IMPA2

The goal of this clinical trial is to assess the safety and effects of a crystalized form of lithium, AL001, when compared to commonly used Lithium Carbonate in healthy volunteers. The main questions this study aims to answer are:
How safe and effective is AL001 when compared to Lithium Carbonate? How is AL001 broken down in the brain and body compared to Lithium Carbonate?
Participants will be asked to:
* Take both the study drug (AL001) and Lithium Carbonate each for a period of 14 days
* Stay overnight at MGH's research unit for two separate 2-week periods
* Participate in two separate 24 hour periods of multiple MRIs and blood draws

主要目的： 比较空腹和餐后给药条件下湖南省湘中制药有限公司提供的碳酸锂片（规格：0.25 g）与LABORATOIRES DELBERT持证的碳酸锂片（商品名：TERALITHE®；规格：0.25 g）在中国健康人群吸收程度和吸收速度的差异。 次要目的： 评价空腹及餐后条件下，湖南省湘中制药有限公司提供的碳酸锂片（规格：0.25 g）与LABORATOIRES DELBERT持证的碳酸锂片（商品名：TERALITHE®；规格：0.25 g）在中国健康人群体内的安全性。

TBR1 is a human gene encoding a brain-specific transcription factor, principally expressed in the excitatory neurons of the neocortex. It regulates development of axonal projection and expression of numerous genes involved in autism spectrum disorders (ASD) and intellectual disability (ID). Recent progress in detection and analysis of rare variants allowed to identify group of genes with strong statistical evidence for association with ASD risk, of which TBR1. Numerous studies on mice showed that TBR1 heterozygous mice display autistic traits as deficiencies in social interaction, in cognitive flexibility, and in associative memory. Functional analyses on human cell lines have demonstrated that de novo truncating variants in TBR1 identified in patients with sporadic ASD disrupt transcriptional repression activity, localization, homodimerization of TBR1 product.
In 2019, only 12 single nucleotide variants (SNVs) and few copy number variations (CNVs) involving TBR1 have been reported in the literature and clinical descriptions were poor. To provide details on the phenotype linked to TBR1 mutations, we and others gathered 25 new individuals with de novo TBR1 SNV and CNV, complemented by a review of individuals previously reported in the literature. On 38 individuals, all presented developmental delay (DD)/ID, ranging from mild to severe, and 76% of them presented autistic traits. Additional behaviour disorders were observed in 85% of individuals, mainly attention deficit and aggressive behaviour. However, the natural history of patients with TBR1 variations is not well known.
Development of RNA-Seq allowed a better understanding of its transcription factor role and revealed that Tbr1 promotes expression of layer 6 markers as Wnt7b. In heterozygous and homozygous TBR1 mutant mice, Fazel Darbandi et al (1), observed that Wnt7b expression is reduced in cortical layer 6 and that neurons have reduced excitatory and inhibitory synaptic density. They showed that lithium chloride and lithium carbonate, WNT-signalling agonists, rescue the dendritic spines, the synaptic and the axonal defects in Tbr1layer5, Tbr1layer6 and Tbr1 constitutive (Tbr1+/-) mutant mice. They also observed an improvement of social interactions in mice after treatment by lithium. These results suggest an important and novel biological mechanism underlying ASD that may have implications for the treatment of patients with TBR1 variants.
Moreover, lithium treatment has already been evaluated in patients with neurocognitive disorders not linked to TBR1 showing an improvement in the adaptative behaviour and cognition function.
As of today, only symptomatic treatments are available. As lithium increase neuronal activity in mice, and may thus improve the symptoms of this disorder, we propose a clinical trial to study the security and efficacy of lithium carbonate targeting the patients with TBR1-related disorders, with specific and adapted endpoints. Lithium carbonate treatment will be administered after an observation period of 6 to 12 months, allowing to ascertain the stability of neurocognitive abnormalities.