Toward Precision Medicine for Cannabidiol Treatment in Epilepsy, and the Impact of Rare Variation in Endocannabinoid System Genes
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1 Toward Precision Medicine for Cannabidiol Treatment in Epilepsy, and the Impact of Rare Variation in Endocannabinoid System Genes Douglas R. Smith, Ph.D. CannMed 2017 Coauthors: Netsanet Gebremedhin, Christine Stanley, Vasisht Tadigotla, Theodore Foss, Eric Marsh 1, Orrin Devinsky 2, Josée Dupuis 3, Kevin McKernan Courtagen Life Sciences, 1 Children s Hospital of Philadelphia, 2 The New York University Medical Center, 3 Boston University School of Public Health
2 Overview Part I Genetic factors that influence response to cannabidiol (CBD) for treatment of treatmentresistant epilepsy Possible response difference in CDKL5 epilepsy Regulatory SNPs associated with better response Part 2 Impact of rare variation in endocannabinoid (ECS) genes Rare variants in CNR1 and DAGLA are associated with neurological phenotypes
3 Genetic Factors in Cannabidiol Response Collaboration with physicians treating patients with Epidiolex in the GW Pharmaceuticals open label trial or Compassionate Access program. Orrin Devinsky (NYU) 50 patients (complete) Eric Marsh (CHOP) 25 patients (complete) Elizabeth Thiele 39 patients (pending response data) Jerzy Szaflarski 55 patients (pending response data) Eric Marsh & colleagues (PA State) 50 patients (recruiting) Analysis of genomic DNA to evaluate the impact of common and rare genetic variants in ECS and epilepsy genes on CBD response first 75 patients
4 Courtagen Clinical Diagnostic Test Overview NGS based tests for Neurological Disorders Epilepsy and Seizure Disorders Neurodevelopmental Disorders Intellectual Disability Autism Spectrum Disorders Mitochondrial and Functional Disorders Adult Neurology (neuropathy and movement disorders) Abdominal Pain, Migraines, EDS > 60 targeted Spotlight panels Comprehensive panels Whole Exome Sequencing
5 Epilepsy Gene Panel Design episeek Comprehensive genes Major epilepsy-associated genes GABA pathway genes Major ECS genes CNR1, CNR2, DAGLA, FAAH, MGLL ECS-associated genes (encoding proteins that bind phyto- or endocannabinoids, or that show expression or activity changes) ARG1, CACNA1H, CCL2, CHRNA4, CHRNA7, CPT1A, GABRB2, GFAP, GLRA1, GPR55, GRIN1, KCNMA1, KRAS, MTOR, OPA1, PAX6, PLA2G6, PLCB1, PPT1, RAF1, SCN10A,, SCN2A, SCN8A, SCN9A, SLC6A4, SLC6A5, SYP, VDAC1 Genes involved in CBD and AED metabolism CYP2C19, CYP2C9, CYP3A4, CYP3A5 (plus SNPs for other major CYP450s)
6 Interpretation of Rare Variants Genotype / Phenotype correlation Significant variants are identified, reviewed and verified Clinical data considered in relation to specific gene variants and their known effects Variants with known or likely pathogenic effects are highlighted on the report Scoring: 5 point scale (1=benign à 5=pathogenic) Driver variant: rare variant that explains phenotype EpiSEEK results for CBD study Driver variants identified in 32 patients (43%) - 7 patients had previously identified 15q duplications 43 patients had variants of uncertain significance
7 Correlation of Driver Genes with Response (32/75 tests) 100% 50% 0% -50% -100% CDKL5 CDKL5 KCNT1 15q duplica7on 15q duplica7on CDKL5 CDKL5 15q duplica7on CDKL5 15q duplica7on MMACHC TREX1 CDKL5 15q duplica7on CDKL5 dele7on ALG13 15q duplica7on Response is defined as the % change in seizure counts averaged over a 12-wk CBD treatment period compared to baseline Average response in patients with variants: -28% vs. -33% for non- Wilcoxon rank sum burden test: P-value: 0.94 No association of response with variants Average response in patients with CDKL5 variants: +3% vs. -36% for non-cdkl5 Wilcoxon rank sum burden test: P-value: Possible association of poor response with CDKL5 variants requires more data
8 Heterozygous LOF mutations in CDKL5 Protein kinase involved in transcriptional modulation and synaptic plasticity Neuronal activity up-regulates expression Process is NMDAR-dependent in mature neurons N-methyl-D-aspartate receptor mutations (GRIN1, GRIN2A, GRIN2B) are also associated with refractory seizure disorders CBD may not influence this pathway (need more data) La Montanara, et al., 2015, JBC 290, 7: Mari et al., 2005, Hum Mol Genet; 14: Kemeshita et al., 2008, BBRC 377:
9 Do Drug-Drug Interactions Play a Role?
10 29/35 of the top responders were receiving Clobazam Clobazam, N-Desmethyl Clobazam and CBD and Levels versus Response 100% 80% Drug levels % 40% 20% 0% -20% -40% -60% % Change in total seizure count Clb level (ng/ml) N-Clb level (ng/ml) CBD level (ng/ml) % change in total seizures -80% 1-100% N-Clb levels increase with CBD treatment (Av: 231%) Plasma levels for CBD, Clb, N-Clb (or the changes in those levels) are not correlated with response (CC < 0.1) Genotypes for CYP2C9, CYP2C19, CYP3A4 & CYP3A5 (normal; intermediate; poor metabolizer) do not predict Clb or N-Clb levels, or response to CBD
11 Do CBD and Clobazam act on the same pathway? Clobazam is a 1, 5 benzodiazepine and GABA A receptor allosteric agonist (preference for α2 > α1 subtypes) GABA signaling and GABAergic interneurons are implicated in the disease mechanism for several genetic epilepsy etiologies Dravet Syndrome (, GABRA1, STXBP1) GABRA3, GABRB3, GABRG2, SLC6A1, UBE3A, ASIC3, CHRNA4, CACNA1A, CACNA1B, etc.
12 CBD is also an Allosteric Agonist of GABA A R CBD effective in low micromolar range, especially on α2β3γ2 subtype 2-AG has similar activity Bakas, et al. Pharmacological Research, 2017, In Press
13 Analysis of Common Genetic Variants Genome Wide Association Studies implicate common variants in many drug response studies Over 90 studies in EBI GWAS catalog CBD study sample size is too small for GWAS Common variants from episeek panel sequencing data can be used for focused analysis Consistent variant calls from all samples Variants filtered by MAC (> 5) and HWE compliance Allelic distribution of individual variants were tested for correlation with response profile by linear regression
14 Results of preliminary scan (55 patients) Oct SCN9A OPA1 GFAP
15 Enrichment for ECS genes Signals far from significant (require P < 8E-06) Low power to detect association with full panel (would require samples) 3/4 top hits were ECS-associated genes Encoding proteins that bind phyto- or endocannabinoids, or that show expression or activity changes in response to them ECS-associated genes only comprise 8% of the panel genes Decided to focus further analysis of pilot study to just the 39 ECS-associated genes
16 ECS-associated genes in 75 samples Chromosome log 10 (p) markers June 2016
17 Top hit: Glial Fibrillary Acidic Protein Still did not reach required significance level: 6E-05 Alternate allele associated with better response; 11% MAF Both SNPs are within a regulatory region (promoter, enhancer, TF, eqtl) Alt allele increases expression of a long noncoding RNA and is in strong LD with other eqtls linked to GFAP and other genes ECS association: CB1 and CB2 blockade results in persistent overexpression; AEA promotes neural precursor cell differentiation into GFAP-positive astroglial cells Increasing sample number to >200 should resolve association status
18 Part 2: Impact of Rare Variants in ECS genes Core ECS genes (CNR1, CNR2, FAAH, MGLL, DAGLA) Search for rare variants - allele frequency <0.001 From total of ~3800 episeek and ~2100 nucseek tests Parse all associated phenotypic terms for cases with rare variants Select terms present in >20% of cases with rare variants Include rare phenotypes if shared amongst those Select random controls (950 lacking target gene variants) Perform Fisher exact test for phenotypes present and absent in cases vs controls No significant associations observed for CNR2, FAAH, MGLL
19 CNR1 - Cannabinoid Receptor, type 1 Phenotype cases controls OR P-value Migraine/headache 8/24 95/ Sleep disorder 6/24 32/ Anxiety 7/24 116/ Migraine/headache and anxiety 5/24 27/ Sleep disorder and anxiety 4/24 9/ Migraine/headache and sleep disorder 2/24 6/ Fatigue 6/24 115/ Seizures 14/24 404/ Developmental disorder 7/24 321/ Variants associated with: Migraine/headache, sleep disorders (alone or with anxiety). Enrichment: CLS AF Av. 4x gnomad AF ( ); 8 with zero AF in gnomad Additional observation: 2/6 cases with an Ala419Glu variant have combined: sleep disturbance, anxiety and abnormality of the autonomic nervous system.
20 Importance of CB1 and CB1 signaling CB1 knockout mice display behaviors related to anxiety and memory: elevated avoidance, freezing and risk-assessment behaviors accelerated early learning and early memory decline Clinical Endocannabinoid Deficiency Syndrome Theory posits that migraine, fibromyalgia and IBS are related manifestations of low AEA and 2-AG levels Those conditions frequently occur together and respond well to cannabinoid therapy (THC primarily). Our results suggest that impaired CB1 signaling is associated with migraine and sleep disorders frequently co-occurring with anxiety Are these candidates for CB1 agonist therapy? Russo, EB, 2016, Cannabis and Cannabinoid Research, 1: 154
21 Rare Variants Mapped to CB1 Structure Gly194Ala Val249Met Binding pocket (taranabant or AM6538) Phe208Leu Thr242Ile Arg409Trp (C-terminus deleted) Arg148His Val306Ile Binding domain appears to be more tolerant to variation compared to cytoplasmic signaling domain
22 DAGLA - Diacylglycerol Lipase Alpha Phenotype cases controls OR P-value Seizures 29/36 579/ Developmental disorder 20/36 298/ Abnormality of brain morphology 3/36 5/ Abnormality of brain morph & seizures 3/36 5/ Seizures and developmental disorder 17/36 231/ Seizures and autism 9/36 97/ Autism 12/36 194/ Developmental and autism 8/36 90/ Variants associated with: Increased susceptibility to seizures and developmental disorders Enrichment: CLS AF Av. 7x gnomad AF ( ); 3 with zero AF in gnomad Additional observation: The rare phenotype: HP: abnormality of brain morphology, is highly enriched in cases with rare DAGLA variants, including 2/5 patients with an Arg815His variant.
23 Rare DAGLA Variants by location Rare variant Case with 2 rare variants 4-transmembrane CYS-rich domain Phosphorylated sites marked C-terminal, phosphorylated domain appears to be more tolerant of variation
24 2-AG Signaling During Development Most abundant endocannabinoid in the brain; involved in retrograde signaling to presynaptic CB1 receptors 2-AG acts over long distances during development Levels drop by ~80% in DAGLA -/- mice; resulting in pronounced anxiety and depression-like behaviors Adult neurogenesis compromised in the hippocampus and subventricular zone (DAGLA -/- mice) Altered cholinergic innervation of CA1 pyramidal cells of the hippocampus (DAGLA -/- mice) Altered axon formation in the midbrain-hindbrain region (vision and locomotion) is altered in transient morpholino DAGLA knockdown in zebrafish fetal adult Martella, et al., 2016, FasebJ., 30: 4275 Gao, et al., 2010, J. Neuroscience, 30: 2017 Keimpema, et al., 2013, Scientific Reports, 3: 2093
25 Summary and Future Directions Rare variants in CNR1 and DAGLA are associated with neurological phenotypes Putative associations with CBD response (75 patients) Poorer response in CDKL5 associated epilepsy Regulatory SNPs in GFAP associated with better response Follow-up with additional patients Elizabeth Thiele - MGH, Jerzy Szaflarsky - UAB, Eric Marsh - CHOP (144 additional patients) Hope to explore full ECS associated gene set in an even larger cohort seeking additional funding to expand study
26 Seeking collaborations To apply genetic analysis to other therapeutic areas relevant to cannabinoid medicine Research SNP panel, includes regulatory SNPs, GWAS and candidate gene hits for: Pain (neuropathic, migraine, abdominal, fibromyalgia), opioid response, substance abuse (opioid, cannabinoid, alcohol, nicotine), TBI, psychotomimetic effect, schizophrenia, depression, PTSD, Endocannabinoid system related genes, drug metabolism Can be combined with any Courtagen gene panel or exome Avantra Genetics Personalized Medicine Panels Low cost exploratory panels for: Migraine Abdominal Pain Autoinflammatory disease Neuropathic Pain Thyroid General Wellness
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