MJFF, Seal Rock collaboration eyes LRRK2 gene-targeting therapies
Foundation's LITE initiative focused on potential treatments for Parkinson's
Seal Rock Therapeutics has joined a Michael J. Fox Foundation (MJFF) initiative to develop therapies targeted at the LRRK2 gene for the treatment of Parkinson’s disease.
The program, LRRK2 Investigative Therapeutics Exchange (LITE), brings together academic and industry collaborators to support preclinical and clinical development aimed at the protein produced from LRRK2. Seal Rock is developing oral therapies that inhibit both the LRRK2 protein and another protein called ASK1. The company expects this to be more effective than targeting LRRK2 alone.
“Seal Rock is honored to be a new industry member of The Michael J. Fox Foundation’s LITE program and be part of a powerful consortium of academic and industry leaders who recognize the potential of LRRK2 inhibition for Parkinson’s disease,” Neil McDonnell, CEO of Seal Rock, said in a company press release. “MJFF’s recognition of the need for collective action and the support to pursue this promising target is a bold step that will likely shave years off the time it takes for new drugs to be available to patients.”
Mutations in LRRK2 gene can lead to disruption in cell function
Parkinson’s is a neurological disease caused by the progressive death of certain nerve cells in the brain, resulting in a variety of both motor and nonmotor symptoms. Several factors, including genetics, can contribute to disease development. Mutations in LRRK2 are one of the most common genetic abnormalities related to Parkinson’s.
LRRK2 contains instructions for cells to manufacture the LRRK2 protein, which is important in several cellular processes. Mutations in the gene can lead to hyperactivity of the protein, disrupting cell function.
One way that LRRK2 may cause dysfunction is through its interactions with ASK1. Although ASK1 is present throughout the body, it is normally inactive. Situations of high biological stress, such as disease states, can activate the protein. With high activity in both LRRK2 and ASK1, their interactions through the LRRK2/ASK1 signaling complex (LASC) may go awry.
By targeting LASC, Seal Rock aims to inhibit both proteins. This may be effective regardless of whether or not a person has LRRK2 mutations, according to the company’s website. LASC inhibition might also avoid some common side effects of inhibiting LRRK2 alone, including toxicity in the lungs and kidneys.
Dual inhibitor protected brain from Parkinson’s-related damage in studies
In preclinical studies, Seal Rock’s SRT-055, a dual inhibitor of LRRK2 and ASK1, effectively protected the brain from Parkinson’s-related damage. Through participation in LITE, Seal Rock hopes to continue developing this line of therapies.
“We are excited to learn more about LASC inhibitors through research by some of the top labs in the field,” McDonnell said. “Through the LITE initiative, we expect to gain a better understanding of their disease activity when both [proteins] are inhibited simultaneously, as well as further exploring the mechanisms behind the elimination of kidney and lung safety findings.”
Through open science and collaboration, LITE hopes to not only test potential LRRK2-targeting therapies, but also develop resources and infrastructure. Some LITE researchers will also focus on identifying and testing biological markers of LRRK2 activity, which could be efficacy metrics in future studies.
“At The Michael J. Fox Foundation, we remain steadfast toward our singular and urgent mission of delivering better treatments and a cure for patients living with Parkinson’s disease,” said Shalini Padmanabhan, PhD, MJFF’s senior vice president and head of translational research. “We look forward to advancing what’s possible in LRRK2 drug development while de-risking industry investment through open-science policies and the collaboration of experts across key opinion leaders, including through the participation of Seal Rock Therapeutics.”
Seal Rock also intends to test the impacts of LASC inhibitors in amyotrophic lateral sclerosis, another neurodegenerative disorder.
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