CNS delivery of therapeutic agents
A subject, a technology of use, applied in the field of CNS delivery of therapeutic agents
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Embodiment 1
[0418] Example 1: Physicochemical Characteristics of Galc Formulations for Intrathecal Delivery
[0419] The physicochemical properties of GalC described in this example were used to understand its behavior and stability under different solution environments during intrathecal (IT) delivery of proteins.
[0420] Among other things, this example describes the preparation of GalC, which is very important for the successful delivery of GalC by IT. In some embodiments, the formulation includes 5 mM sodium phosphate + 150 mM NaCl, pH 6.0 + 0.005% polysorbate 20. In some embodiments, the formulation includes 5.5 and a pH < 7.0.
[0421] PBS delivery of different phosphate molarity and pH value of the vehicle, in adult cynomolgus monkeys ( image 3 ) were tested. 5 mM phosphate in the 5.5-7.0 pH range showed no adverse effects, while 20 mM phosphate at pH 7.0-7.5 and between 10-20 mM phosphate at pH 7.5-8.0 were shown to produce Negative Effects( image 3 ). The thermostabilit...
Embodiment 2
[0446] Example 2: Single intrathecal administration or single intravenous bolus injection 125 Radiopharmacokinetics and tissue distribution in Sprague-Dawley rats after I-HGALC
[0447] This example describes exemplary results demonstrating post-injection in male Sprague-Dawley rats following a single intrathecal administration or intravenous injection. 125 Pharmacokinetics and tissue distribution of I-hGALC. The concentration and radioactivity content in whole blood, serum, red blood cells, cerebrospinal fluid (CSF) and tissues were determined, and the obtained data were analyzed by non-compartmental pharmacokinetics. The intrathecal and intravenous routes were chosen as they are the expected routes of administration in humans. Dosing levels are selected based on potential human exposure, available toxicity and pharmacokinetic data, and any limitations imposed on the test article. The rat was chosen for the study because it is a recognized species for pharmacokinetic and t...
Embodiment 3
[0684] Example 3: Preclinical Study of ICV and ICV / IP RMGALC Injection and Prolonged Survival in Twitcher Mice
[0685] This example demonstrates the implementation of a preclinical study showing prolonged survival following weekly IP injections of rmGALC in twitcher mice. In this embodiment, improved myelination was observed in the sciatic nerve, with reduced sphingosine levels and improved gross motor function (ie, gait). In some embodiments, twitcher mice treated with a single ICV or ICV / IP rmGALC injection exhibited increased survival and a 63% reduction in brain sphingosine levels. Positive results for important endpoints (i.e., survival, brain sphingosine levels) after ICV administration of rmGALC alone, and little improvement in these endpoints after additional systemic administration (ICV / IP) suggest that the CNS-only regimen is Viable clinical options for the treatment of GLD.
[0686] introduce
[0687] Glomerocytic leukodystrophy (GLD) is an autosomal recessive...
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