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SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small molecules to increase levels of functional SMN protein. Compound 2was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients. It was safe and well tolerated and increased SMN protein levels up to 2-fold in patients. Nevertheless, its development was stopped as a precautionary measure because retinal toxicity was observed in cynomolgus monkeys after chronic daily oral dosing (39 weeks) at exposures in excess of those investigated in patients. Herein, we describe the discovery of 1(risdiplam, RG7916, RO7034067) that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is undergoing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages with SMA.

We appreciate the comment by Palma on our research.1The presence of serum AAV2 neutralizing antibodies (nAbs) was determined using a validated ELISA method at baseline and then at 1-, 3-, 6-, and 12-month postinfusion of AAV2-AADC gene therapy. At baseline, all treated participants met the inclusion criterion with nAb ≤1:1,200 and 11 participants (73%) had nAb below the lower limit of detection. Twelve months after administration of VY-AADC01, most participants (12, 80%) developed nAb at titers ranging from 1:57 to 1:7,273, whereas 2 participants from cohort 1 and 1 participant from cohort 2 had no detectable nAb. Peak titers appeared at 6 months with either stable or lower titers at 12 months. Neither the presence of preexisting nAb above the detection limit nor an increase in nAb titer from baseline precluded an increase in 6-[18F]fluoro-l-dopa uptake ratio after administration of VY-AADC01. These findings, along with the clinical stability of these participants over the 3-year study, suggest that an inflammatory response to AAV2 did not affect AADC gene expression.

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18–45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=−0.8, p=0.03) and fear (ES=−0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=−0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. ClinicalTrials.gov identifier: NCT01474278 A Study of RO5028442 in Adult Male High-Functioning Autistic Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT01474278

We appreciate the comment by Kang et al. on our research.1While we acknowledge findings of toxicity in a mouse model of elevated cellular dopamine due to overexpression of the dopamine transporter,2such toxicity has not been observed in rodent or primate models of Parkinson disease (PD) in which the aromatic L-amino acid decarboxylase (AADC) gene therapy was tested.3,4Moreover, in our observations of these participants 3 years after AADC therapy,1we did not see evidence of significant clinical worsening, which would be expected if the AADC gene therapy was causing injury to medium spiny neurons.

Rare genetic diseases that affect behavior and cognition provide a unique opportunity to study the mechanisms of neurodevelopmental disorders through the examination of animal models, which can lead to development of hypotheses and treatments testable in human beings. Rett syndrome (RTT) and tuberous sclerosis complex (TSC) are both Mendelian disorders that present with autism, epilepsy, and intellectual disability, in which animal model work has been directly translated into clinical treatment trials currently underway. Here, we review the recent advances in our understanding of RTT and TSC pathogenesis and signaling pathways that may be targeted for novel treatments.

Contiguous arrays of yeast artificial chromosomes (YACs) extending from proximal heterochromatic Yq into the pseudoautosomal portion of the Y chromosome and separated by a small interval at the centromere have been constructed. A total of 97 YACs have been aligned along the Y chromosome by STS content analysis using 222 sequence tagged sites (STSs) that detect 263 loci. Forty-five of the STSs used are novel. Their inclusion provides a significant improvement over previously available maps on the density of STS coverage along the Y chromosome, reducing the average spacing to 120 kb assuming a length of 30 Mb for the euchromatin. The average size of 61 YACs determined by pulsed-field gel electrophoresis analysis was at least 0.9 Mb. Minor differences noted between the ordering of STSs on this map compared with those previously reported may be attributed to inherent polymorphism between the Y chromosomes used to construct the YAC libraries. Copyright 1994, 1999 Academic Press

In the VANILLA phase 2 clinical trial, balovaptan treatment resulted in improved adaptive behaviors in adult men with autism.

Taher: Ionis Pharmaceuticals: Consultancy; Celgene Corp.: Research Funding; La Jolla Pharmaceutical: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Protagonist Therapeutics: Consultancy. Viprakasit:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Agios: Consultancy, Research Funding. Cappellini:Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Vifor: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Kraus:F. Hoffmann-La Roche Ltd: Employment. Cech:F.Hoffmann-La Roche Ltd: Employment. Dietmar:F. Hoffmann-La Roche Ltd: Employment. Winter:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mazer:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Nave:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Dukart:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Schaedeli Stark:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Koerner:F. Hoffmann-La Roche Ltd: Employment. Khwaja:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Hermosilla:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership.

Beta-thalassemia is a hereditary blood disorder characterized by reduced or absent synthesis of the beta-globin chain, one of the major components of adult hemoglobin (Hb). The unbalanced synthesis of globin chains leads to a relative excess of alpha-globin and heme, resulting in hemichrome-induced cellular damage in bone marrow erythroblasts and circulating erythrocytes. This, in turn, contributes to ineffective erythropoiesis, hemolysis and reduced red blood cell (RBC) survival, hallmarks of beta-thalassemia. We have previously reported that reduction in cellular heme synthesis by bitopertin, an oral, reversible, potent and selective glycine transporter 1 (GlyT1) inhibitor, positively impacts the disease pathology in a beta-thalassemia mouse model. It was hypothesized that reduced heme synthesis down-regulates globin production and as such diminishes the alpha-chain excess, driving the observed improvements in Hb, hemolysis and RBC survival in beta-thalassemia mice.

This corrects the article DOI: 10.1038/npp.2016.232

Brugnara: F. Hoffmann-La Roche Ltd, Basel, Switzerland: Consultancy. Harmeier:F. Hoffmann-La Roche Ltd, Basel, Switzerland: Employment. De Franceschi:F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding. Matte:F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding. Winter:F. Hoffmann-La Roche Ltd, Basel, Switzerland: Employment. Koerner:F. Hoffmann-La Roche Ltd, Basel, Switzerland: Employment. Khwaja:F. Hoffmann-La Roche Ltd, Basel, Switzerland: Employment. Singer:F. Hoffmann-La Roche Ltd, Basel, Switzerland: Employment. Beneduce:Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding. Federti:Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding. Siciliano:Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding.

The unbalanced hemoglobin chain synthesis in beta-thalassemias leads to hemichrome-induced damage that contributes to ineffective erythropoiesis, hemolysis and reduced red cell survival. Iron overload related to ineffective erythropoiesis and abnormally low Hepcidin (Hamp), combined with the cytotoxic effects of free heme with free-alpha-chains play a key role in the increased generation of reactive oxygen species (ROS) in beta thalassemias.[2][HA{3] Here we used a specific and selective inhibitor of the plasma membrane expressed glycine transporter GlyT1 (Ro4917838). Use of Ro4917838 has been associated with a dose-dependent decrease in MCH, Hb, soluble transferrin receptor, and increase in absolute reticulocytes and RBC counts in several animal species, attributed to reduce glycine bioavailability in erythroblasts and decreased heme synthesis. In rats, Ro4917838 reduces heme synthesis, and down-regulates erythroid transferrin receptor, but does not interfere with hepcidin regulation and systemic iron homeostasis (Winter et al. Exp Hematol, DOI: 10.1016/j.exphem.2016.07.003). We aimed to determine if reduced cellular availability of glycine in erythroblasts may reduce heme synthesis, and impact pathologic erythropoiesis in a mouse model for b-thalassemia. Wild-type control (WT) C57B6/2J, and beta-thalassemia Hbbth3/+ mice were treated with either vehicle or Ro4917838 at dosages of 3, 10, 30 mg/kg/d administered over 4 weeks once daily by gavage. [6]RO4917838 administration was associated with significant improvements of central hallmarks of the b-thalassemia pathology. Reduced erythrocyte destruction was seen bydemonstrated by [8][WM{9]as significant improvements in erythrocyte morphology and amelioration of hemoglobin reduction in reticulocytes. We also observed an impressively quick reduction of the circulating erythroblast count within 1 week of initiating treatment. This was also associated with decreased hemolysis biomarkers. Ro4917838 induced a significant reduction in extramedullary erythropoiesis and reduction in orthochromatic erythroblasts as well as insoluble alpha chain aggregates in circulating red cells. Red cell survival of b-thal mice treated with 30 mg/kg/day Ro4917838 significantly increased by more than 50%. CD71+ erythroid precursors significantly decreased in WT mice treated with Ro4917838 at 30 mg/kg and in b-thal mice at the dosage of 30 mg/kg/ d. [10]These data suggest that Ro4917838 ameliorates anemia in a b-thalassemia mouse model and positively affects ineffective erythropoiesis and red cell survival in peripheral circulation. Ro4917838 may represent a novel therapeutic approach for the treatment of anemia in b-thalassemia patients. [1] I do see the point for beta-thalassemia, but this does not apply for all thalassemias, I mean the free alpha chains. The ROS yes, they have in common. In this sentence it seems to be that the alpha chains are culprit for ROS in all thalassemias. [HA{3]I do see the point for beta-thalassemia, but this does not apply for all thalassemias, I mean the free alpha chains. The ROS yes, they have in common. In this sentence it seems to be that the alpha chains are culprit for ROS in all thalassemias. ROS was not measured, therefore I would refrain mentioning it. No data is shown. [HA{5]ROS was not measured, therefore I would refrain mentioning it. No data is shown. I propose deletion of the PK info. Although the information is correct I don't think this is the level of detail needed for the abstract. It may even be confusing as it is not the focus of the abstract to do a cross species comparison. [AK7]I propose deletion of the PK info. Although the information is correct I don't think this is the level of detail needed for the abstract. It may even be confusing as it is not the focus of the abstract to do a cross species comparison. Dosing and dosing frequency is already described above, we do not need to repeat this here. [WM{9]Dosing and dosing frequency is already described above, we do not need to repeat this here. Was the liver expression determined or the serum Hepcidin levels measured? I would rephrase it if latter is the case. [HA{11]Was the liver expression determined or the serum Hepcidin levels measured? I would rephrase it if latter is the case.