Use of igf-2 receptor agonist ligands for treatment of angelman syndrome and autism
A technology of IGF-2 and agonists, which is applied in the treatment of neurodevelopmental disorders such as Angelman syndrome and autism, and in the field of neurodegenerative diseases, and can solve the problems that there are no feasible treatments for improving various symptoms
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Embodiment 1
[0039] The mouse model used: through the mutant male mice (B6.129S7-Ube3atm1Alb / J) carrying the parental imprinted Ube3A (ubiquitin protein ligase E3A) knockout mutation (purchased from Jackson Laboratory www.jax.org; stock number #016590) were bred with C57BL / 6J female normal mice to obtain mice. Female heterozygous mice were bred to male C57BL / 6J mice; the offspring of this cross were heterozygous males (maternally transmitted), heterozygous females (maternally transmitted), wild-type males and wild-type females. These offspring were used for behavioral and biochemical studies. These mice are referred to herein as mice, and their normal littermates are referred to as wild-type (WT) mice or control mice.
[0040] Treatment: Subcutaneous (s.c.) injection of IGF-2 or vehicle control solution 20 minutes before the start of the behavioral program.
[0041] result:
[0042] IGF-2 reverses impaired memory and motor responses and repetitive behaviors in AS mice.
[0043] As a me...
Embodiment 2
[0053] This example demonstrates that systemic administration of mannose-6-phosphate (M6P) reverses memory deficits in a mouse model of Angelman syndrome. We first tested the effect of different M6P concentrations on memory enhancement in normal mice. The result is as Figure 4 shown. IGF2R.L1 is M6P.
[0054] Furthermore, we found that systemic administration of M6P reversed memory impairment in Angelman syndrome-mimicking mice (Ube3a- / + mice, AS mice) ( Figure 5 ).
[0055] Specifically, we used the novel object recognition (nOR) paradigm in mice to assess non-aversive episodic memory. In this task, rodents' innate preference for novel objects is exploited. During training, mice were allowed to explore 2 identical objects. On test day, replace one of the training objects with a new object. Because mice naturally like new things, if a mouse recognizes a familiar object, it will spend more time on the new object.
[0056] Subcutaneous injection of M6P reversed memory ...
Embodiment 3
[0060] We tested a modified M6P: the phosphonate M6P (PnM6P) called IGF-2R.L2 (or L2). Such as Figure 6 As shown, 4 hours after training, L2 injected at 850 μg / kg significantly reversed the nOR deficit in AS mice and significantly enhanced the nOR memory in WT mice ( Figure 6 A). 24 hours after training, both WT and AS mice injected with L2 showed significant memory improvement compared to the vehicle-injected group. When retested 5 days after training (5-day test), none of the groups (injected vehicle or L2) showed significant memory improvement, although the WT control group showed a strong trend towards memory enhancement, if more With a large number of objects, these tendencies become apparent.
[0061] L2 can also reverse motor deficits in AS mice as shown by the RotaRod test (as described in paragraph 0034). Although vehicle-injected AS mice exhibited marked motor deficits compared to WT control mice ( Figure 6 B), but AS mice injected with L2 significantly impro...
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