The National Institute of Neurological Disorders and Stroke (NINDS) established the Spinal Muscular Atrophy (SMA) Project as a means to accelerate the development of therapeutic candidates for SMA. The project presented a new drug candidate which showed an increase in SMN protein levels and in vitro testing showed that the compound had a relatively good brain penetration.
Early on, the SMA Project decided to focus on small molecule drugs, rather than gene therapy, stem cells or biologics. Indoprofen was chosen as the starting point for a medicinal chemistry program after a systematic review of FDA approved drugs that had demonstrated activity in SMA-relevant assays and models. Previous studies, as part of the NINDS-sponsored Drug Screening Consortium, had shown that indoprofen could significantly increase SMN expression in a human reporter gene assay and in fibroblast cells derived from SMA patients. In addition, the increase in expression observed with indoprofen treatment translated into improved in utero survival in a very severe mouse model of SMA.
Over a 5-year-period, the SMA Project synthesized and screened more than 1,400 analogs of indoprofen. Of the compounds screened in tier 1 assays, over 150 were selected for further characterization and advanced to the next tier of the testing funnel. This included several assays to measure increases in SMN protein levels in patient fibroblasts, and assessments of compound bioavailability, genotoxicity and safety profiles.
Among the indoprofen series of compounds, one analog in particular, ALB-111, emerged as a potential drug candidate for SMA. After two key in vitro assays had shown that ALB-111 could increase cellular SMN protein levels, and the compound was shown to have relatively good brain penetration, ALB-111 was tested in vivo in two different SMA mouse models, the moderately affected C/C mice and Arthur Burghes' more severely affected delta7 mice. The SMA voluntary organizations had played a key role in the development of these two SMA animal models. Significant increases in SMN protein levels were observed in the liver and—to a lesser extent—the brain of C/C mice treated with ALB-111 for 15 days.
SMA Project researchers at PsychoGenics performed a hind-limb strength test on delta7 mice and observed a significant improvement in animals treated with ALB-111 compared to controls in three of four trials. Treatment with ALB-111 did not, however, alter body weight, survival or gravitationally directed movement in these severely affected SMA mice, which have an average lifespan of only about 12 days. SMA Project researchers also conducted toxicity and pharmacokinetic analyses of ALB-111 and found that the compound has good drug and safety properties, and could be delivered orally to patients. The main hurdle of ALB-111 has been its limited solubility. A consultant of the SMA Project recently devised a formulation approach to improve the solubility and oral availability of the compound. ALB-111 is now at the late lead compound stage of the preclinical drug development process.
Read their whole report at NINDS website.
Early on, the SMA Project decided to focus on small molecule drugs, rather than gene therapy, stem cells or biologics. Indoprofen was chosen as the starting point for a medicinal chemistry program after a systematic review of FDA approved drugs that had demonstrated activity in SMA-relevant assays and models. Previous studies, as part of the NINDS-sponsored Drug Screening Consortium, had shown that indoprofen could significantly increase SMN expression in a human reporter gene assay and in fibroblast cells derived from SMA patients. In addition, the increase in expression observed with indoprofen treatment translated into improved in utero survival in a very severe mouse model of SMA.
Over a 5-year-period, the SMA Project synthesized and screened more than 1,400 analogs of indoprofen. Of the compounds screened in tier 1 assays, over 150 were selected for further characterization and advanced to the next tier of the testing funnel. This included several assays to measure increases in SMN protein levels in patient fibroblasts, and assessments of compound bioavailability, genotoxicity and safety profiles.
Among the indoprofen series of compounds, one analog in particular, ALB-111, emerged as a potential drug candidate for SMA. After two key in vitro assays had shown that ALB-111 could increase cellular SMN protein levels, and the compound was shown to have relatively good brain penetration, ALB-111 was tested in vivo in two different SMA mouse models, the moderately affected C/C mice and Arthur Burghes' more severely affected delta7 mice. The SMA voluntary organizations had played a key role in the development of these two SMA animal models. Significant increases in SMN protein levels were observed in the liver and—to a lesser extent—the brain of C/C mice treated with ALB-111 for 15 days.
SMA Project researchers at PsychoGenics performed a hind-limb strength test on delta7 mice and observed a significant improvement in animals treated with ALB-111 compared to controls in three of four trials. Treatment with ALB-111 did not, however, alter body weight, survival or gravitationally directed movement in these severely affected SMA mice, which have an average lifespan of only about 12 days. SMA Project researchers also conducted toxicity and pharmacokinetic analyses of ALB-111 and found that the compound has good drug and safety properties, and could be delivered orally to patients. The main hurdle of ALB-111 has been its limited solubility. A consultant of the SMA Project recently devised a formulation approach to improve the solubility and oral availability of the compound. ALB-111 is now at the late lead compound stage of the preclinical drug development process.
Read their whole report at NINDS website.
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