Entrada Therapeutics is developing an enzyme replacement therapy, called ENTR-501, as a potential new treatment strategy for people with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).
MNGIE is a rare inherited disease caused by mutations in the nuclear TYMP gene, which encodes the thymidine phosphorylase (TP) enzyme. Low or no TP causes cells to accumulate high levels of thymidine and deoxyuridine molecules, which disrupt mitochondria’s ability to maintain and repair their DNA, leading to mitochondrial dysfunction.
Patients with this genetic disorder often first show symptoms during childhood. Abnormal activity of the gastrointestinal organs, progressive paralysis of the muscles around the eyes, and damage of peripheral nerve cells are some common progressive symptoms that may become fatal.
“MNGIE is a rare, autosomal recessive disorder that results in a clinically distinct combination of severe gastrointestinal and neurological manifestations caused by the systemic accumulation of toxic metabolites in the affected tissues,” Michio Hirano, MD, chief of neuromuscular medicine at Columbia University Vagelos College of Physicians and Surgeons, said in a press release.
MNGIE treatment strategies so far have been based on hematopoietic stem cell transplant and liver transplants. These have been shown to effectively reduce the levels of thymidine and deoxyuridine, since both hematopoietic cells and liver tissue increase TP activity. However, these options are invasive, and are associated with potentially severe risks.
“There is a critical need for a therapeutic option that addresses the underlying thymidine phosphorylase deficiency in MNGIE patients,” Hirano added.
Enzyme replacement therapy (ERT), a medical treatment that replaces a deficient or absent enzyme, is a potential strategy to lessen MNGIE symptoms and delay disease progression.
ENTR-501 is a recombinant (lab-made) form of the TP enzyme designed with Entrada’s proprietary Endothymidine phosphorylasesomal Escape Vehicle (EEV) technology. EEV is a system that allows the delivery of molecules, such as TP, to cells while avoiding its degradation inside cells. Preclinical data with mouse models of MNGIE showed that treatment with ENTR-501 prevented the accumulation of toxic metabolites, namely thymidine.
A natural history study of MNGIE is currently recruiting participants. The study (NCT01694953), aiming to enroll a total of 20 participants with MNGIE, will follow them for six-month intervals for up to five years to assess clinical symptoms, such as gastrointestinal and neurological function, quality of life, and other lab parameters.
The study will conducted at Columbia University, in New York City, under the direction of Hirano.
“The need for a therapy that will address the underlying cause of MNGIE is clear to anyone who has seen the debilitating effects of this disease. We are proud to work with Dr. Hirano and the MNGIE patient community,” said Dipal Doshi, president and CEO of Entrada.
“We believe that success with ENTR-501, our most advanced program in a rapidly expanding portfolio, will provide support for the clinical potential of our overall intracellular biologics platform. We expect that our EEV technology will allow us to develop intracellular biologics for a wide range of patients who currently have limited or no treatment options,” he added.