A Placebo-controlled Evaluation of Low Dose Lithium Carbonate in Patients with TBR1-related Neurocognitive Disorders: a 24-month Multi-centre Pilot Study

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.

开始日期2025-02-01

申办/合作机构

Centre Hospitalier Universitaire de Dijon

NCT06719544

/ Recruiting临床1期

A Clinical Study to Evaluate the Effect of Enlicitide on the Pharmacokinetics of Lithium in Healthy Adult Participants

Researchers have designed a new study medicine called enlicitide decanoate (MK-0616) as a new way to lower the amount of low-density lipoprotein cholesterol (LDL-C) in a person's blood. Enlicitide decanoate will be called "enlicitide" from this point forward. Lithium (also called lithium carbonate) is a medicine used in bipolar disorder.
Researchers want to learn about lithium when taken at the same time with enlicitide.
They want to:
* Measure a person's blood to find out if the amount of lithium in the blood is the same when lithium is taken alone or with enlicitide
* Learn about the safety of lithium when taken alone or with enlicitide and if people tolerate it

开始日期2025-01-02

申办/合作机构

Merck Sharp & Dohme Corp.

NCT06729970

/ Not yet recruiting临床1期

A Phase 1, 4-part, Open-label, Fixed-sequence Study to Evaluate the Effects of Lithium and Valproic Acid on the Single-dose Pharmacokinetics of KarXT and Effects of KarXT on the Single-dose Pharmacokinetics of Lithium and Valproic Acid in Healthy Participants

The purpose of this study is to evaluate the effects of lithium and valproic acid on the single-dose pharmacokinetics (PK) of KarXT and the effect of KarXT on the single-dose PK of lithium and valproic acid in healthy participants.

开始日期2024-12-23

申办/合作机构

Karuna Therapeutics, Inc.

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100 项与碳酸锂相关的转化医学

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100 项与碳酸锂相关的专利（医药）

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项与碳酸锂相关的文献（医药）

2025-02-01·Neuroscience

Lithium restores nuclear REST and Mitigates oxidative stress in down syndrome iPSC-Derived neurons

Article

作者: Cheah, Pike-See ; Maniam, Sandra ; Lam, Xin-Jieh ; Ling, King-Hwa

Down syndrome (DS), caused by trisomy 21, is characterized by intellectual disability and accelerated aging, with chronic oxidative stress contributing to neurological deficits. REST (Repressor Element-1 Silencing Transcription factor), a crucial regulator of neuronal gene expression implicated in DS neuropathology. This study investigates the neuroprotective potential of lithium, a mood stabilizer with known cognitive-enhancing effects, in restoring levels of REST. Using three pairs of human disomic and trisomic DS induced pluripotent stem cell (iPSC) isogenic lines, we differentiated neurons and treated them with lithium. Nuclear REST expression and reactive oxygen species (ROS) levels were quantified. Results showed the significantly lower nuclear REST expression in DS neurons was restored after 24 h of 10 mM lithium carbonate treatment. Notably, lithium treatment selectively reduced ROS levels in DS neurons to near-baseline levels. When challenged with hydrogen peroxide, DS neurons exhibited increased vulnerability to oxidative stress. The lithium treatment also significantly reduced ROS levels in the stressed control neurons. These findings reveal a positive association between lithium treatment, REST restoration, and oxidative stress reduction, suggesting that repurposing lithium could contribute to developing therapeutic strategies for DS neuropathologies. This study provides novel insights into DS molecular mechanisms and highlights the potential of lithium as a targeted intervention for improving neuronal function in DS.

2025-01-01·Experimental Neurology

Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models

Article

作者: Silani, Vincenzo ; Venturin, Marco ; Bossolasco, Patrizia ; Colombrita, Claudia ; Sorce, Marta Nice ; Lattuada, Chiara ; Ratti, Antonia ; Battaglia, Cristina ; Santangelo, Serena ; Invernizzi, Sabrina ; Casiraghi, Valeria

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized neuropathologically by TDP-43 proteinopathy with loss of TDP-43 nuclear splicing activity and formation of cytoplasmic TDP-43 aggregates. The lack of suitable experimental models of TDP-43 proteinopathy has hampered the discovery of effective therapies. We already showed that chronic and mild oxidative insult by sodium arsenite (ARS) triggered TDP-43 cytoplasmic aggregation and stress granules (SGs) formation in ALS patient-derived fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs). However, whether this insult induces a reduction of TDP-43 splicing activity in the nucleus, thus recapitulating both gain and loss of function pathomechanisms, still remains to be determined. In this study we first showed that chronic ARS in human neuroblastoma cells triggered TDP-43 cytoplasmic mislocalization, SGs formation and defective splicing of TDP-43 target genes UNC13A and POLDIP3 as functional readouts of TDP-43 proteinopathy. Additionally, a dysregulation of autophagy and senescence markers was observed in this condition. In a preliminary drug screening approach with autophagy-promoting drugs, namely rapamycin, lithium carbonate and metformin, only rapamycin prevented ARS-induced loss of TDP-43 splicing activity. We then demonstrated that, in addition to TDP-43 cytoplasmic aggregation, chronic ARS triggered TDP-43 loss of splicing activity also in ALS patient-derived primary fibroblasts and iPSC-MNs and that rapamycin was beneficial to reduce these TDP-43 pathological features. By switching to a neuro-glial 3D in vitro model, we observed that treatment of ALS iPSC-brain organoids with chronic ARS also induced a defective TDP-43 splicing activity which was prevented by rapamycin. Collectively, we established different human cell models of TDP-43 proteinopathy which recapitulate TDP-43 gain and loss of function, prevented by rapamycin administration. Human neuroblastoma cells and patient-derived fibroblasts and 2D- and 3D-iPSC models exposed to chronic oxidative stress represent therefore suitable in vitro platforms for future drug screening approaches in ALS.

2024-12-01·Alzheimer's & Dementia

Lithium as a pharmacological approach to treat behavioral complications in Alzheimer’s disease: a preclinical study

Article

作者: Forlenza, Orestes Vicente ; Britto, Luiz Roberto ; Talib, Leda Leme ; Singulani, Monique Patricio ; Camarini, Rosana

AbstractBackgroundNearly all individuals with Alzheimer’s disease (AD) develop neuropsychiatric symptoms (NPS). Lithium is a mood‐stabilizer and is efficient in reducing disruptive behaviors in bipolar‐disorder; this characteristic could be an opportunity to investigate the use of lithium in treating behavioral changes in AD.MethodWe tested lithium carbonate treatment in 3xTg‐AD and age‐matched Wild‐type male mice (CEUA/PROCESS: 1605/2020; 4127240122). The drug was administered ad libitum via lithium‐supplemented chow (1.0g Li2CO3/kg of chow; 12‐weeks) from 9‐ to 12‐month‐old. Two behavioral test batteries were performed: (1) open‐field test (OFT), novel‐object recognition test (NORT), elevated zero‐maze test (EZMT), and rotarod test; (2) tail‐suspension test (TST), forced‐swim test (FST), and sucrose preference test (SPT). Immunohistochemistry method was performed to analyze amyloid‐β (Aβ) accumulation (6E10) in areas of the brain. Statistical analysis was performed using two‐way ANOVA followed by Bonferroni post‐hoc test and unpaired t‐test (IBM_SPSS Statistics® software 23). We considered statistically significant p<0.05.ResultOur results demonstrated that lithium had a significant rescue/prevention effect on anxiety‐ and depression‐related behaviors in AD. In both OFT (F(1, 28) = 37.15; p<0.001) and EZMT (F(1, 28) = 19.44; p<0.001), a suppression in anxiety‐related responses was detected in 3xTg‐AD+Lithium mice versus 3xTg‐AD. Similar results were found in TST (F(1, 28) = 11.70; p<0.01) and FST (F(1, 28) = 7.96; p<0.01) with reduction of depressive‐related behavior. In SPT (F(1, 24) = 17.86; p<0.001), 3xTg‐AD+Lithium mice presented an increase in sucrose preference versus 3xTg‐AD, suggesting benefice effects of lithium on anhedonia signs detected in AD. In NORT, 3xTg‐AD+Lithium mice demonstrated greater index in recognition memory parameter versus 3xTg‐AD, suggesting prevention of short‐ (F(1, 28) = 8.37; p<0.01) and long‐term memory (F(1, 28) = 7.99; p<0.01) in AD. We also reported reduction of nearly 50% in Aβ immunoreactivity in areas such as parietal cortex (F(1, 21) = 571.90; p<0.001), CA1 (F(1, 20) = 357.28; p<0.001), dentate gyrus (F(1, 20) = 417.74; p<0.001), subiculum (F(1, 20) = 7073.19; p<0.001), entorhinal cortex (F(1, 21) = 1562.86; p<0.001), and amygdala (F(1, 22) = 419.79; p<0.001), in 3xTg‐AD+Lithium mice versus 3xtg‐AD; suggesting the neuroprotective action of lithium, which partially explains the positive cognitive and non‐cognitive behavioral changes observed with chronic lithium treatment.ConclusionThe efficacy of a low‐dose lithium treatment in improving cognitive loss and NPS suggest it as therapeutic potential to treat AD.

项与碳酸锂相关的新闻（医药）

2024-12-18

·ir.alzamend.com

Alzamend Neuro to Present Non-Clinical Data Update at the Society of Toxicology 2025 Annual Meeting and ToxExpo

Presentation Topic is the Pharmacokinetics of AL001, a Lithium Salicylate/L-Proline Co-crystal, as a Potentially Beneficial Lithium Sparing Treatment for Bipolar Disorder Type 1, Alzheimer’s Disease, Major Depressive Disorder and Post-Traumatic Stress Disorder ATLANTA--(BUSINESS WIRE)-- Alzamend Neuro, Inc. (Nasdaq: ALZN) (“Alzamend”), a clinical-stage biopharmaceutical company, focused on developing novel products for the treatment of Alzheimer’s disease (“Alzheimer’s”), bipolar disorder (“BD”), major depressive disorder (“MDD”) and post-traumatic stress disorder (“PTSD”), today announced it will have a poster presentation at the Society of Toxicology (“SOT”) Annual Meeting and ToxExpo, being held from March 16-20, 2025, in Orlando, Florida. “Our poster presentation at SOT in 2025 with data from our non-clinical study: Comparing Brain and Plasma Lithium Exposures between AL001 and Lithium Carbonate in Alzheimer’s Transgenic Mice, demonstrates the potential of AL001 to enhance brain-specific lithium delivery while minimizing systemic exposure in an Alzheimer’s disease mouse model, guiding development of enhanced lithium effectiveness and safety in human diseases,” said Stephan Jackman, Chief Executive Officer of Alzamend. “Following successful results from this study and our Phase I and IIA trials, AL001 is positioned for five Phase II trials in partnership with Massachusetts General Hospital in 2025. These trials aim to redefine lithium therapy across neurodegenerative and neuropsychiatric conditions by leveraging a lower-dose, high-efficacy approach anticipated to qualify for the U.S. Food and Administration 505(b)(2) approval pathway.” Abstract 3266/H393 – Poster presentation: Title: Pharmacokinetics of AL001, Lithium Salicylate/L-Proline Co-crystal: A Potentially Beneficial Lithium Sparing Treatment for Bipolar Disorder Type 1 (BD1), Alzheimer’s Disease (AD), Major Depressive Disorder (MDD) and Post-traumatic Stress Disorder (PTSD) Session Title: Pharmaceutical Safety and Drug Discovery Session Date and Time: Monday, March 17, 2025; 9:15AM ET – 11:45AM ET Session Location: Orange County Convention Center, ToxExpo Hall Presenting Author: Darrell Sawmiller, Ph.D, Assistant Professor, Center of Excellence for Aging & Brain Repair, University of South Florida, Tampa, FL, USA Summary: No Undue Adverse Effects: Both treatments had no negative impact on the mice's body weight or clinical signs during the treatment period. Reduced Systemic Exposure: AL001 showed lower plasma lithium levels than lithium carbonate, reducing the risk of adverse systemic effects, suggesting an expansion for safety of lithium’s therapeutic index. Enhanced Brain Penetration: AL001 showed consistently higher lithium concentrations in brain tissues, particularly at lower doses, compared to lithium carbonate. Targeted Brain Structures: The study found that different brain regions absorb and retain lithium differently. This means treatments can potentially be tailored to target specific brain areas, allowing for more precise treatment of various brain-related conditions when applied in human studies. Further information can be found at https://www.toxicology.org/events/am/AM2025/index.asp. About AL001 Non-Clinical Study The study involved administering AL001, a good manufacturing practices-quality active pharmaceutical ingredient (“API”) to 5XFAD mice, a recognized model for Alzheimer’s research, to compare its effects against lithium carbonate, a U.S. Food and Drug Administration approved and marketed API. Mice received either high or low doses scaled to humans of both AL001 and lithium carbonate over a 14-day period to observe pharmacokinetic steady-state drug conditions. On the 15th day, the mice were analyzed to assess how the treatments affected lithium concentrations in different brain regions and in their plasma. The results mentioned in the summary highlight the potential clinical advantages of AL001 for conditions like Alzheimer’s, BD, MDD and PTSD at low doses. By reducing the systemic burden, AL001 could lessen the risk of side effects such as thyroid and kidney complications often associated with extant lithium therapies. This positions AL001 as a promising candidate for safer long-term treatment options, without the need for routine blood lithium monitoring. This innovation is specifically designed to address the needs of fragile populations, such as elderly and Alzheimer’s patients, by offering a potentially more efficient and safer alternative to existing treatments. About Alzamend Neuro Alzamend Neuro is a clinical-stage biopharmaceutical company focused on developing novel products for the treatment of Alzheimer’s, BD, MDD and PTSD. Our mission is to rapidly develop and market safe and effective treatments. Our current pipeline consists of two novel therapeutic drug candidates, AL001 - a patented ionic cocrystal technology delivering lithium via a therapeutic combination of lithium, salicylate and L-proline, and ALZN002 - a patented method using a mutant-peptide sensitized cell as a cell-based therapeutic vaccine that seeks to restore the ability of a patient’s immunological system to combat Alzheimer’s. Both of our product candidates are licensed from the University of South Florida Research Foundation, Inc. pursuant to royalty-bearing exclusive worldwide licenses. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as “believes,” “plans,” “anticipates,” “projects,” “estimates,” “expects,” “intends,” “strategy,” “future,” “opportunity,” “may,” “will,” “should,” “could,” “potential,” or similar expressions. Statements that are not historical facts are forward-looking statements. Forward-looking statements are based on current beliefs and assumptions that are subject to risks and uncertainties. Forward-looking statements speak only as of the date they are made, and Alzamend undertakes no obligation to update any of them publicly in light of new information or future events. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors. More information, including potential risk factors, that could affect Alzamend’s business and financial results are included in Alzamend’s filings with the U.S. Securities and Exchange Commission. All filings are available at www.sec.gov and on Alzamend’s website at www.Alzamend.com. View source version on businesswire.com: https://www.businesswire.com/news/home/20241218800562/en/ Email: Info@Alzamend.com or call: 1-844-722-6333 Source: Alzamend Neuro, Inc. Released December 18, 2024

临床2期疫苗临床结果

2024-11-19

·Business Wire

Alzamend Neuro Announces Full Data Set from its Nonclinical Study: Comparing Brain and Plasma Lithium Exposures between AL001 and Lithium Carbonate in Alzheimer’s Transgenic Mice

ATLANTA--( BUSINESS WIRE )-- Alzamend Neuro, Inc. (Nasdaq: ALZN) (“ Alzamend ”), a clinical-stage biopharmaceutical company focused on developing novel products for the treatment of Alzheimer’s disease (“ Alzheimer’s ”), bipolar disorder (“ BD ”), major depressive disorder (“ MDD ”) and post-traumatic stress disorder (“ PTSD ”), today announced that it has finished analyzing the final full data set from a nonclinical study comparing brain and plasma lithium exposures between AL001 and lithium carbonate in Alzheimer’s transgenic mice. The study was conducted at the University of South Florida and the bioanalytical procedures for determination of lithium concentration in the brain and plasma samples were conducted under good laboratory practice standards by Sannova Analytical LLC. The study involved administering AL001, a good manufacturing practices-quality active pharmaceutical ingredient (“ API ”) to 5XFAD mice, a recognized model for Alzheimer’s research, to compare its effects against lithium carbonate, a U.S. Food and Drug Administration (“ FDA ”) approved and marketed API. Mice received either high or low doses scaled to humans of both AL001 and lithium carbonate over a 14-day period to observe pharmacokinetic steady-state drug conditions. On the 15th day, the mice were analyzed to assess how the treatments affected lithium concentrations in different brain regions and in their plasma. Key Findings : No Undue Adverse Effects: Both treatments had no negative impact on the mice's body weight or clinical signs during the treatment period. Reduced Systemic Exposure: AL001 showed lower plasma lithium levels than lithium carbonate, reducing the risk of adverse systemic effects, suggesting an expansion for safety of lithium’s therapeutic index. Enhanced Brain Penetration: AL001 showed consistently higher lithium concentrations in brain tissues, particularly at lower doses, compared to lithium carbonate. Targeted Brain Structures: The study found that different brain regions absorb and retain lithium differently. This means treatments can potentially be tailored to target specific brain areas, allowing for more precise treatment of various brain-related conditions when applied in human studies. Clinical Implications: These results highlight the potential clinical advantages of AL001 for conditions like Alzheimer’s, BD, MDD and PTSD at low doses. By reducing the systemic burden, AL001 could lessen the risk of side effects such as thyroid and kidney complications often associated with extant lithium therapies. This positions AL001 as a promising candidate for safer long-term treatment options, without the need for routine blood lithium monitoring. This innovation is specifically designed to address the needs of fragile populations, such as elderly and Alzheimer’s patients, by offering a potentially more efficient and safer alternative to existing treatments. “This is a major step towards potentially providing an important treatment innovation for the 43+ million Americans afflicted with Alzheimer’s, BD, MDD and PTSD. These results demonstrated the potential of AL001 to enhance brain-specific lithium delivery while minimizing systemic exposure in an Alzheimer’s disease mouse model, guiding development of enhanced lithium effectiveness and safety in human diseases,” said Stephan Jackman, Chief Executive Officer of Alzamend. “We appreciate the extraordinary efforts of our colleagues and partners. We look forward to further evaluating AL001 in five ‘Lithium in Brain’ Phase II clinical trials in healthy subjects and patients diagnosed with mild to moderate Alzheimer’s, BD, MDD and PTSD, in partnership with Massachusetts General Hospital at the dosing level observed to be appropriate in this nonclinical study.” About Alzamend Neuro Alzamend is an early clinical-stage biopharmaceutical company focused on developing novel products for the treatment of Alzheimer’s, BD, MDD and PTSD. Our mission is to rapidly develop and market safe and effective treatments. Our current pipeline consists of two novel therapeutic drug candidates, AL001 - a patented ionic cocrystal technology delivering lithium via a therapeutic combination of lithium, salicylate, and L-proline, and AL002 - a patented method using a mutant-peptide sensitized cell as a cell-based therapeutic biologic vaccine that seeks to restore the ability of a patient’s immunological system to combat Alzheimer’s. Both of our product candidates are licensed from the University of South Florida Research Foundation, Inc. pursuant to royalty-bearing exclusive worldwide licenses. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as “believes,” “plans,” “anticipates,” “projects,” “estimates,” “expects,” “intends,” “strategy,” “future,” “opportunity,” “may,” “will,” “should,” “could,” “potential,” or similar expressions. Statements that are not historical facts are forward-looking statements. Forward-looking statements are based on current beliefs and assumptions that are subject to risks and uncertainties. Forward-looking statements speak only as of the date they are made, and Alzamend undertakes no obligation to update any of them publicly in light of new information or future events. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors. More information, including potential risk factors, that could affect Alzamend’s business and financial results are included in Alzamend’s filings with the U.S. Securities and Exchange Commission. All filings are available at www.sec.gov and on Alzamend’s website at www.Alzamend.com .

疫苗临床2期临床结果

2024-10-16

·贵州医科大学

国际首次！贵州医科大学谭俊教授团队发现全新小分子USP11抑制剂用于阿尔茨海默病治疗

阿尔茨海默症（Alzheimer’s disease，AD）是一种进行性神经退行性疾病，主要病理学特征由细胞外淀粉样蛋白-β（Amyloid β, Aβ）沉积形成的老年斑（Senile plaques, SP）和神经元细胞内高度磷酸化tau聚集形成的神经纤维缠结（Neurofibrillary tangles, NFTs）构成。这两种病理蛋白在脑内的异常积累与突触功能障碍、神经元死亡和AD认知缺陷密切相关。因此靶向上述蛋白及其病理机制开发疾病修饰（disease-modifying）治疗药物一直是AD领域的研究热点。 2022年发表的Cell文章发现，X染色体相关的泛素特异性肽酶11（Ubiquitin-specific protease 11，USP11）的高表达会促进 tau 的去泛素化和稳定性，从而阻止 tau 蛋白的正常清除，加速 tau 的病理性聚集，导致 AD 小鼠的认知功能障碍。USP11基因敲除后，能够显著改善AD小鼠的tau病变和认知功能的受损。因此抑制USP11介导的tau去泛素化进而改善AD病理有望为AD治疗提供全新的策略。目前已知的 USP11 小分子抑制剂主要是米托蒽醌，主要用于治疗急性髓系白血病等多种恶性肿瘤。但由于水溶性差、长期使用有较为严重的药物不良反应，尤其是在老年、合并症多的患者中出现特别的心脏毒性，因此难于在临床上推广应用于老年AD患者。为此，安全有效的新型小分子USP11抑制剂的研发仍然亟待解决。历经四年，贵州医科大学谭俊教授团队与大连医科大学附属第一医院李崧研究员合作通过大量的筛选优化得到了全新结构的小分子USP11选择性抑制剂IsoLiPro（尼布林），并利用多种转基因AD动物模型反复进行实验，在国际上首次明确了其临床前抗AD的作用。这一研究结果，不仅有助于我们全面了解AD的发病机制，同时也为AD新药开发开辟了全新的方向，并对其它以USP11为靶点的临床疾病的治疗产生了重要影响。据了解，全新小分子USP11抑制剂已经由谭俊教授团队成立的新药研发公司——安域生物科技（杭州）有限公司进行产业化的开发应用，预计在2024年底或2025年初在中国开展临床试验。 2024年10月，贵州医科大学/浙大城市学院谭俊教授团队和大连医科大学附属第一医院李崧研究员合作在EMBO Molecular Medicine杂志在线发表了题为“Targeting USP11 regulation improvesneuropathologies and cognition in Alzheimer transgenic mice”的研究文章。该研究在国际上首次明确了小分子USP11抑制剂能够通过增加tau蛋白泛素化，促进其降解清除，从而改善AD病理和认知损害，发挥抗AD作用。这一研究发现为开发新的AD治疗策略提供了全新的靶标。同时，全方位探索了尼布林作为新药在长期应用中的毒副作用以及药代学特征，结果表明，尼布林具有低的毒性且具有较好的动力学特征，为后续的临床研究提供基础。（拓展阅读：谭俊课题组往期进展，详见“逻辑神经科学”报道（点击阅读）：CMLS︱贵州医科大学谭俊团队合作揭示淀粉样前体蛋白N端通过调控胞外tau蛋白跨膜转运加剧阿尔茨海默病tau病理的机制；Transl Psychiatry︱浙江大学谭俊团队合作发现淀粉样前体蛋白促进SARS-CoV-2入侵并加剧阿尔茨海默病风险） 1、尼布林的合成与表征图1 Synthesis and characterization of IsoLiPro. 将等摩尔量的异丁酸锂（LiIB）和L-脯氨酸（Pro）在正丁醇中加热回流，搅拌约3 h后自然冷却结晶，收集产生的晶体并对其进行了结构解析和性质表征（图1）。XRPD、1H-NMR、FT-IR等多种分析技术均证明，尼布林是一种结构稳定的配位化合物。 2、IsoLiPro 在体外和体内均可显著降低 USP11 蛋白水平为了进一步探索尼布林对USP11的抑制效果，课题组在SH-SY5Y细胞和HEK293细胞中筛选多种小分子药物和尼布林对细胞中USP11的抑制作用，结果表明尼布林对USP11 的抑制效果最明显，且能够时间和剂量依赖性降低SH-SY5Y细胞的USP11表达水平，同时这一抑制作用具有USP11选择性。在体内研究中，9.5月龄的3xTg-AD小鼠灌胃给药尼布林4月后，尼布林对USP11蛋白水平也有相同的抑制作用，其海马和皮层区域的USP11表达水平均显著降低（图2）。图2 IsoLiPro markedly decreases USP11 protein level inSH-SY5Y cells and the mice brain 3、IsoLiPro 显着增加 HEK293-hTau 细胞中的 tau 泛素化水平为了进一步探讨尼布林加速tau蛋白清除的机制，课题组通过免疫沉淀（IP）结合液相色谱-质谱联用技术（LC-MS/MS）对tau蛋白的泛素化进行了分析。实验结果表明，尼布林处理HEK293-hTau细胞后，tau蛋白的K48泛素化水平显著升高（图3）。这一结果进一步提示，尼布林能够通过降低USP11表达，抑制tau蛋白的去泛素化，从而增加其降解清除，最终降低总tau和磷酸化tau水平。图3 IsoLiPro alters tau ubiquitination levels inHEK293-hTau cells. 4、尼布林显著缓解AD 转基因小鼠模型大脑中的病理变化，并改善认知功能障碍在上述细胞水平实验的基础上，课题组进一步利用3xTg-AD和5xFAD两种转基因AD动物模型，评估了尼布林对tau病理的影响。研究人员发现，9.5月龄的3xTg-AD小鼠和10周龄的5xFAD小鼠口服尼布林后，大脑中的总tau蛋白和磷酸化tau蛋白（p-tau181, p-tau202/205和p-tau396）显著降低。同时，尼布林还能显著降低 5xFAD 小鼠脑组织海马区的Iba1和 GFAP 水平，表明尼布林能够改善胶质细胞激活和神经炎症反应。意外的是，尼布林给药后不仅显著改善 tau 病理和神经炎症，还能显著降低脑内Aβ水平和斑块沉积，这一结果可能与尼布林通过抑制USP11表达，参与BACE1泛素化和降解以及 Li 对 GSK-3β 激酶的活性降低有关。除了tau病理、神经炎症和Aβ 病理斑块外，课题组的研究结果还发现尼布林长期给药后能够增加突触标志物SYN-1和PSD95蛋白的表达，并显著提高神经元树突棘密度和数量，表明尼布林能够显著改善AD模型动物的神经突触可塑性（图4）。Morris水迷宫和Y迷宫实验结果表明，与对照组相比，经过尼布林治疗的实验动物展示出更好的行为表现。此外，除了验证了尼布林对缓解AD病变作用及机制进行研究外，还对其毒性以及药代等试验结果进行了评估。结果表明，尼布林在长期给药过程中未发现明显的毒性反应。与碳酸锂相比，到达大脑中的锂浓度更高，具有较好的药代学特征，。这些均为尼布林的临床研究提供更进一步的基础。图4 IsoLiPro ameliorates synaptic plasticity deficits andspatial memory impairment 图5 尼布林抗AD作用机制示意图文章结论与讨论，启发与展望本研究首次在体内和体外模型中证实了尼布林能够有效降低USP11蛋白水平。机制研究表明，这一作用主要通过调节USP11的蛋白质降解途径实现，而非直接影响其酶活性。通过降低USP11的蛋白水平，尼布林能够增强tau蛋白的泛素化，从而加速其降解，改善AD转基因动物模型中的病理特征。这些结果揭示了USP11作为阿尔茨海默病（AD）治疗潜在靶点的重要性，并为通过抑制USP11蛋白水平治疗AD提供了新思路（图5）。然而，本研究也存在一些值得进一步探索的问题。首先，虽然本研究表明尼布林能够调控USP11蛋白降解，但要准确反映其在体内的作用机制，还需要进一步定量分析尼布林在大脑中的分布和浓度。通过明确其剂量-反应关系，可以更加精准地评估尼布林的有效剂量范围，优化治疗方案。此外，未来的研究应进一步聚焦尼布林与USP11在体内尤其是大脑中的直接相互作用，以揭示更为精准的分子机制。结合这些信息，我们的研究将能够为尼布林作为AD治疗药物提供更强的基础理论支持，并有助于开发相关疾病中基于USP11的靶向治疗策略。原文链接：https://www.embopress.org/doi/full/10.1038/s44321-024-00146-7 本文共同通讯作者：谭俊博士，贵州医科大学特聘教授；李崧博士，大连医科大学附属第一医院神经疾病研究所研究员。本文第一作者为贵州医科大学郭义博士。来源：逻辑神经科学作者：郭义李崧编辑：李菡逸一审：李牧二审：钱禾三审：陈颖往期回顾 RECENTLY RELEASED 贵州医科大学2025年硕士研究生招生章程及专业目录贵州医科大学2025届毕业生冬季校园招聘会邀请函探索校园 | 从临床医学院“协和楼”，探寻中式建筑之美贵州医科大学版权所有期待投稿合作邮箱：gmctougao@163.com

临床结果临床研究

100 项与碳酸锂相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D00801	碳酸锂	N05AN01	DB14509

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适应症	国家/地区	公司	日期
躁郁症1型	美国	Hikma Pharmaceuticals USA, Inc.	1982-01-29
躁郁症	美国	ANI Pharmaceuticals, Inc.	1979-04-27

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适应症	最高研发状态	国家/地区	公司	日期
克莱恩-莱文综合征	临床前	欧盟	Laboratoires Delbert SAS	2023-08-16

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASN2022	N/A	肾性尿崩症	-	Lithium Carbonate 300 mg	簾夢鹹蓋構顧淵餘壓觸(壓蓋構遞鏇鏇淵艱選鹹) = 鑰繭淵鬱鹽願襯繭鹽繭廠膚選繭窪膚艱艱遞網 (製簾憲築築鑰選蓋鑰艱 )	-	2022-11-06
ASN2022	N/A	肾性尿崩症	-	Thiazide diuretic	簾夢鹹蓋構顧淵餘壓觸(壓蓋構遞鏇鏇淵艱選鹹) = 艱壓廠鏇蓋憲積簾鏇襯廠膚選繭窪膚艱艱遞網 (製簾憲築築鑰選蓋鑰艱 )	-	2022-11-06
ISN WCN2022	N/A	中毒 \| 间质性肾炎	-	Lithium carbonate 900 mg/day	獵糧鑰觸夢製憲膚餘繭(淵鏇醖簾範膚鑰窪淵鬱) = The diagnosis of chronic interstitial nephritis was made based on suggestive clinical and biological signs 淵鹽簾窪選構築夢餘淵 (窪糧淵憲衊顧鑰築膚衊 )	-	2022-02-01
ISN WCN2022	N/A	中毒 \| 间质性肾炎	-	No lithium therapy		-	2022-02-01
ENDO2021	N/A	甲状腺功能亢进症 \| 粒细胞减少症一线	-	Methimazole	夢網積範繭齋壓廠艱網(艱蓋鏇齋蓋糧網餘鹽憲) = 顧鑰窪積鏇壓齋鏇範製繭觸積糧鹽淵顧膚壓觸 (壓襯淵觸憲製膚淵餘齋 ) 更多	-	2021-05-03
ENDO2021	N/A	甲状腺功能亢进症 \| 粒细胞减少症一线	-	Lithium Carbonate	夢網積範繭齋壓廠艱網(艱蓋鏇齋蓋糧網餘鹽憲) = 淵簾膚膚餘範艱選廠蓋繭觸積糧鹽淵顧膚壓觸 (壓襯淵觸憲製膚淵餘齋 )	-	2021-05-03
NCT02918097 (CTgov)	临床4期	躁郁症	78	Lithium Carbonate+Risperidone+Nortriptyline+Sertraline	窪觸淵獵積遞餘顧遞鬱(齋襯鏇淵齋繭艱淵觸鑰) = 築鏇鹽遞構鏇艱獵鹹餘衊觸鬱獵鑰範獵觸膚繭 (齋遞艱製顧選廠範願積, 齋淵窪壓蓋艱範範觸窪 ~ 願積壓淵鑰構鑰願襯壓) 更多	-	2020-10-14
NCT01820624 (Pubmed) 人工标引	临床1期	急性髓性白血病	9	lithium carbonate+tretinoin	(簾夢壓憲壓憲構廠範構) = 積鹽鏇鏇構範蓋壓顧獵鑰膚淵廠夢遞淵製積願 (衊選構選構繭蓋鏇顧獵 )	不佳	2020-03-10
NCT01553916 (CTgov)	临床1/2期	小细胞肺癌	19	Prophylactic cranial irradiation+Lithium Carbonate	醖壓鏇壓齋糧壓觸壓範(製窪鬱衊網繭積淵觸糧) = 獵遞鹽餘鹹醖鑰簾鹽簾齋壓鬱積網淵膚壓構蓋 (艱鏇鬱夢憲齋鬱醖醖獵, 齋襯憲餘廠遞簾壓鑰壓 ~ 窪鹹蓋壓襯製膚餘築鏇) 更多	-	2017-11-08
NCT00501540 (CTgov)	临床2期	神经内分泌肿瘤	15	Lithium Carbonate	(壓繭廠衊遞顧艱構積獵) = 製壓夢膚鬱獵鏇醖獵鏇範壓壓築鹹壓鬱淵膚積 (鏇膚製襯網齋顧窪廠艱, 膚艱衊遞壓淵鬱築糧鏇 ~ 窪鑰鑰蓋積鏇壓窪遞獵) 更多	-	2017-05-03
NCT00408681 (GVHD, CTgov)	N/A	复发性急性髓细胞白血病 \| 复发性边缘区淋巴瘤 \| 妊娠滋养细胞疾病 \| 成人急性髓性白血病 \| 伯基特淋巴瘤 \| BCR/ABL阴性非典型性慢性髓系白血病 \| 难治性成人急性淋巴细胞白血病 \| 加速期慢性骨髄性白血病 \| 复发性霍奇金淋巴瘤 \| 继发性骨髓增生异常综合征 \| 毛细胞白血病 \| 幼年型骨髓单核细胞白血病 \| 多发性骨髓瘤 \| 原发性皮肤间变性大细胞淋巴瘤 \| 塞扎里综合征 \| 难治性慢性淋巴细胞白血病 \| 慢性嗜酸性粒细胞白血病 \| 小淋巴细胞淋巴瘤 \| 原发性骨髓纤维化 \| 淋巴母细胞淋巴瘤 \| 3型乳腺癌 \| 慢性期慢性髓性白血病 \| 急性移植物抗宿主病 \| 复发性成人急性淋巴细胞白血病 \| 肾母细胞瘤 \| 并发症 \| 慢性粒单核细胞白血病 \| 弥漫性大B细胞淋巴瘤 \| 卵巢生殖细胞癌 \| 急性转化期慢性粒细胞性白血病 \| 复发性套细胞淋巴瘤 \| 睾丸生殖细胞肿瘤 \| 急性早幼粒细胞白血病 \| 复发性 B 细胞急性淋巴细胞白血病 \| 小儿横纹肌肉瘤 \| 复发性卵巢癌 \| 复发性神经母细胞瘤 \| 未经治疗的小儿急性非淋巴细胞白血病 \| 慢性中性粒细胞白血病 \| 免疫母细胞大细胞淋巴瘤 \| 伴有 11q23 异常的急性髓系白血病 \| 复发性 3a 级滤泡性淋巴瘤 \| 转移性乳腺癌 \| 小儿淋巴母细胞非霍奇金淋巴瘤 \| 卵巢上皮癌 \| II 期非连续成人弥漫性小裂细胞淋巴瘤	20	laboratory biomarker analysis+lithium carbonate	製觸膚鏇鬱醖糧構衊夢(範淵廠蓋繭鏇願鹽壓廠) = 窪蓋艱齋壓獵糧鏇積築蓋鏇願積簾餘廠窪餘鹹 (夢觸遞膚蓋製衊築鹹齋, 憲鑰製壓壓壓蓋顧膚壓 ~ 餘範願夢膚淵網鑰鑰築)	-	2017-01-20
NCT00582712 (CTgov)	临床2期	甲状腺髓样癌	5	Lithium carbonate	蓋壓窪齋鏇築顧範淵網(範膚壓遞壓壓艱鏇艱觸) = 願淵齋窪齋鏇衊鑰糧餘獵襯鑰積構築製衊衊構 (願窪網夢範築選艱鑰構, 衊糧廠繭鹹憲襯遞餘夢 ~ 壓獵製繭遞積繭鑰獵蓋) 更多	-	2016-12-12
NCT00240110 (CTgov)	临床1/2期	可卡因相关疾病 \| 躁郁症	152	Lithium Carbonate+Placebo (Lithium Carbonate Add on Placebo)	蓋觸襯鬱鏇構夢網齋齋(鹽鬱餘憲築餘齋齋鏇鹽) = 築鹹觸廠衊艱鹹鏇鏇鬱廠艱膚艱繭夢構獵鬱淵 (獵齋淵製壓網壓構顧淵, 膚夢襯製餘餘鹽築廠夢 ~ 願遞廠壓憲鹽蓋積夢淵) 更多	-	2016-10-17
NCT00240110 (CTgov)	临床1/2期	可卡因相关疾病 \| 躁郁症	152	Lithium Carbonate+Valproate (Lithium Carbonate Add on Valproate)	蓋觸襯鬱鏇構夢網齋齋(鹽鬱餘憲築餘齋齋鏇鹽) = 艱築餘淵鬱憲餘夢夢鑰廠艱膚艱繭夢構獵鬱淵 (獵齋淵製壓網壓構顧淵, 壓顧廠築窪窪鏇壓蓋繭 ~ 壓遞積衊製範顧鏇蓋壓) 更多	-	2016-10-17