Hurler Syndrome – Treatments and Management

The primary treatment option for Hurler Syndrome is enzyme replacement therapy (ERT). The drug laronidase (commercially available as Aldurazyme) was originally developed for long term use to treat the non-central nervous system manifestations of the disease. Aldurazyme is a recombinant version of the normal human α-L-Iduronidase (IDUA) protein expressed in Chinese hamster ovary cells (CHO). In enzyme replacement therapy, the functional enzyme is injected intravenously into the patient where it performs the normal functions that the patient’s enzymes cannot. The treatment is not curative; rather, it prevents symptoms from progressing or worsening. ERT is intended to be administered for life (FDA). The central nervous system is more difficult to treat with ERT because of the blood brain barrier (BBB). Recombinant enzyme can be transported across the BBB via the mannose-6-phosphate receptor; however, the expression of the receptor is down-regulated after the first two weeks of life. To that end, recent research in the mouse model has shown that high-dose ERT is capable of rescuing brain function. Researchers repeatedly injected a dose equal to 20x the normal dose into mice and showed that functional enzyme reached the brain and that it rescued function by over 50%. They postulated that the high blood concentration of the enzyme allowed for nonspecific pinocytosis across the blood brain barrier. The downside is that the increase in dosage stimulated a more sever immune response, so more research is necessary for this high-dose therapy (Ou et al. 2014). Since early disease development can cause severe neurological and physical symptoms, early treatment has proven to be essential in successfully treating the disease. Other drugs taken to ameliorate the visceral effects of the disease (like statins) have not been shown to interfere with ERT (Chiaro et al. 2014).

Other treatment options have been explored to treat the symptoms of the central nervous system. The most popular option has been hematopoietic stem cell (bone marrow) transplantation. In a successful transplantation, the donor marrow cells develop into blood cells that produce functional versions of IDUA. Notably, differentiation into macrophages that can cross the blood brain barrier means that the enzyme can be delivered to the central nervous system as well as peripheral tissue (Watson et al 2014). Over 500 transplantations have occurred to treat Hurler Syndrome (Aldenhoven et al. 2008). In visceral tissue, symptoms are largely ameliorated if not fully cured. Sleep apnea decreases, normal myocardial function is restored and heart size reduces, and hepatosplenomegaly is reduced. Neurocognitive improvements are also observed. While relatively low levels of the enzyme are found in the brain, glycosaminoglycan (GAG) are restored to normal (Ellinwood et al. 2006). Significant outcomes in the skeletal system and cornea are less prevalent (Souillet et al. 2003). The downside to stem cell transplantation is the high failure rate of the procedure. 44% of patients require further transplantation. It has been shown that heparan sulfate, which accumulates in Hurler Syndrome patients, decreases stem cell mobility and can disrupt successful engraftment (Watson et al. 2014). Recent changes to the international protocol for transplant pre-treatment have increased the overall survival of recipients while decreasing the number of adverse events that occur after transplantation (Aldenhoven et al. 2015). As with ERT, the best outcomes have been observed when transplantation occurs as early as possible (12 months or younger) (Poe et al 2014).

                Because of the risks and costs associated with ERT and stem cell transplantation, gene therapies (GT) are also being explored as treatment options. Also, GT intends to be a one-treatment cure. In one study, a retrovirus coding for canine IDUA was injected into mice livers. The coded enzyme expressed a mannose-6-phosphate so that it could be transported across the BBB. High dosages of the virus resulted in stable expression of the enzyme after eight months; low dosage ultimately led to a loss of expression. Heart health was completely restored, but skeletal defects were not rescued. Researchers observed an initial immune response to the high dose therapy (Liu et al. 2006). In another study, a retrovirus coding for human IDUA was injected directly into the lateral ventricles of mouse brains in order to prevent neurocognitive defects of Hurler Syndrome. The researchers were successful in preventing neurological defects in infant Hurler Syndrome mice and observed normal levels of GAGs in the brains. Further, mice performed well in a water-maze test, indicating that their learning faculties were preserved. They hypothesized that the direct injection into the nervous system tissue allowed for higher levels of enzyme to be expressed in the brain than if relying on the mannose-6-phosphate-mediated transport from the blood. (Wolf et al. 2011). Other experiments have run with the idea of spinal cord injections. Spinal cord injections in a cat model have shown full correction of the disease in the central nervous system (Hinderer et al. 2014). Like the other treatments, early treatments correlated to more successful outcomes. Further, there are many hurdles in the way of translation into humans. Notably, human IDUA is very immunogenic, and many animal models show cytotoxic T lymphocyte responses to gene therapy, which can be particularly troubling for injections into the central nervous system. Newborn mice, the model in which many gene therapy experiments take place, do not show an immune response that newborn humans do. That, combined with the dangers of direct injections into the human central nervous system, are significant challenges to human gene therapy development to treat Hurler Syndrome (Wolf et al. 2011).

| History and Metabolic Context | Molecular Basis of the Disease State | Treatments and Disease Management | Conclusions and Proposals for Future Work | Annotated Bibliography |