, reduced tracheal deformities, and improved mobility. Enhanced effects of sc treatment included GAG reduction in urine and tissues, greater endurance on a rotarod, and better improvements in articular cartilage and bone in some dose groups. Optimal therapeutic effects were observed at 2 mg/kg, sc. No drug-related increases in liver enzymes, coagulation factor abnormalities or other adverse effects were identified following 6 months of sc PPS administration.</p><p>Conclusions</p><p>Once weekly sc administration of PPS in MPS VI rats led to equal or better therapeutic effects than daily oral administration, including a surprising reduction in urine and tissue GAGs. No adverse effects from sc PPS administration were observed over the 6-month study period.</p></div

Flexural mechanics of normal, untreated MPS VI, and PPS-treated MPS VI femurs.

<p>The whole bone stiffness (<b>A</b>) and flexural modulus (<b>B</b>) were decreased in MPS VI compared to normal animals, and no changes were observed in the PPS treatment groups. However, force at break (<b>C</b>) and flexural strength (<b>D</b>) did reveal increasing improvements in a dose dependent manner, indicating that sc PPS treatment moderately enhanced the fracture strength of the femurs.</p

GAG reduction in PPS-treated MPS VI rats.

<p>(<b>A</b>) Total urine GAGs were significantly reduced in all PPS-treated MPS VI rat groups compared to untreated MPS control animals, regardless of the mode of administration. Subcutaneous treatment also significantly reduced urine GAGs compared to oral treatment. Tissue GAGs were significantly reduced only in the MPS VI rats treated with sc PPS. (<b>B</b>) kidney, (<b>C</b>) liver and (<b>D</b>) spleen. A dose responsive reduction was observed in the kidney and liver. *P<0.05 comparing treated to untreated MPS VI rats. ** P<0.05 comparing sc to oral treatment.</p

Serum inflammatory markers in normal, untreated and PPS treated MPS VI rats.

<p>Tumor necrosis factor-α (TNF-α (<b>A</b>), tumor necrosis factor receptor-1 (TNFR1) (<b>B</b>), interleukin-8 (IL-8) (<b>C</b>), protein S100A8/A9 (<b>D</b>), and C-reactive protein (CRP) (<b>E</b>), were quantified by ELISA assays as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100882#s2" target="_blank">Materials and Methods</a>. White columns, normal rats; black columns, untreated MPS VI rats; light gray columns, 4 mg/kg sc PPS treated MPS VI rats; dark gray columns, 2 mg/kg sc PPS treated MPS VI rats; grey hatched columns, 1 mg/kg sc PPS treated MPS VI rats and white hatched columns, 4 mg/kg oral PPS treated MPS VI rats. N = 6/group. All doses are HED <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100882#pone.0100882-ReaganShaw1" target="_blank">[22]</a>. The vertical lines in each column indicate the ranges. * P<0.05 comparing treated to untreated MPS VI rats. **P<0.05 comparing sc PPS administration to oral.</p

Femoral trabecular analysis of PPS-treated MPS VI rats.

<p>MicroCT analysis of the femurs was performed as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100882#s2" target="_blank">Materials and Methods</a>. Representative images are shown for 7-month-old (<b>A</b>) normal, (<b>B</b>) untreated MPS VI, (<b>C</b>) 1 mg/kg, (<b>D</b>) 2 mg/kg, and (<b>E</b>) 4 mg/kg sc PPS-treated animals. Black arrows indicate the trabecular regions. MicroCT quantification of the trabeculae is shown below the images. Dose responsive improvements in several criteria were observed, including % bone volume/tissue volume (BV/TV), bone surface/volume ratio (BS/BV), trabecular number (Tb.N), trabecular separation (Tb.Sp), total porosity Po(tot), and bone mineral density (BMD). *indicates statistical differences between untreated and treatment groups (p<0.05).</p