Dravet Syndrome is a severe genetic epilepsy characterized by lifelong seizures and neurodevelopmental impairment beginning in infancy. Most patients experience 10-20 seizures per month and developmental delay is considered permanent by late adolescence. Life expectancy for Dravet patients is 40-50 years, with 10-20% succumbing in childhood.
80% of Dravet patients have mutations in the SCN1A gene, resulting in decreased expression of a sodium channel that impacts electrical activity leading to predisposition to seizures. Current treatments are non-specific anti-epileptics and the size of the SCN1A gene makes it incompatible with traditional gene therapy approaches. We believe that upregulation of endogenous SCN1A will eliminate seizures (or reduce their frequency and severity) and preserve neurodevelopmental milestones.
Frontotemporal dementia is a progressively debilitating and devastating disease caused by nerve loss in the brain. This form of dementia can be caused by mutations to multiple different genes; manifests earlier in life than Alzheimer’s (typically 40s to early 60s); and results in altered personality, language deficits, and deterioration of motor control.
Loss-of-function mutations in the GRANULIN gene account for ~10% of FTD cases (FTD-GRN). Within 3-4 years of FTD-GRN diagnosis, patients progress to late-stage dementia and require full caregiver support, with a typical life expectancy of seven years. Our approach is to upregulate the GRN mRNA in both neurons and microglia, to restore normal levels of progranulin and have a targeted impact at the site of neurodegeneration.
Urea cycle disorders is are a set of liver diseases with life-threatening neurological effects. Caused by a defect in one of several genes involved in processing ammonia in the body, UCD results in excessive build-up of ammonia, leading to cognitive delay, coma, and seizures. UCD classically occurs in newborn babies where it is associated with a 24% mortality rate.
The most common form of the disease is linked to loss of function mutations in the OTC gene. By upregulating endogenous OTC production, we aim to improve the patient’s ability to process and eliminate ammonia. We believe that this approach will yield a therapy that is disease-modifying and can be titrated – especially important as pediatric patients grow.
Urea cycle disorders are a set of liver diseases with life-threatening neurological effects. Caused by a defect in one of several genes involved in processing ammonia in the body, UCD results in excessive build-up of ammonia, leading to cognitive delay, coma, and seizures. UCD classically occurs in newborn babies where it is associated with a 24% mortality rate.
Our approach aims to help the patient’s body better process and eliminate ammonia by upregulating production of a rate limiting specific protein involved in urea cycle. We believe that this approach will yield a therapy that is disease-modifying for all late-onset UCD patients and can be titrated – especially important as pediatric patients grow.
Hereditary angioedema is a life-threatening monogenic disease originating in the liver. HAE attacks are characterized by recurrent swelling (edema) in the face, larynx, hands, feet and/or abdomen, and can require emergency medical care to address pain and prevent airway obstruction. Current prophylactic treatments are inconvenient and/or have serious side effects, and despite recent improvements in efficacy, patients still experience attacks upwards of six times a year.
The majority of HAE cases are caused by haploinsufficiency of the C1-INH, protein coded by SERPING1 gene. By upregulating the SERPING1 mRNA with a targeted RNA Actuator, we believe we can induce a therapeutic increase in C1-INH production to restore bradykinin levels that is triggered during an HAE attack.
Primary Biliary Cholangitis is characterized by toxic bile acid accumulation in the liver. The body’s inability to clear bile acid is caused by auto-immune mediated inflammation and, over time, leads to debilitating itching, fatigue, end stage liver disease and ultimately liver transplantation.
Our strategy is to increase efflux of bile acids from the liver by upregulating an endogenous transporter thereby decreasing liver cell damage and normalizing the liver function. The approach will also help with rebalancing the bile acid pool in the enterohepatic system.