Article published in Nucleic Acid Therapeutics outlines challenges and a potential regulatory solution for patients requiring an allele-selective therapeutic approach

n-Lorem, a nonprofit foundation, announced today the publication of an article in the journal Nucleic Acid Therapeutics that explores potential regulatory approaches that could be taken to develop treatments for patients with rare heterozygous toxic gain-of-function (TGOF) mutations. The paper, titled Addressing the Challenges of Treating Patients with Heterozygous Gain of Function Mutations, was authored by Stanley T. Crooke, M.D., Ph.D., Founder, Chairman and CEO of the n-Lorem Foundation. (Crooke, S.T.,Nucleic Acid Ther, (2024) doi: 10.1089/nat.2024.0060)

“We have now accepted 150 nano-rare patients for treatment at n-Lorem. Of these, more than 50 percent express heterozygous TGOF mutations in a diverse set of genes that result in an equally diverse variety of syndromes. As such, we have extensive experience creating allele-selective ASO medicines for our patients and have demonstrated that this approach can be safe and effective in patients with heterozygous TGOF mutations,” said Stanley T. Crooke, M.D., Ph.D., Founder, Chairman and CEO, n-Lorem Foundation.

Every gene has two copies in the cell. For patients with heterozygous TGOF mutations, the patient has both a mutant and a normal copy of the gene and, as a result, a mutant and a normal copy of the messenger RNA (mRNA) and a mutant and a normal protein that is produced from the gene. Currently, only antisense oligonucleotide (ASO) technology can be used to create medicines that selectively target the mutant mRNA and reduce the production of the toxic protein. ASO technology is well validated and has been shown to be safe and effective at treating heterozygous TGOF patients.

“As more people undergo whole genome sequencing, we are likely to see more and more patients identified with TGOF heterozygous mutations, therefore syndromes we once thought were nano-rare could prove to afflict many more people,” Dr. Crooke said. “We used to believe KIF1A gene mutations were exceedingly rare, but as many as 1,000 people have now been diagnosed with it. At that threshold, it makes sense to start exploring how to commercialize a drug to treat the illness, but our work has also shown us that not all KIF1A patients can be treated with the same ASO, which can make clinical trials extremely difficult to conduct.”

In this commentary, Dr. Crooke outlines a regulatory strategy that is cost-effective and could be used to evaluate a patient population that have the same affected gene, but require several allele-selective medicines to treat the majority of the patient population. Because people who have been identified with a particular genetic mutation can have variants that require different treatments, it can be difficult to find enough patients to participate in a clinical trial. The paper proposes conducting a single Phase 3 study in which patients would be stratified by disease severity and variant, and treated with the same variant-selective ASO. At the end of the study in which patients were treated with several variant-selective ASOs, the data could be aggregated and compared to placebo before being submitted to regulatory agencies for review and potential approval.

“This approach could make the development of several allele-selective ASOs cost- and time-effective enough that it could appeal to commercial companies while also shortening the time to approval for such treatments,” concluded Dr. Crooke. “But it will require that we take a fresh look at the regulatory requirements and find innovative ways to address the needs of patients with heterozygous toxic gain-of-function mutations.”

About n-Lorem

n-Lorem Foundation is a non-profit organization established to apply the efficiency, versatility and specificity of antisense technology to charitably provide experimental antisense oligonucleotide (ASO) medicines to treat nano-rare patients diagnosed with diseases that are the result of a single genetic defect unique to only one or very few individuals. Nano-rare patients describe a very small group of patients (1-30 worldwide) who, because of their small numbers, have few if any treatment options. n-Lorem Foundation was created to provide hope to these nano-rare patients by developing individualized ASO medicines, which are short strands of modified DNA that can specifically target the transcripts of a defective gene to correct the abnormality. The advantage of experimental ASO medicines is that they can be developed rapidly, inexpensively and are highly specific. To date, n-Lorem received approximately 300 applications for treatment with approximately 150 nano-rare patients approved. n-Lorem was founded by Stanley T. Crooke, M.D., Ph.D., former chairman and CEO of Ionis Pharmaceuticals, who founded Ionis Pharmaceuticals in 1989 and, through his vision and leadership, established the company as the leader in RNA-targeted therapeutics. Follow us on Twitter, Facebook, LinkedIn and YouTube.

To learn more about n-Lorem’s mission at www.nlorem.org, and please consider giving to n-Lorem to bring hope, possibility and treatment options to these patients and families in need.

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