We are developing a portfolio of GeneTAC™ product candidates designed to address genetic diseases driven by inherited nucleotide repeat expansions. GeneTAC™ molecules 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.
In March 2022, we initiated a Phase 1 clinical trial to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of FXN levels from single ascending doses of our FA GeneTAC™ molecule DT-216 in adult patients with FA.
Fuchs Endothelial Corneal Dystrophy Program
Fuchs Endothelial Corneal Dystrophy (FECD) is a genetic eye disease characterized by bilateral degeneration of corneal endothelial cells (CECs) and progressive loss of vision. Typically, the disease manifests after age 40 and can be detected through routine eye exam. As individuals age, CECs become dysfunctional and degenerate. As a consequence, fluid accumulates in the cornea (corneal edema), causing reduced visual acuity, reduced contrast sensitivity, glare, and eventual corneal blindness. Other symptoms include pain and grittiness in the eye.
This genetic eye disease affects more than one million people in the U.S. Over 70% of FECD cases are caused by cytosine-thymine-guanine (CTG) nucleotide repeat expansions in the TCF4 gene, which is transcribed into pathogenic TCF4 RNA that forms nuclear foci and sequesters splicing proteins, leading to transcript mis-splicing (spliceopathy) and CEC death. CECs harbor the longest known TCF4 repeat expansions in the body, potentially explaining why the cornea is the only affected tissue. There is currently no effective therapeutic intervention that addresses the root cause of the disease. Corneal transplantation, including various modalities of keratoplasty, is the only treatment option to correct advanced FECD.
Our FECD program leverages our expertise in designing GeneTAC™ small molecules that address the underlying cause of the disease. FECD GeneTAC™ molecules have shown to markedly reduce nuclear foci and improve spliceopathy in FECD CEC cultures derived from donors who underwent corneal transplant.
In December 2022, DT-168 was declared a drug candidate for FECD. DT-168 is a GeneTAC™ small molecule designed to target the CTG repeats in the TCF4 gene and selectively block transcription of the expansion-containing allele. It is also designed to be applied as an eye drop. We plan to submit an Investigational New Drug (IND) application for DT-168 in the second half of 2023.
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™ molecules are 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 Fragile-X syndrome, spinocerebellar ataxias, Huntington disease, spinobulbar muscular atrophy, and C9orf72-amyotrophic lateral sclerosis/frontal-temporal lobe dementia. We believe our experiences with GeneTAC™ molecules allow us to more rapidly design GeneTAC™ molecules for additional indications.