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Columbia, N-Lorem Develop Individualized Antisense Oligonucleotide Therapies for ALS


This article was updated to correct the number of patient applications accepted by N-Lorem. The correct number is 120, not 160.

NEW YORK – Buoyed by a $15 million grant from the US National Institutes of Health's Ultra-rare Gene-based Therapy (URGenT) Network, a Columbia University researcher is designing personalized gene silencing therapies for nine people with extremely rare forms of amlyotrophic lateral sclerosis (ALS).

Neil Shneider, the director of the Columbia ALS Center who received the grant, is designing antisense oligonucleotides (ASOs) that specifically target and silence the genetic mutation underlying each individual's case of ALS.

ALS is a neurodegenerative disease that primarily affects motor neurons, causing progressive loss of voluntary limb control and difficulty breathing. The specific genes and gene variants contributing to ALS can vary from person to person. ASOs are short, synthetic antisense nucleic acids that can be designed to target the mRNA of pathogenic variants to stem the production of the faulty proteins that contribute to disease onset and progression.

Shneider founded an initiative called Silence ALS in 2022 in an effort to develop individualized antisense drugs for patients with forms of ALS too rare for pharmaceutical companies to pursue, affecting roughly between one and 30 people globally.

"There's not really a market for these drugs," Shneider said.

"You really need to take an individualized approach," he added. "And that's very expensive and time-consuming, and can only really be done on a nonprofit basis."

Silence ALS was founded as a collaboration between Columbia University and the N-Lorem Foundation, which researches ASO treatments for ultra-rare diseases. It was initally funded by a $400,000 grant from charitable research foundation Target ALS, alongside funds from N-Lorem and the Columbia ALS Center. 

Shneider has already designed and treated an ALS patient with an ASO targeting an ultra-rare mutation in the TARDBP gene. That patient, he said, tolerated initial dosing well, but treatment had to be discontinued after five doses due to disease progression. Shneider has also recently obtained an Investigational New Drug approval for an additional ASO targeting a pathogenic form of the CHCHD10 gene, which codes for a mitochondrial protein and is associated with frontotemporal demetia as well as ALS. As each ASO must be designed specifically for each patient or group of patients, a separate IND is needed for each one.

Now with funding in place to treat nine additional patients, Shneider hopes that the data resulting from comparing patients with different mutations in the same gene and patients with mutations in different ALS genes will shed light on of the disease mechanisms contributing to the condition.

"There are clearly shared pathways [in ALS]," Shneider said. "We don't understand what they are, but that's something that I think will emerge from the study of these ultra-rare genetic forms of the disease."

For example, he explained, understanding how genes affected in ALS are functionally related might reveal where a therapy for one form of ALS could be used in another.

"Could a CHCHD10 ASO be used," he asked, "in SOD1 ALS, or another form of ALS?"

The eventual goal, Shneider said, is to be able to treat people very early on after symptom onset or, ideally, even before symptoms arise by developing biomarkers that predict disease onset.

Shneider's prior ALS research led to a collaboration with Ionis Pharmaceuticals to develop an ASO targeting a conserved sequence within the FUS gene pre-mRNA. Mutations in FUS are associated with more common types of ALS and targeting the conserved sequence in that gene, rather than a specific miutation, makes the therapy useful in cases of multiple pathogenic mutations. That therapy, called ulefnersen or ION363, is currently being evaluated in the Phase III FUSION trial.

In partnership with Biogen, Ionis has also developed the ASO Qalsody (tofersen), which was approved by the US Food and Drug Administration last year for treatment of SOD1 ALS, another ultra-rare form of the disorder.

According to Emily Papp, assistant director of product and pipeline communications at Ionis, the company, in partnership with Biogen, is also evaluating the ASO ION541 in patients who have a mutation in the ATXN2 gene as well as patients who have sporadic ALS in a Phase I/II clinical trial.

Stan Crooke, founder, CEO, and chairman of N-Lorem, the nonprofit collaborating with Shneider on his Silence ALS program, said that the ASO "technology is fully validated, it's personalized, rapid, [and] it works."

Crooke's research has for decades revolved around designing ASOs and he founded N-Lorem in January 2020 as a way to fund the development of such therapies for cases that had no commercial value.

Crooke said that more than 260 people have applied to N-Lorem for treatment so far, and the foundation has accepted applications from approximately 120 of those individuals.

"We've treated 13 [patients] this year," Crooke said, "and we will file between 15 and 20 INDs, depending on how much funding we have."

"We really don't know the prevalence of most of these mutations that are just being discovered now, thanks to whole-genome sequencing," he said.

N-Lorem is funded entirely through charitable donations, although Crooke hopes eventually to be able to leverage the intellectual property the foundation owns surrounding its ASOs to supplement that funding through licensing to commercial drug developers. If N-Lorem's researchers think that a patient population may be larger than a single individual or small group and could attract commercial interest, then Crooke said they would evaluate the possibility of filing a patent on the related ASO.

"Long term," he said, "that's a part of our plan for sustainability."

However, the n-of-1 trials needed to put these therapies into the hands of patients require different standards of evidence than larger randomized, controlled trials, and the FDA and other stakeholders are still debating what exactly these should be.

The FDA published draft guidance in 2021 on how to file INDs for ASO therapies designed to treat life-threatening conditions for extremely rare disease populations, as well as draft guidance to describe the preclinical information recommended to support INDs, although some researchers voiced concern that the guidances were light on details.

Crooke, however, largely waved off regulatory concerns, pointing out that the FDA has already approved dozens of ASO therapies and is familiar with the technology in play.

"I think the FDA has confidence in the technology and appreciates the need that these patients have and the fact that there is no commercial solution today," he said.

Shneider added that further approvals are also likely to encourage insurers to cover ASO therapies, which would, in turn, help lower the financial burden of developing them.

"This is just the beginning of a larger effort that is going to require all kinds of funding, both public and private," Shneider said.

While Crooke acknowledged the hurdles to making individualized ASO therapies a more commonplace reality, he sees none of them as insurmountable.

"Having been in this [field] now, for a long time," Crooke said. "I'm optimistic that we're going to be able to see this through to the finish line and, and create a sustainable solution for patients who have no other no other recourse."