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Report for Clinical Trial NCT03117530

Developed by Shray Alag, 2020.
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
HPO: Autism Autistic behavior

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 201
SNORD116-1 DHDDS OTX2 BAZ1B EHMT1 SCN8A BCKDK KCNA2 PARS2 KDM5C ALDH5A1 ND4 RFC2 IQSEC2 OPHN1 RERE ATRX MKRN3 GABRA2 GATM SDHD DHCR7 YWHAG PROKR2 MAOA TRNQ TBX1 PIGL GTF2IRD1 SIM1 UBA5 NECAP1 GRIA3 SMC3 SCN3A SATB2 NLGN3 SNRPN PWRN1 IFNG GABRG2 NAGA SETD5 MECP2 ANKRD11 CYFIP2 GRIN2D CACNA1C HIRA DNM1 MAN1B1 CLIP2 NRXN1 TRNF UBE3A EP300 ELN PDE4D FLCN SHANK3 PTEN DYM NDP LHX1 TSC1 PTEN SLC1A2 TBL2 DPYD HNF1B SNORD115-1 RAI1 STXBP1 HDAC8 ARVCF SEC24C NFIB ND6 ADSL SH2B1 JMJD1C MECP2 ARNT2 ND5 TMLHE SMAD4 NAGA FMR1 COMT UFD1 TBR1 NONO HERC2 SKI SOX2 SNRPN PTCHD1 TSC2 GTF2I SLC13A5 AARS1 GJA5 MEIS2 SDHC TRNH NLGN3 IPW PRDM16 FGFR1 PLXND1 AP3B2 FTSJ1 NPAP1 SLC9A6 EHMT1 TRNL1 FMR1 HDAC4 ARV1 STS KMT2A NLGN4X GABRD AUTS2 GP1BB CACNA1B TRNS2 ALMS1 STS CHRNA7 TRNS1 ALG13 LIMK1 GAMT TRAK1 GJA8 MED12 SYNGAP1 HCN1 CACNA1A PDE4D DHCR7 NIPBL SMC1A AKT1 PAH WWOX SCN8A NDN COX1 HESX1 GABRB2 MAGEL2 KCNA2 NHS SLC35C1 MKRN3-AS1 RAD21 CHD8 ND1 TBX1 PWAR1 GABRA5 PPP3CA TRNW COX3 RREB1 IL1RAPL1 NLGN4X TCF12 KLLN SIN3A NUS1 SEC23B SZT2 MYT1 FGF12 ZBTB20 PIK3CA COX2 REV3L EEF1A2 ACTL6B SEMA3E WFS1 CNKSR2 NTRK2 CNTNAP2 CHD7 SOX3 MED13L SDHB KCNAB2 KCNB1 ATP6V1A CREBBP CLTC TBX1 PRKAR1A SYNJ1 DYRK1A
Autistic behavior
Genes 519
GRN GATAD2B ALG13 ARID1B STXBP1 TBC1D24 CUX2 SLC6A1 SCN9A PARS2 PRODH KDM5C GABRB3 IQSEC2 OPHN1 MKRN3 SCN1A CEP290 GABRA2 NDUFAF4 SCN1A SDHD DHCR7 NUBPL NDUFB10 YWHAG PROKR2 ADGRV1 MAOA GRIN1 UBA5 KCNA1 GRIA3 USP9X SCN3A DNAJC6 NLGN3 SLC35A3 OTUD6B GNAO1 MAN1B1 NDUFAF5 PGAP1 TUSC3 CAMTA1 GABRG2 CDKL5 NDUFV2 PPM1D PIGV MECP2 GPHN NDUFA11 HECW2 ALDH18A1 HIRA NUS1 PRSS12 MCTP2 CLIP2 NRXN1 PUF60 CNTNAP2 TRNF UBE3A NDUFS2 EP300 CHD1 PDE4D EXT2 SH2B1 UCHL1 SHANK3 CNNM2 PAK3 PIGW NDP PIGP IQSEC2 LHX1 TNIK RSPRY1 NSUN2 PTEN SCN2A TMEM216 TBL2 ST3GAL5 PTCHD1 DPYD RAB11B LINS1 SNORD115-1 RAI1 STXBP1 AP2M1 ARVCF AP3B2 RARS1 KDM5B SEC24C B3GALNT2 TMEM237 FRRS1L AGTPBP1 PODXL CLCN4 SLC9A7 SH2B1 MED23 ZC3H14 MBOAT7 JMJD1C STAG2 CDKL5 ND5 TMLHE EDC3 NAGA COMT TBR1 ZNF81 NONO HERC2 FMN2 SKI NAA10 DCPS METTL23 SOX2 PTCHD1 CXORF56 GTF2I MID2 SLC25A22 GJA5 MEIS2 TBX2 SNCA DEPDC5 SIM1 TRNH SLC35A3 NLGN3 PRDM16 FGFR1 GABRG2 RSRC1 NPAP1 GNAQ EZR NDUFAF3 TRNL1 PSEN1 NAA10 STS ND2 THOC2 CC2D1A KMT2A NDUFS1 GABRD AUTS2 GP1BB PRKN CACNA1B BCOR WASHC4 ND1 NDUFS4 RORA VCP NEUROD2 PINK1 PACS2 CHD2 NDUFA6 TRNS1 ALG13 CLP1 CARS2 TRAK1 GJA8 SYNGAP1 CHD2 MEIS2 NIPBL ADNP DPYD SETD2 TMEM231 ARFGEF2 WWOX MED12 NEXMIF NDN COX1 HESX1 RPS23 GABRB2 KCNA2 NHS C12ORF4 ST3GAL3 NDUFS6 RERE PCGF2 CTNNB1 MAPK10 CHD8 NEXMIF TCF4 SPECC1L NDUFB9 ALG13 PACS1 TRNW COX3 RREB1 IL1RAPL1 NLGN4X PCDH19 C9ORF72 TCF12 SIN3A TIMMDC1 CNKSR2 NUS1 MYT1 ASH1L FGF12 CTCF COX2 ARX LRRK2 TRAPPC9 FOXRED1 EEF1A2 CUX2 FRMPD4 TUBB3 POGZ NTRK2 TMEM126B TRIM8 MED13L NDUFAF1 SETD5 FBXO31 TSPAN7 MEF2C TBR1 CREBBP NDUFAF2 RPS6KA3 CLTC ANK3 AP1S2 SYN1 PRKAR1A SLC6A8 CHD2 SYNJ1 DYRK1A GRIK2 HCN1 SNORD116-1 IL1RAPL1 DHDDS OTX2 NDUFA1 NDUFB3 SON BAZ1B EHMT1 SCN8A BCKDK ZNF41 BCORL1 KCNA2 TREM2 MED25 PSMD12 WFS1 STX1B IREB2 ALDH5A1 ND4 RFC2 UBA5 RERE MAPK8IP3 ATRX CLCN4 GATM DLG3 FOXG1 PIGQ TRNQ SIK1 TBX1 PIGL GTF2IRD1 SIM1 CACNA2D2 NECAP1 MECP2 TLK2 CRBN ARX SMC3 CC2D2A NDST1 SATB2 MECP2 AUTS2 CDH15 NTRK2 ALG11 SQSTM1 SCN1B AGTR2 AIMP1 SNRPN PWRN1 IFNG SCN2A KDM6B NAGA SETD5 SLC25A12 PIGP PIGY ADNP ANKRD11 NDUFAF4 CYFIP2 GRIN2D CACNA1C MTOR DNM1 COG5 MAN1B1 NEUROD2 PIGC HNMT POLA1 PGAP2 UPF3B TMEM106B ELN CLCN4 MAPT KCNT1 FLCN PTEN DYM SMG9 TSC1 MICOS13 PARK7 SLC1A2 ZNF423 HNF1B HDAC8 SRY SLC45A1 TAF1 NFIB NDUFV1 ND6 HTRA2 CRADD KMT2C ADSL NALCN ACADL MECP2 ARNT2 ARHGEF6 USP27X SHANK3 NDUFA13 SMAD4 FMR1 NDUFB11 UFD1 DEAF1 EGF NDUFAF3 ATP1A3 TMEM138 TWNK SNRPN SNX14 TSC2 SLC13A5 AARS1 OTUD6B SDHC C12ORF4 CLIP1 IPW PLXND1 GDI1 NDUFS7 VPS13C CASK AP3B2 FTSJ1 SLC9A6 EHMT1 SYP TAF1 DDX3X FMR1 SH2B1 PIGL HDAC4 ARV1 EP300 NLGN4X TRRAP DMD POLA1 TRNS2 HIVEP2 PIGO RNF135 HNRNPH2 SLC25A1 ALMS1 TM4SF20 FTSJ1 STS CHRNA7 NAA15 LIMK1 TCF4 GAMT MEF2C KMT5B ST3GAL3 MED12 POMT1 HCN1 CACNA1A NDUFS3 PDE4D DHCR7 SMC1A MECP2 MBOAT7 AKT1 TRIO PAH SCN8A NDUFS8 ACOX1 PGAP3 CHMP2B GRIA3 MAGEL2 WARS2 SLC35C1 MKRN3-AS1 RAD21 AFF2 ND1 IQSEC2 GABRD TBX1 ZNF711 ASXL3 PWAR1 GABRA5 PPP3CA HERC2 TECR KLLN SLC6A8 SEC23B SZT2 PNKP ZBTB20 PIK3CA REV3L FRMPD4 ZFPM2 ND3 ACTL6B ST3GAL5 SEMA3E WFS1 CNKSR2 FOXP2 SARS1 TCF20 CXORF56 CNTNAP2 CHD7 PPP2CA SOX3 GFM1 SDHB KCNAB2 KCNB1 ATP6V1A TBC1D23 SYNGAP1 MSTO1 RAB39B HCN1 LMAN2L DNM1 ACSL4 TBX1 NDUFS4 HCFC1