We are developing a portfolio of GeneTAC product candidates designed to address genetic diseases driven by inherited nucleotide repeat expansions. GeneTACs are designed to be a novel class of disease-modifying small molecule therapeutic candidates. We prioritized our development efforts where we believe the underlying cause is amenable to intervention using our technology and where there is a clear and efficient path to advance these candidates through clinical development Our goal is to provide a disease-modifying therapy for these patients.
Friedreich Ataxia Program
Friedreich ataxia (FA) is a devastating monogenic, autosomal recessive progressive disease where over 95% of cases are caused by homozygous guanine-adenine-adenine (GAA) triplet repeat expansions in the first intron of the frataxian (FXN) gene, which encodes the mitochondrial protein FXN. The disease is characterized by spinocerebellar ataxia, dysarthria, pyramidal weakness, deep sensory loss, hypertrophic cardiomyopathy, skeletal abnormalities and diabetes mellitus. Clinical onset occurs most often around puberty, leads to severe disability by early adulthood, with substantial functional loss, wheelchair dependence and loss of quality of life. Affected individuals have reduced life expectancy, with many premature deaths caused by complications of cardiomyopathy at about the end of the fourth decade of life. The estimated prevalence of FA is 1 in 40,000–50,000, affecting more than 5,000 individuals living in the United States and more than 20,000 in Europe.
Our FA program, designed to address the underlying cause of disease, is based on GeneTAC small molecules consisting of a DNA-binding moiety designed to bind to the expanded GAA sequence in the first intron of the FXN gene in FA patients, linked to a ligand moiety designed to recruit an endogenous transcriptional elongation complex to unblock the transcriptional machinery and restore the production of functional natural FXN proteins to therapeutic levels.
Myotonic Dystrophy Program
Myotonic dystrophy (DM1) is a monogenic, autosomal dominant, progressive neuromuscular disease that affects skeletal muscle, heart, brain and other organs. The cardinal features include muscle weakness, myotonia (slow muscle relaxation) and early cataracts. In addition, affected individuals often experience cardiac arrhythmias and changes in neuropsychological function. DM1 is caused by a mutation in the DMPK gene and is estimated to have a genetic prevalence of 1 in 2,300–8,000 people, affecting more than 70,000 people in the United States and more than 90,000 people in Europe.
Our DM1 program is based on GeneTAC small molecule candidates consisting of a DNA-binding moiety designed to bind to the CTG repeats in the 3’ untranslated region of the DMPK gene, linked to a ligand moiety that is designed to block transcription of the mutant expanded CTG repeat without disrupting the normal DMPK expression. As a result, the DM1 GeneTAC is designed to prevent the formation of the CUG hairpin structures that trap splicing proteins and produce nuclear foci. Like our FA program, the DM1 program is designed to address the underlying cause of the disease and benefit from the favorable development advantages of small molecules.
We are also advancing our GeneTAC portfolio in other serious nucleotide repeat expansion-driven monogenic diseases, such as Fuchs corneal endothelial dystrophy (FECD), Fragile-X syndrome, spinocerebellar ataxias, Huntington disease and spinobulbar muscular atrophy. We believe our experiences with GeneTACs allow us to more rapidly design GeneTACs for additional indications.