SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03117530

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Targeting Microglial Activation for Treatment of Autism Spectrum Disorder (ASD): A Proof-of-Concept, Target-Engagement Study

Autism spectrum disorders (ASD) are highly disabling, persistent neurodevelopmental disorders. There are no available treatments for core symptoms of ASD or biologically-based clinical biomarkers. Emerging evidence indicates that levels of brain inflammation are increased in ASD. In particular, recent work implicates hyperactivity of microglial cells, the resident immune cells of the brain. However, the functional consequences of microglial activation remain unknown. This study will measure microglial activation in ASD using positron emission tomography (PET) brain imaging. Adult males with ASD (n=15) and healthy controls (n=15) will be recruited for this study and undergo comprehensive clinical and behavioral baseline assessment. All subjects will then undergo baseline PET imaging using a radiotracer that labels activated microglia. Subjects with ASD will then undergo 12-week open label treatment with minocycline, an FDA-approved antibiotic thought to block microglial activation. PET imaging will be repeated at 12 weeks to confirm target engagement. A subset of control subjects will also undergo repeat PET imaging to determine test-retest reliability. During minocycline treatment, ASD subjects will be evaluated every 2 weeks for safety, clinical impression, behavioral functioning, and measures of cognition. Results will provide important information regarding the relationship between levels of brain inflammation, cognitive and behavioral function in ASD.

NCT03117530 Autism Spectrum Disorder
MeSH: Autistic Disorder Autism Spectrum Disorder Child Development Disorders, Pervasive Encephalitis
HPO: Autism Autistic behavior Encephalitis

1 Interventions

Name: Minocycline

Description: Following initial baseline PET-CT imaging and clinical evaluation, adults with ASD will undergo a 12- week open-label treatment trial of minocycline to be conducted at UCLA under supervision of the UCLA IRB. During weeks 1-6, ASD subjects will be treated with 50 mg minocycline twice daily (low dose). From weeks 7-12, dosing will be increased to 100mg twice daily (typical clinical dosage). Every two weeks during this phase, a treating clinician will measure vital signs, assess safety, record adverse effects, and monitor compliance. Compliance will be obtained as an index of tolerability and will assessed through weekly medication diaries and pill counts.

Type: Drug

Minocycline


Primary Outcomes

Measure: Evaluate differences in CNS microglial activation in adults with ASD versus healthy volunteers via in vivo CNS binding of [11C]-DAA1106

Time: Data will be collected at PET scan #1, which will take place during screening (Days -28 to 0) for the study

Measure: Evaluate the effect of 12-weeks of minocycline exposure on CNS microglial activation in adults with ASD by measuring change in [11C]-DAA1106 binding pre- and post- treatment

Time: Data will be collected at PET scan #1 (between days -28 and 0 before intervention) and at PET scan #2 during Week 12 of intervention

Secondary Outcomes

Measure: Effect of minocycline exposure on cognition across seven cognitive domains before and after low dose intervention and regular dose intervention as measured by MCCB (MATRICS Consensus Cognitive Battery) subdomain scores

Time: Data will be collected at baseline and during Weeks 6 and 12 of intervention

Measure: Effect of minocycline exposure on self-rated anxiety and emotion regulation as measured by ADAMS (Anxiety and Depression Mood Scale)

Time: Data will be collected at baseline and during Weeks 6 and 12 of intervention

Measure: Effect of minocycline exposure on peripheral inflammatory cytokine profiles as measured by DNA and RNA expression in blood samples

Time: Data will be collected PET #1 (week 0) and at PET scan #2 (Week 12)

Other Outcomes

Measure: Change in clinician-rated global improvement as measured by CGI

Time: Data will be collected at Screening Visit #1 (between days -28 and 0 before intervention) and at visits during Weeks 6 and 12 of intervention

Measure: Change in self-reported symptoms of ASD with minocycline treatment as measured by SRS-2

Time: Data will be collected at Screening Visit #1 (between days -28 and 0 before intervention) and at visits during Weeks 6 and 12 of intervention

Measure: Change in informant-reported symptoms of ASD with minocycline treatment as measured by ABC-CV

Time: Data will be collected at Screening Visit #1 (between days -28 and 0 before intervention) and at visits during Weeks 6 and 12 of intervention

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 rs6971

hepatic, neurologic, renal disease) to increase risk to the subject 3. Presence of severe behavioral disturbance likely to require initiation of treatment during the course of the protocol 4. Clinical judgment of the study physician of inability to perform the requirements of the study 5. Current or recent (past 30 days) treatment with minocycline or related compounds, immunosuppressives, or benzodiazepines 6. Homozygous genotype for minor allele of rs6971 7. History of recent febrile illness in past 30 days 8. History of allergic reactions to tetracycline antibiotics 9. Concomitant medication treatment not stable for the 4 weeks prior to study entry or anticipated to change 10.

hepatic, neurologic, renal disease) to increase risk to the subject 4. Presence of current or lifetime severe psychopathology potentially confounding assessment of TSPO binding (psychosis, severe depression, bipolar disorder, Obsessive-Compulsive Disorder) 5. Current prescribed medication likely to confound assessment of TSPO binding 6. Clinical judgment of the study physician of inability to perform the requirements of the study 7. Current or recent (past 30 days) treatment with minocycline or related compounds, immunosuppressives, benzodiazepines, or psychotropic medications likely to confound assessment of TSPO binding 8. Homozygous genotype for minor allele of rs6971 9. SRS-2 T-score score of >59 10.



HPO Nodes


HPO:
Autism
Genes 168
GABRB2 SOX2 MKRN3 SOX3 GABRD SNORD115-1 CACNA1A UBA5 CACNA1C ATP6V1A DPYD PIGL AARS HNF1B SATB2 MAGEL2 PDE4D DYM ZBTB20 TCF12 FMR1 WWOX HDAC4 COMT MAOA ARV1 ATRX CLIP2 SZT2 WFS1 SLC35C1 HCN1 KDM5C SMC1A NTRK2 BCKDK IQSEC2 NAGA HDAC8 KCNAB2 DYRK1A GATM IPW PWRN1 BAZ1B DHDDS GRIA3 FTSJ1 TSC1 TSC2 CNKSR2 NDN CHD7 NDP SIN3A PLXND1 GRIN2D REV3L SIM1 MED13L RFC2 RREB1 PTEN GTF2IRD1 SKI SLC1A2 CREBBP MECP2 YWHAG JMJD1C SHANK3 SH2B1 CHRNA7 SNORD116-1 HESX1 MEIS2 CYFIP2 OPHN1 NECAP1 TRAK1 HIRA MKRN3-AS1 EEF1A2 SYNGAP1 IL1RAPL1 LHX1 GJA5 GJA8 LIMK1 KLLN OTX2 GTF2I KCNA2 PPP3CA STS STXBP1 NLGN4X ADSL SEC24C COX1 ALMS1 KCNB1 COX2 COX3 SYNJ1 PROKR2 ARVCF SMC3 SETD5 UBE3A PIK3CA NFIB DHCR7 NUS1 ND1 SCN3A AP3B2 UFD1 ND4 ARNT2 ND5 CLTC ND6 PAH SCN8A NPAP1 ANKRD11 EHMT1 AUTS2 PRKAR1A FLCN KMT2A NHS SLC13A5 TRNF AKT1 FGF12 FGFR1 TRNH ELN TRNL1 RERE PWAR1 HERC2 TRNQ TRNS1 DNM1 TRNS2 TRNW PRDM16 ALDH5A1 NIPBL SNRPN SLC9A6 MED12 TBL2 EP300 SEC23B TBX1 SDHB RAI1 SDHC SDHD SMAD4 SEMA3E GP1BB RAD21 ALG13
Autistic behavior
Genes 282
GABRB2 SOX2 MKRN3 GABRB3 SOX3 GPHN GABRD SNORD115-1 UBA5 ATP6V1A RAB11B AARS CNNM2 PDE4D DYM ZBTB20 HIVEP2 PIGP WWOX FRMPD4 HDAC4 PSEN1 MAOA ACADL ATRX MICOS13 TMEM237 MAPT SLC35C1 NEXMIF KDM5C ZNF423 SMC1A ACOX1 BCKDK IQSEC2 TMEM216 NAGA HDAC8 ASH1L NAA10 GATM IPW PWRN1 DHDDS FTSJ1 SRY TSC1 CHD1 TSC2 CHD2 NDN RPS23 NDP PLXND1 RREB1 PTEN BCOR MECP2 MEF2C CHRNA7 SNORD116-1 HESX1 HNRNPH2 MEIS2 NDUFS4 DDX3X TBC1D24 HIRA SYNGAP1 CDKL5 KMT2C TUBB3 GJA5 GJA8 ARID1B KCNA2 NEUROD2 STXBP1 NLGN4X ADSL CLCN4 ALMS1 KCNB1 SYNJ1 NALCN PROKR2 ST3GAL5 UBE3A PIK3CA NFIB SQSTM1 HECW2 SCN1A DHCR7 PCDH19 SCN3A UFD1 ARNT2 CLTC SCN8A NPAP1 SYN1 SMG9 ALDH18A1 CC2D2A AP1S2 KMT2A PACS2 NHS AKT1 FGF12 FGFR1 GNAQ TAF1 PWAR1 HERC2 CAMTA1 TMEM231 DNM1 CLP1 ALDH5A1 NIPBL KCNT1 SLC9A6 MED12 FOXG1 SEC23B TBX1 SDHB SDHC AGTPBP1 VCP SDHD GP1BB RAD21 TBX2 TLK2 CACNA1A CACNA1C TCF4 DPYD C12ORF4 PIGL HNF1B SATB2 CUX2 MAGEL2 DEAF1 NAA15 TCF12 FMR1 RARS AFF2 COMT ARV1 CLIP2 MBOAT7 SZT2 WFS1 PUF60 PPM1D HCN1 NTRK2 CEP290 NDUFAF3 RNF135 KCNAB2 DYRK1A ARFGEF2 TMEM138 BAZ1B GRIA3 TWNK GRN CNKSR2 CHD7 SIN3A GRIN1 ST3GAL3 SPECC1L POMT1 GRIN2D REV3L SIM1 MED13L RFC2 GTF2IRD1 SKI ADNP SLC1A2 CREBBP YWHAG JMJD1C SHANK3 SH2B1 MSTO1 RSPRY1 ZFPM2 CYFIP2 OPHN1 NECAP1 CHMP2B TRAK1 MKRN3-AS1 EEF1A2 SLC6A1 IL1RAPL1 NDUFA13 LHX1 SLC6A8 TMEM106B PPP2CA SNX14 LIMK1 SETD2 SLC35A3 KLLN NDUFAF4 OTX2 GTF2I PPP3CA SLC25A12 STS EGF SEC24C COX1 COX2 COX3 ARVCF SMC3 KMT5B CTCF SETD5 SLC25A1 OTUD6B NUS1 ND1 AP3B2 ND4 ND5 CXORF56 ND6 PAH CNTNAP2 TREM2 ANKRD11 EHMT1 AUTS2 PRKAR1A FLCN SLC13A5 TRNF RORA DEPDC5 TRNH ELN TRNL1 RERE TBR1 TRNQ TBC1D23 ATP1A3 TRNS1 TRNS2 C9ORF72 TRNW MAPK10 GFM1 MCTP2 PRDM16 SNRPN STAG2 TBL2 EP300 CDH15 RAI1 SMAD4 PRODH SEMA3E SON ALG13
Encephalitis
Genes 30
IL10 IKBKG IL12A L2HGDH XIAP CCR1 UBAC2 C4A BCL10 LBR ATRX HLA-B FAS SH2D1A CIITA ERAP1 RFX5 RFXAP IL12A-AS1 KLRC4 PRF1 RFXANK MEFV IL23R STAT1 BTK STAT4 TMEM70 TLR4 SLC6A19