Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB

Abstract

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and non-human primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well-tolerated as compared to administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and HS-NRE in CSF and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests, had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathological, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects.

Disease pathology signatures in a mouse model of Mucopolysaccharidosis type IIIB

“…Due to the vulnerability of the MPS IIIB pediatric patient population and the developmental etiology of the disease, it is increasingly important to utilize the Naglu KO model to gain a better insight into the embryonic and early postnatal stages of disease onset and progression. Despite some success in preclinical models 24 , 29 , there are still no therapies for MPS IIIB that successfully resolve neurological symptoms in patients, prompting the need for initiating treatment early in development (prenatally). To this end, the very recent success of the first reported in utero ERT treatment for infantile Pompe disease 77 , offers an encouraging new route for treatment of these debilitating neurodevelopmental LSDs.…”

“…Despite our detailed knowledge of the genetic and molecular drivers of MPS III, our current understanding of how exactly HS accumulation and lysosomal dysfunction lead to global defects in other cell organelles and cell death remains incomplete. Due to the low frequency of MPS IIIB occurrence, as with most LSDs, animal model availability—from rodents to large stock animal species 27 – 29 , has been a key factor in studying mechanisms of disease pathogenesis and has enabled translational research towards finding a cure. In this study, we provide a systematic and comprehensive histological, behavioral and proteomic analysis of the most commonly used MPS IIIB mouse model—the Naglu knock-out (KO) mouse genetic model 30 .…”

A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B

“…According to this model, ICV delivery should result in little distribution of tralesinidase alfa in the brain. Our preclinical data have established that tralesinidase alfa can be effectively distributed throughout the brain of NAGLU-deficient mice and dogs, thereby preventing disease manifestations (10,11). Data in the dog model of MPS IIIB have demonstrated that HS-NRE levels in CSF and brain correlate with each other; the normalization of HS-NRE in CSF predicts benefits (11).…”

“…Our preclinical data have established that tralesinidase alfa can be effectively distributed throughout the brain of NAGLU-deficient mice and dogs, thereby preventing disease manifestations (10,11). Data in the dog model of MPS IIIB have demonstrated that HS-NRE levels in CSF and brain correlate with each other; the normalization of HS-NRE in CSF predicts benefits (11). Others have also recognized the value of CSF HS as a predictive marker of clinical efficacy (17); unfortunately, intravenous delivery of recombinant N-sulfoglucosamine sulfohydrolase resulted in no resolution of hepatosplenomegaly and no clear clinical benefits in a clinical study recruiting six subjects suffering from MPS IIIA.…”

“…In both mouse and dog models, lysosomal size decreased with tralesinidase alfa treatment, demonstrating that it is effectively clearing HS from the targeted lysosome. Additional work in a dog model of MPS IIIB has shown that tralesinidase alfa-mediated reduction in HS and HS-NRE in both CSF and brain tissue leads to improvement in a T-maze learning task (11).…”