What is HCHWA-D?
Amylon’s lead research program aims to develop a therapy for the genetic disorder Hereditary Cerebral Hemorrhage with Amyloidosis Dutch Type (HCHWA-D), also referred to as Katwijk’s disease, the most common form of hereditary cerebral amyloid angiopathy (CAA). The disease is named after the town Katwijk in the Netherlands, where the disease originates from and where a large part of the patient population is currently living. HCHWA-D is a serious familial disorder characterized by the formation of amyloid-β, a toxic protein, which aggregates in the blood vessels of the brain and causes strokes at middle-age. These strokes severely damage the brain and can eventually be fatal. Currently, there is no therapy available for patients with HCHWA-D, presenting a high unmet medical need.
The biology behind the disease explained
HCHWA-D is caused by a mutation, or mistake, known as the Dutch mutation, in the gene of the Amyloid Precursor Protein (APP). In each of our cells we store genetic information, called DNA, which tells the cell how to make the proteins that our body needs to function. The mutation in the DNA of HCHWA-D patients leads to a single amino acid change in the Amyloid-β peptide sequence. The Dutch mutant form of Amyloid-β is not efficiently cleared and is prone to aggregation in the blood vessels of the brain. This makes the blood vessels fragile and can lead to ruptures in the vessel wall and hemorrhagic (bleeding) stroke at an early age.
A gateway to global disease
The opportunity doesn’t end with HCHWA-D. Further to the Dutch mutation there are five known mutations in the Amyloid-β peptide that cause various forms of HCHWA. Collectively these are all hereditary subtypes of the much more common, age-related, sporadic form of CAA.
HCHWA-D offers us a gateway to potentially treat all these CAA diseases with a single therapy. The unique characteristics of the Dutch form of the disease allows us to start with a razor-sharp focus in a well-defined patient population, and use what we learn to expand and leave no patient untreated.
AT-01 is a first-in-class antisense oligonucleotide (ASO) that induces splicing modulation in the APP mRNA. By binding to the exon with the disease-causing mutation in the pre-mRNA, this exon is skipped, resulting in a protein that lacks the aggregation prone amyloid-β peptide. By preventing the formation of amyloid-β, AT-01 could potentially prevent or delay the onset of HCHWA-D and other forms of CAA.