Our Programs

Friedreich Ataxia Program

Friedreich ataxia (FA) is a devastating monogenic, autosomal recessive progressive disease caused by low levels of endogenous Frataxin (FXN) due to abnormally expanded GAA triplet repeat expansions in the first intron of the FXN gene. 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, leading 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 endogenous FXN proteins to therapeutic levels.

In August 2023, we reported data from the MAD Phase 1 clinical trial showing that DT-216 was generally well-tolerated and exhibited the ability to overcome the FXN transcription impairment that causes FA. We have developed a new drug product candidate, DT-216P2, for patients with FA that demonstrated an improved pharmacokinetic profile and a favorable injection site safety profile in nonclinical studies.

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 exams. 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 submitted an IND for DT-168 in late 2023 and have received FDA clearance.

Huntington’s Disease

Huntington’s disease (HD) is a dominantly inherited, monogenic neurodegenerative disease characterized by progressive movement, cognitive and psychiatric disorders. Symptoms of HD typically appear between the ages of 30 and 50 and worsen over the next 10 to 25 years, leading to death in approximately 15 years, on average, after the onset of motor signs and symptoms. People with advanced HD need full-time care to help with their day-to-day activities and ultimately succumb to pneumonia, heart failure or other complications. It is estimated that approximately 40,000 people in the United States have symptomatic HD, and more than 200,000 people in the United States are at risk of developing HD. There are currently no approved therapies that can reverse or slow down the course of HD.

HD is caused by a mutation that leads to an increased number of CAG triplet repeats in Exon 1 of the Huntingtin (HTT) gene. Expression of mutant HTT (mtHTT) negatively affects many cellular functions, leading to neuronal death and brain atrophy as symptoms manifest. Wild-type HTT (wtHTT) is thought to be important for normal neuronal function in the adult central nervous system (CNS). It is reported to be involved in axonal transport, synaptic function and cell survival. Increasing lines of evidence also suggest that loss of normal HTT function contributes to the HD pathology. Thus, we believe an allele-selective therapeutic that can dial down mtHTT expression and reduce mtHTT mRNA and protein while preserving wtHTT expression represents a highly desirable therapeutic profile.

Our HD program is based on GeneTAC™ molecules consisting of a DNA-targeting moiety designed to target to the CAG repeats in the Exon 1 region of the HTT gene, linked to a ligand moiety that is designed to dial down the transcription of the mutant allele without disrupting the normal HTT expression. These HD GeneTAC™ small molecules are designed to address the root cause of HD by selectively reducing the toxic mtHTT gene product and distribute to the whole brain when administered systemically.

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 target 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. As with our other programs, the DM1 program is designed to address the underlying cause of the disease and benefit from the favorable development advantages of small molecules.

Our DM1 GeneTAC™ small molecules were shown to reduce observable CUG nuclear foci and correct splicing defects in DM1 patient-derived myotubes. We are working toward selection of a development candidate in anticipation of a future IND submission.

GeneTAC™ Platform
Research Programs

Discovery efforts for multiple other small molecule genomic medicines are also underway. We believe our experiences with GeneTAC™ molecules allow us to more rapidly design GeneTAC™ molecules for additional indications.