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ION716

Generation 2+ antisense drug

ION716 is an antisense oligonucleotide (ASO) targeting prion protein (PrP) messenger ribonucleic acid (mRNA). ION716 is designed to inhibit the production of cellular PrP protein (PrPC) and is being developed as a potential therapy for Prion diseases. ASO-mediated reduction of PrPC has the potential to ameliorate, prevent, or even reverse Prion diseases.

About Prion Diseases

Prion disease is a fatal, incurable neurodegenerative disease that typically presents as a rapidly progressive dementia. Regardless of etiology – sporadic, genetic, or acquired, and regardless of clinical name – Creutzfeldt-Jakob disease, fatal familial insomina, or Gerstmann-Straussler-Scheinker syndrome, all prion diseases are caused by conformational change of PrP from its native fold to a self-propagating misfolded form (PrPSc), which is an abnormal, pathogenic agent that causes brain damage.

ION581

Generation 2+ antisense drug

ION581 is an antisense oligonucleotide (ASO) that targets Ubiquitin Protein Ligase E3A-Antisense Transcript (UBE3A-ATS), which is a long non-coding ribonucleic acid (lncRNA). ION581 reduces the levels of UBE3A-ATS and is being developed as a potential therapy for Angelman Syndrome (AS). Angelman Syndrome is caused by maternal deficiency of the Ubiquitin Protein Ligase E3A (UBE3A). The paternal copy of the UBE3A gene is usually intact but is silenced by the UBE3A-ATS. It has been shown in iPSC neurons derived from AS patients and in an AS mouse model that ASO-mediated suppression of UBE3A-ATS results in UBE3A unsilencing and robust expression from the paternal allele. ASO-mediated up-regulation of UBE3A mRNA has the potential to restore the levels of UBE3A protein in neurons in patients with AS.

About Angelman syndrome

Angelman syndrome is a rare neurogenetic disorder caused by the loss of function of the maternally inherited UBE3A gene and affects approximately 1 in 15,000 individuals. Angelman syndrome presents early in life with profound and severe developmental delays in motor, language and cognitive functioning, seizures and ataxia. It is a non-degenerative, life-long disorder that generally remains clinically unchanged, resulting in complete dependence on a caregiver throughout their life. Some symptoms can be managed with existing drugs; however, there is no disease modifying therapy.

ION260

Generation 2+ antisense drug

ION283

Generation 2+ antisense drug

ION283 is an antisense drug designed to reduce the accumulation of glycogen by inhibiting the production of brain glycogen synthase type 1 (GYS1), the enzyme that makes glycogen in the brain. Mutations that are the genetic cause of Lafora disease (LD) result in the accumulation of excess glycogen and result in the formation of Lafora Bodies in the brain and spinal cord, which results in neurodegeneration.  In animal models of LD, reduction of GYS1 reduced glycogen accumulation and prevented the formation of Lafora Bodies and neurodegeneration.

About Lafora Disease

Lafora disease (LD) is an inherited and very severe epilepsy syndrome.  Although children are born with LD, the disease does not manifest itself until adolescence when seizures begin.

LD is characterized by a progressive increase in intensity of seizures, a rapid cognitive decline (dementia) and motor incoordination (ataxia).  Patients who suffer from this devastating disease have difficulty walking, speaking and eating and will eventually become wheelchair bound, and lose the ability to speak and feed themselves.  Lafora patients typically die within 10 years.

LD is autosomal recessive disease caused by mutations in the laforin or malin genes. The underlying pathology is the result of glycogen accumulation in neurons and glial cells that form toxic Lafora Bodies. Currently, there is no disease-modifying therapy and seizures are poorly managed with anti-epileptic drugs.

ION373

Generation 2+ antisense drug

ION373 is an antisense oligonucleotide (ASO) targeting glial fibrillary acidic protein (GFAP) messenger ribonucleic acid (mRNA). ION373 is designed to inhibit the production of GFAP and is being developed as a potential therapy for Alexander disease (AxD). Nearly all cases of AxD are caused by gain-of-function mutations in GFAP that lead to spontaneous overproduction and toxic accumulation of GFAP into abnormal protein deposits called Rosenthal fibers in the brain. ASO-mediated reduction of GFAP has the potential to ameliorate the underlying cause of disease pathology and reverse or prevent disease progression.

About Alexander disease

Alexander disease (AxD) is a rare neurological condition characterized as a leukodystrophy, or a disease affecting the myelin sheath (the fatty insulation that protects a nerve fiber and supports signal conduction). Two major types of AxD have been defined. Type I onset typically occurs before 4 years of age and patients can experience head enlargement, seizures, limb stiffness, delayed or declining cognition, and lack of growth. Type II onset typically occurs after the age of 4 and symptoms can include difficulty speaking, swallowing, and making coordinated movements. AxD is most often fatal. There are treatments that can relieve symptoms, but there is no disease modifying therapy yet available to patients.

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