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Generation 2+ LICA antisense drug

IONIS-GHR-LRx  is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of the growth hormone receptor (GHr) to decrease the circulating level of insulin-like growth factor-1 (IGF-1). IGF-1 is a hormone primarily produced in the liver that plays an important role in childhood growth and has anabolic effects in adults. Several different diseases result from abnormally low or high levels of IGF-1, or an inappropriate response to this hormone. When produced in excess, IGF-1 results in acromegaly, a chronic, slowly progressing and life-threatening disease.

About GHr and Acromegaly

Acromegaly is a chronic, slowly progressing and life-threatening disease most often caused by oversecretion of growth hormone (GH) by benign pituitary tumors. Elevated levels of GH can overstimulate growth hormone receptors (GHr) and induce excess production of insulin-like growth factor-1 (IGF-1). High levels of circulating GH and IGF-1 lead to this multisystem disease characterized by organ overgrowth and physical disfigurement, such as enlarged hands, feet, and facial features. Patients with acromegaly also experience multiple comorbidities, such as type 2 diabetes, hypertension, and respiratory complications, as well as premature mortality. Because IGF-1 mediates the majority of the growth-promoting action of GH, reducing GHr production could in turn decrease levels of IGF-1 and provide a potential treatment to patients with acromegaly. Current treatments to block IGF-1 include surgical removal of the pituitary gland, which is often unsuccessful. Drug treatments to normalize IGF-1 levels are also available but are associated with potentially serious side effects.


Generation 2.5 antisense drug

ION357, formerly known as IONIS-RHO-2.5Rx, is an antisense oligonucleotide (ASO) drug designed to selectively reduce the production of the rhodopsin P23H mutant protein in the eye while allowing normal protein to be expressed. The allele-selective targeting of the ASO to the single-base P23H mutation prevents degeneration of rod photoreceptor cells and preserves cone photoreceptor cell function. ION357 provides a novel approach to treating autosomal dominant retinitis pigmentosa, in which patients have limited therapeutic options.

About Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of rare inherited eye disorders causing photoreceptor degeneration that leads to progressive vision loss. The disease is clinically and genetically heterogeneous and can have an autosomal recessive, autosomaldominant, or X-linked pattern of inheritance. Affected patients first experience defective dark adaptation during adolescence or young adulthood, followed by loss of peripheral visual field when rod photoreceptor function declines. Patients eventually have only a residual central island of vision, which ultimately leads to complete blindness around the age of sixty.



Generation 2.5 antisense drug

IONIS-ENAC-2.5Rx is an antisense drug designed to reduce the production of epithelial sodium channel (ENaC) protein in the lung. ENaC is believed to be hyperactive in cystic fibrosis (CF), which is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. Reduction of ENaC with antisense oligonucleotides (ASOs) in preclinical mouse models of cystic fibrosis lung disease leads to significant decrease of mucus accumulation and inflammation, hallmarks of CF lung disease, and improved lung function. This drug is delivered to the lung via aerosol delivery, which results in broad distribution of ASO in the lung with minimal systemic exposure.

About Cystic Fibrosis

Cystic fibrosis (CF) is one of the most common life-threatening genetic diseases, affecting ~30,000 people within US and about 70,000 worldwide. It is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel expressed in epithelial cells in the lung, liver, pancreas, digestive tract, reproductive tract, and skin. Although CF is a multisystem disease, the main cause of morbidity and mortality is lung disease that is characterized by small airway obstruction due to mucus accumulation, decreased mucociliary clearance, and subsequent inflammation and infections.

Select Publications

1. Crosby, J.R. et al. (2017) Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice. Journal of Cystic Fibrosis , Volume 16 , Issue 6 , 671 – 680

Clinical trial post

* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.