Aicardi-Goutières Syndrome (AGS) Nervous System Diseases
Conditions
Interventions
In this study, all participants will receive TPN101. The participant, their caregiver, and the study team will know the dose of TPN101 the participant receives. If the participant qualifies for enrolm
Sponsors
Transposon Therapeutics, Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female participants of the following ages: 1.1. Cohort 1: Adults (=18 years of age) 1.2. Cohort 2: Adolescents (12 to 17 years of age) 1.3. Cohort 3: Children 5 to 11 years of age 1.4. Cohort 4: Children =6 kg in weight 2. Molecular diagnosis of AGS due to biallelic mutations in 1 of the following 5 genes: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, or SAMHD1, or due to a recognized dominant mutation in TREX1. 3. IFN score in peripheral blood >2 standard deviations above the mean score of healthy controls measured on 3 occasions, approximately 2 weeks apart, during the 6-week Screening Period. The IFN score, determined on a Nanostring panel, is the median fold change in expression of a panel of 24 interferon-stimulated genes (ISGs) compared with the median IFN score of healthy controls. 4. Clinical syndrome consistent with AGS diagnosis based on clinical, CSF, and radiological findings. The following are examples of such findings (none of these are required for inclusion): 4.1. Early onset encephalopathy with psychomotor delay, spasticity, extrapyramidal signs, and microcephaly, the latter appearing in the first year of life 4.2. Calcifications particularly visible at basal ganglia level (putamen, pallidus, and thalamus), but also extending to the periventricular white matter 4.3. Cerebral white matter abnormalities 4.4. Cerebral atrophy 4.5. Important systemic symptoms in the early stages of the disease including irritability, feeding and sleeping difficulties, unexplained fevers, and the appearance of chilblain-like skin lesions on the fingers, toes, and ears 5. Women of childbearing potential (WOCBP) must be surgically sterilized (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or agree to use highly effective methods of contraception, e.g., combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner (provided that the partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success); or sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments), from Screening through 3 months after the last dose of the study medication. Women who are pregnant or breastfeeding are not eligible for enrollment. 6. Has a reliable caregiver to accompany the patient to all study visits. Caregiver must have frequent contact with patient and be willing to monitor the patient's health and concomitant medications throughout the study.
Exclusion criteria
Exclusion criteria: 1. Mutation in IFIH1, ADAR1, LSM11, or RNU7-1. 2. Pre-/perinatal infections, in particular the TORCH complex (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus) 3. Presence of other significant neurological disorders; brain tumor or other space-occupying lesion; history of severe head injury 4. Clinically significant intercurrent illness, medical condition (e.g., hematological, endocrine, cardiovascular, renal, hepatic, or gastrointestinal disease) or medical history (including neurological or mental illness) that would jeopardize the safety of the patient, limit participation, or compromise the interpretation of the data derived from the patient 5. Autoimmune disease requiring treatment or management (quiescent rheumatoid arthritis, psoriasis, treated autoimmune thyroiditis, or controlled Type 1 diabetes are acceptable) 6. History of human immunodeficiency virus (HIV), hepatitis B, or any active infection during Screening, unless the patient will have been symptom-free for at least 30 days prior to study drug administration. Patients with treated hepatitis C with no laboratory evidence of active disease and liver enzymes 1.4 or other coagulopathy; platelet count of 2× ULN, confirmed by repeat testing 16.4. Total bilirubin >1.2 × the ULN (unless due to Gilbert's syndrome) 16.5. Serum creatinine >168 µmol/L (1.9 mg/dL), confirmed by repeat testing 16.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Determine the reduction in innate immune signalling, as assessed by the expression of 24 ISG, used to calculate an IFN score in whole blood from screening (Day -42) through to Day 420 (follow-up) 2. Determine the incidence and severity of treatment-emergent adverse events (TEAEs) with TPN-101 administered for up to 48 weeks in patients with AGS | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Determine concentrations of TPN-101 in plasma and CSF from screening (Day -42) , day 84 and day 336 2. Determine L1 expression, including L1 RNA on days 1, 28, 84, 168, 252 and 336. 3. Determine IFN status in blood and CSF, including IFN-alpha and IFN-gamma, as well as by measuring antiviral protective capacity (IFN activity) in patient serum and CSF, and genome-wide RNA Seq expression analysis in whole blood from screening (Day -42) through to Day 420 (follow-up 4. Determine other inflammatory biomarkers in blood and CSF, (e.g., neopterin) from screening (Day -42) through to Day 420 (follow-up) 5. Determine neurodegeneration biomarkers, including NfL, UCHL-1, tau, and GFAP in blood and CSF from screening (Day -42) through to Day 420 (follow-up) 6. Determine brain magnetic resonance imaging (MRI) including arterial spin labelling for measurement of cerebral blood flow at Days 1 and 336 7. Determine clinical and functional status, as measured by Vineland-3, AGS Scale, Caregiver Diary Score, BSID III, WPPSI-IV, WISC-V, WAIS-IV, GMFM-88, and classification according to 5 systems: GMFCS, MACS, CFCS, EDACS, and VFCS at days 1, 168, 336 and 420 | — |
Countries
France, Italy, Scotland, United Kingdom
Outcome results
None listed