Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Participants and Patient Stratification
2.2. Participant-Derived Lymphoblastoid Cell-Line Generation
2.3. Measurement of NADH Production in Participant-Derived LCLs
2.4. NADH Production Data Analysis
2.5. RNA-Seq Profiling from Patient Blood Samples
2.6. Differential Gene Expression Analysis
2.7. RNA-Seq Profiling of Sulforaphane, STP1, and Vehicle-Treated Cell Lines
2.8. Gene Set Enrichment Analyses
2.9. The Similarity between ASD-Phen1 and Relevant Drug Transcriptomic Signatures
3. Results
3.1. Clinical Validation and Prevalence of ASD-Phen1 Population
3.2. Metabolic Profile of LCLs from ASD-Phen1 versus ASD-Non-Phen1 and Control
3.3. Effect of Sulforaphane on the Metabolic Profile of LCLs from ASD-Phen1 versus ASD-Non-Phen1 and TD
3.4. Over-Activation of NF-κB and NRF2 as the ASD-Phen1-Specific Disease Transcriptomic Signature
3.5. STP1 as a Suitable Drug Candidate to Revert NF-κB and NRF2 Over-Activation in ASD-Phen1
3.6. Effect of Cyclic Adenosine Monophosphate on the Ability of ASD-Phen1 LCLs to Metabolize Glucose
4. Discussion
5. Conclusions
6. Patents
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Group | Overall Gender Distribution (N Males/N Females) | Mean Age at Time of Blood Draw for LCLs * (y.) (s.d.) | Mean Age at Time of Blood Draw for RNA-Seq (y.) (s.d.) | Mean Head Circumference (HC) Percentile (s.d.) |
---|---|---|---|---|
ASD-Phen1 | 18/2 | 7 (5.99) | 14 (7.53) | 89 (6.99) |
ASD-non-Phen1 | 18/1 | 6 (4.03) | 9 (5.14) | 32 (23.94) |
TD | 15/5 | 5 (1.57) | NA | NA |
Ensembl | Entrez | HGNC Symbol | baseMean | log2FC | p-Value | Padj |
---|---|---|---|---|---|---|
ENSG00000143546 | 6279 | S100A8 | 2339 | 2.02 | 8.2 × 10−8 | 0.001 |
ENSG00000138738 | 11107 | PRDM5 | 114 | 1.39 | 2.3 × 10−7 | 0.002 |
ENSG00000165480 | 221150 | SKA3 | 151 | 1.64 | 3.3 × 10−7 | 0.002 |
ENSG00000109674 | 55247 | NEIL3 | 423 | 1.54 | 4.5 × 10−7 | 0.002 |
ENSG00000116668 | 54823 | SWT1 | 495 | 1.07 | 3.0 × 10−6 | 0.010 |
ENSG00000163221 | 6283 | S100A12 | 587 | 1.67 | 4.1 × 10−6 | 0.012 |
ENSG00000196092 | 5079 | PAX5 | 453 | −1.02 | 1.3 × 10−5 | 0.030 |
ENSG00000232112 | 51372 | TMA7 | 71 | 1.70 | 1.4 × 10−5 | 0.030 |
ENSG00000140379 | 597 | BCL2A1 | 280 | 1.41 | 2.2 × 10−5 | 0.043 |
ENSG00000146278 | 10957 | PNRC1 | 3133 | 0.44 | 2.5 × 10−5 | 0.044 |
Transcriptomic Signatures | ESNRF2 | p-Value | ESNF-κB | p-Value |
---|---|---|---|---|
ASD-Phen1 vs. nonPhen1 | 0.21 | 5.6 × 10−9 | 0.24 | <1 × 10−9 |
patient STPT000248 | −0.08 | 0.10 | 0.11 | 0.01 |
patient STPT000247 | 0.05 | 0.7 | 0.19 | 1 × 10−6 |
sulforaphane (5 µM) | 0.30 | 5 × 10−16 | −0.18 | 2 × 10−10 |
commercial LCL treated with STP1 (5 µM) | −0.13 | 8 × 10−4 | −0.08 | 0.02 |
patient STPT000248 LCL treated with STP1 (5 µM) | −0.19 | 2 × 10−7 | −0.15 | 7 × 10−7 |
patient STPT000247 LCL treated with STP1 (5 µM) | −0.17 | 4 × 10−6 | −0.15 | 6 × 10−7 |
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Pérez-Cano, L.; Boccuto, L.; Sirci, F.; Hidalgo, J.M.; Valentini, S.; Bosio, M.; Liogier D’Ardhuy, X.; Skinner, C.; Cascio, L.; Srikanth, S.; et al. Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment. Biomedicines 2024, 12, 991. https://doi.org/10.3390/biomedicines12050991
Pérez-Cano L, Boccuto L, Sirci F, Hidalgo JM, Valentini S, Bosio M, Liogier D’Ardhuy X, Skinner C, Cascio L, Srikanth S, et al. Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment. Biomedicines. 2024; 12(5):991. https://doi.org/10.3390/biomedicines12050991
Chicago/Turabian StylePérez-Cano, Laura, Luigi Boccuto, Francesco Sirci, Jose Manuel Hidalgo, Samuel Valentini, Mattia Bosio, Xavier Liogier D’Ardhuy, Cindy Skinner, Lauren Cascio, Sujata Srikanth, and et al. 2024. "Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment" Biomedicines 12, no. 5: 991. https://doi.org/10.3390/biomedicines12050991