ROME Therapeutics

ROME Therapeutics, a biotechnology company illuminating the intersection of the dark genome and innate immunity to develop breakthrough medicines for autoimmune and neurodegenerative diseases, presented data yesterday demonstrating the potential of the company’s LINE-1 RT inhibitors as a novel treatment for neurodegenerative diseases. The new findings were presented during a poster session at the 3rd Annual Dark Genome Symposium, being held November 20-21, 2024, at NYU Langone in New York City.

“Neurodegenerative diseases are woefully undertreated and represent an urgent need for innovative treatment approaches,” said Rosana Kapeller, M.D., Ph.D., Co-Founder, President and CEO of ROME Therapeutics. “The potential of LINE-1 RT inhibitors to block both the inflammation and genomic instability that underlie neurodegeneration holds the promise to deliver a new class of disease-modifying drugs for these devastating diseases. The strong and exciting preclinical data we’ve unveiled at the Dark Genome Symposium led us to conduct further in vivo studies in Parkinson’s and in ALS mouse models.”

Mounting scientific evidence suggests that the increased expression and activity of LINE-1 are associated with Parkinson’s, ALS and other neurodegenerative diseases. Specifically, LINE-1 can reverse transcribe RNA into DNA in the cytosol, generating a viral mimicry response that triggers neuroinflammation. LINE-1 can also retrotranspose (or reinsert itself into new locations on chromosomes) in the nucleus, causing genomic instability, which leads to DNA damage and defects in DNA repair in neurons.

As shown in the poster presentation entitled, “Exploring the potential of LINE-1 RT inhibitors in Parkinson’s disease,” ROME leveraged its proprietary nucleoside compound library to identify selective and potent LINE-1 RT inhibitors that demonstrated favorable oral bioavailability, tolerability, and brain penetrance in rodents.

ROME scientists conducted in vitro and in vivo studies to assesses the activity of the selected LINE-1 RT inhibitors in mouse primary neurons injured with 6-hydroxydopamine (6-OHDA), a common tool to induce mitochondrial dysfunction in Parkinson’s disease models. In the 6-OHDA injury model, ROME’s LINE-1 RT inhibitors prevented cell death in dopaminergic (TH+) neurons and led to a reduction in alpha-synuclein aggregation, a hallmark of Parkinson’s disease.

Additionally, upon 6-OHDA stress, an increase in Orf1p – one of the two proteins encoded by the LINE-1 element – was observed in TH+ neurons, further signaling an increase in LINE-1 expression in the injured neuronal cells. Treatment with ROME’s LINE-1 RT inhibitors reduced the Orf1p upregulation. In the in vivo 6-OHDA injury model, ROME’s orally dosed LINE-1 RT inhibitors were protective in relation to both LINE-1 RT potency and pharmacokinetic (PK) properties after 14 days of treatment, with no adverse events, supporting longer term dosing for in vivo neuro models.