Biopharmaceutical launches with goal to develop treatment for ALS
Trace to use $101M financing to develop UNC13A protein-targeted therapy
A new biopharmaceutical company has launched in the U.S. with more than $100 million in financing and a goal to develop a genomic medicine targeting the UNC13A protein as a novel treatment for people with amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.
Trace Neuroscience kicked off its operations in California with $101 million in Series A financing, which the company will use to continue developing its lead treatment candidate.
That candidate was designed based on research showing that UNC13A, a protein important for nerve cell communication, is deficient in most people with ALS. By targeting it, the company believes it could offer a treatment that would work for the majority of ALS patients.
“Our focus is now on rapidly translating this science into a life-changing medicine by advancing our lead program toward the clinic,” Pietro Fratta, MD, PhD, a Trace cofounder and professor at the University College of London, said in a company press release.
Added Eric Green, MD, PhD, CEO of Trace and also a cofounder: “We envision a world where UNC13A restoration improves outcomes across a range of neurodegenerative diseases, including for the approximately 30,000 people in the U.S. living with ALS.”
Founders note need for ALS treatment ‘grounded in human genetics’
ALS is caused by the loss of nerve cells that communicate with muscles to control voluntary movements. Patients experience symptoms marked by progressively worsening muscle weakness, which eventually leads to paralysis and respiratory failure.
While some genes have been linked to the development of ALS, the vast majority of patients have no mutations in known disease-associated genes. Thus, most genomic medicines that target the genetic causes of ALS have so far only been developed for a small proportion of patients carrying mutations in specific genes.
Aaron Gitler, PhD, a Trace cofounder and professor at Stanford University in California, said “genomic-based therapies have begun to transform the lives of people living with ALS.”
But to date, Gitler said, such treatment has “only been effective for those rare forms of the disease caused by SOD1 or FUS mutations, which account for only 3% of all ALS cases. The remaining people [with ALS] … need new treatments grounded in human genetics with defined mechanisms of action.”
Trace is working on a treatment that it believes will have broader therapeutic potential.
In nearly all cases of ALS, nerve cells produce an abnormal version of the TDP-43 protein that does not fold properly and is prone to form toxic clumps. TDP-43 is normally involved in processing messenger RNA, called mRNA — a template molecule used to make proteins from DNA — in the nucleus, where genetic material is stored. However, the abnormal protein accumulates in the cytoplasm, the fluid that fills the cell outside the nucleus, making it unable to perform its normal functions.
Among the mRNAs regulated by TDP-43 is UNC13A’s mRNA, which provides the instructions for a protein of the same name. That protein is important for the proper function of synapses, or the sites where nerve cells connect and communicate to facilitate brain signaling.
Mutations in the UNC13A gene have been associated with ALS development, progression, and survival. But even in people without mutations in this gene, a dysfunction in TDP-43 can alter UNC13A’s mRNA in ways that similarly result in a loss of UNC13A protein production.
According to Trace, about 97% of people with ALS produce insufficient amounts of UNC13A, which makes it a promising target for treating the majority of ALS patients.
Genomic-based therapies have begun to transform the lives of people living with ALS. … [But to date, such treatment has] only been effective for … rare forms of the disease.
Trace’s lead treatment candidate is an antisense oligonucleotide (ASO) — a small string of genetic material — that binds to UNC13A’s mRNA to enable its proper processing to produce a functional protein.
This is expected to help restore more normal signaling between the brain and muscles, thereby helping preserve, and possibly improve, muscle function in people with ALS.
According to Fratta, the potential to re-establish lost communication between nerve and muscle cells “is groundbreaking.” The scientist adds that “this is an exciting time in brain disease innovation.”
TDP-43 dysfunction and UNC13A deficiency also can be seen in other neurodegenerative conditions, such as Alzheimer’s disease and frontotemporal dementia. Trace thus anticipates that its genetic medicine will have applications beyond ALS.
Meanwhile, other companies also are looking to develop ALS therapeutics targeting UNC13A. Both Eli Lilly and AcuraStem have UNC13A-targeted ASOs in preclinical development.
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