Intravenous administration of a transferrin receptor antibody-nerve growth factor conjugate prevents the degeneration of cholinergic striatal neurons in a model of Huntington disease.

Abstract

Intrastriatal injections of qn c acid induce a pattern of neuronal degeneration similr to that seen in Huntington disease. In the present study, nerve growth factor (NGF) crossed the blo-brain barrier in a dose-dependent fashion following intravenous infusion when conjugated to an antibody directed against the transferrin receptor (9). In this regard, striatal cholinergic interneurons express the low-affinity p75 NGF receptor during development and the high-affinity TrkA NGF receptor throughout their lifetime, indicating that these neurons can respond to NGF (10-13).Whereas trophic factors such as NGF may be powerful tools for modulating the function and survival of specific neuronal populations, their clinical utility is limited by their inability to cross the blood-brain barrier. As a result, administration of neurotrophic factors to the central nervous system (CNS) requires invasive neurosurgical procedures such as infusion into the ventricular space (14), directly into brain parenchyma (15), or grafting neurotrophin-producing cells into CNS sites (16-18).To develop a noninvasive system for the delivery of macromolecules to the brain, Friden et al. (19,20) showed that NGF crosses the blood-brain barrier when conjugated to an antibody directed against the transferrin receptor (TfR). This delivery system takes advantage of the endogenous transport mechanism responsible for the delivery of iron to the brain and the fact that capillary endothelial cells within the brain express a high density of TfR (19,21 (19,20). Intravenous injections of OX-26-NGF conjugate (20 pg of NGF per injection; n = 12 rats), a nonconjugated mixture of OX-26 and NGF that was identical in composition to the conjugate (20 .g of NGF per injection; n = 8 rats), or vehicle (0.1 M sodium phosphate/5 mM EDTA, pH 6.0; n = 9 rats) were made through a jugular catheter in 0.5-ml volumes and the injections were flushed with 0.3 ml of heparinized saline. Intravenous injections were made for two consecutive days prior to a unilateral intrastriatal infusion of 120 nmol of quinolinic acid, the day of the lesion, and on alternate days thereafter for 14 days. Occasionally, the jugular catheter became occluded. Under these conditions, the rats received their injection via the tail vein.Quinolinic Acid Lesion Model. Young adult male SpragueDawley rats (200-300 g) were used in this study. Rats were first anesthetized with sodium pentobarbital (15 mg/kg, i.p.) and a PE10 (Clay Adams) catheter was placed into the left jugular vein. Three days later, rats were reanesthetized with sodium pentobarbital (15 mg/kg, i.p.) and placed in a Kopf stereotaxic frame. Quinolinic acid (120 nmol) was dissolved and sonicated in 0.9%6 NaCl and was drawn up into a 10-/4Hamilton syringe fitted with a sharp-tipped 26-gauge needle. The Hamilton syringe was lowered into the striatum at the following coordinates: 0.8 mm anterior to bregma; 2.5 mm

Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and α-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length

“…More-over, irreversible inactivation of brain succinate dehydrogenase by 3-nitropropionate induces many of the motor and histological features of HD in experimental animals (50). The excitotoxin quinolinate (51) and neuronal NO synthase (in association with huntingtin binding protein) (52) also may play roles in the disease process. GAPDH possesses a sulfhydryl that is extremely sensitive to NO (53) and on prolonged exposure is irreversibly inactivated (53).…”

Developing Therapeutic Antibodies for Neurodegenerative Disease

“…OX-26 binds to an extracellular epitope of TfR that does not interfere with Tf binding, and thus iron transport is unaffected. Conjugation of a therapeutic cargo to TfR antibodies has also been explored, where fusion with compounds such as brain-derived neurotrophic factor or nerve growth factor correlated with indirect improvements in neuroprotection [116][117][118]. Because OX-26 recognizes only the rat TfR, murine cross-reactive 8D3 and R17-217 are additional anti-TfRs that have been generated and explored for their ability to delivery large molecules to the brain [115,119].…”

Brain Drug Delivery Systems for Neurodegenerative Disorders

“…NGF is one those neurotrophic factors that have been described in preventing the neuropathological and behavioral sequelae resulting from intrastriatal injections of excitotoxins, including quinolinic acid [113][114][115][116][117][118]. The intraestriatal infusion of the NMDA receptor agonist quinolinic acid [119,120] represents a well known animal model of the disease.…”