Out of ‘Stealth’ Mode, QurAlis Expects First QRL-201 Trial in 2022
The stem cell technology company said it is now conducting formal preclinical studies to assess QRL-201’s therapeutic potential, and expects to use the data it collects to support the future launch of first-in-human trials.
“We are excited to bring QRL-201 out of stealth and continue advancing our program to the clinic so that we can bring this potentially transformative treatment to patients rapidly,” Kasper Roet, PhD, QurAlis’ CEO and co-founder, said in a press release.
There is no cure for ALS and the two therapies approved for its treatment have shown only a mild effect in slowing disease progression. Thus, current disease management is mostly limited to supportive care.
QRL-201 is a first-in-class molecule that works by increasing the production of stathmin-2, a protein essential for neuronal growth and repair that is found at lower-than-normal levels in nearly all ALS patients.
In animal models, loss of the STMN2 gene, which contains the instructions to produce stathmin-2, caused nerve cell fiber degeneration, which is the primary functional deficit leading to paralysis in ALS patients.
Previous research led by Kevin Eggan, PhD, QurAlis’ co-founder and a Harvard University professor, showed that stathmin-2 deficiency in ALS patients is caused by impaired function of TDP43, a protein that regulates gene activity by binding to DNA and RNA.
In most people with ALS, TDP43 — which is typically found in the cell’s nucleus, the control center where the genetic information is kept — is instead located outside the nucleus, where it accumulates and forms toxic clumps that impair nerve cell function.
Notably, Eggan and his team found that TDP43 typically prevents the inclusion of a cryptic exon in STMN2’s messenger RNA or mRNA.
mRNA is the intermediate molecule derived from DNA that guides protein production. Exons are the sections of a gene containing the information necessary to build proteins, and cryptic exons are smaller sections that are normally excluded from the mature mRNA molecule.
The absence of TDP43 in the nucleus was found to promote the inclusion of this cryptic exon in STMN2’s mRNA, leading to an early stop in protein production and the generation of a shorter, non-working stathmin-2.
Importantly, Eggan’s research also showed that restoring stathmin-2 levels could rescue impaired neuronal repair in lab-grown human motor neurons with TDP43 deficiency — a cellular model that mimics what happens in ALS patients.
As such, QRL-201 “could potentially benefit ALS patients who have a loss of STMN2 due to TDP43 [mislocalization] which could in turn slow disease progression,” Roet said.
He added that QurAlis’ therapeutic strategy “is based on the groundbreaking discovery of Dr. Eggan which solidifies our understanding of ALS because the regulation of STMN2 provides a genetic precision medicine target for sporadic ALS patients.”
QurAlis now is announcing its nomination of QRL-201 as its development candidate for treating ALS. The company expects to launch its first clinical trial of QRL-201 in the second half of 2022.
According to Roet, one challenge of developing the treatment candidate is that STMN2’s cryptic exon is only present in humans and great apes, and does not exist in animal models.
Thus, researchers had to “rely on human stem cell models to understand the development of ALS in sub-groups of patients, to identify precision medicine targets, and to test potential therapeutic molecules,” Roet said.
The company also announced a second year of funding from Target ALS and the Association for Frontotemporal Degeneration that’s meant to help identify biomarkers and viable treatments for ALS and frontotemporal dementia (FTD). FTD is the most common form of dementia and also is associated with TDP43 mislocalization and toxic clumps.
In collaboration with the University of Massachusetts Medical School and Harvard University, QurAlis won a 2020 grant to explore therapeutic approaches to restore stathmin 2’s normal production, which likely led to the development of QRL-201.
The scientists also used the grant monies to develop a rodent model for drug discovery in ALS and FTD, to discover potential treatment candidates, and to identify biomarkers that help determine if therapeutic candidates are working as intended in patients.