QurAlis is a company currently focused on developing oligonucleotide therapies for ALS and other CNS diseases. The company’s Chief Technology Officer, Hagan Cramer, discussed in this presentation an overview of ALS, their oligonucleotide manufacturing process, and the challenges that the company face in their development.
Cramer began by noting the mostly sporadic, rather than familial, nature of ALS which makes it a difficult disease to predict. The familial cases that do occur are usually caused by the genes C9orf72, TBK1, and SOD1.
Unfortunately, due to the rapid decline in the condition of patients with ALS, it can be difficult to research. The steady loss of motor neurons in the brain’s motor cortex, spinal cord, and peripheral nerves, and the fact that median survival is only three to five years means that there is often not enough time after diagnosis to conduct proper clinical studies.
However, there have been recent success in drugging the disease. Cramer highlighted the approval of antisense oligonucleotide gene therapy Tofersen from Biogen and Ionis. This was a significant breakthrough, showing unprecedented muscle strength improvements in ALS patients.
QurAlis is focussing on TDP-43 pathology using small molecules and ASOs targeting Kv7, STMN2, and UNC13A. The company uses stem cell model systems derived from ALS patients' skin cells. Cramer said that these models were more representative than animal models due to the considerable differences in animal and human brain biology.
The presentation detailed the oligonucleotide manufacturing process beginning with solid-phase synthesis and phosphor amidite chemistry. Cramer noted that analytical tools like UHP CMS are crucial for identifying and controlling impurities. These tools help determine whether impurities come from raw materials or the process itself.
Impurities are a significant concern in oligonucleotide manufacturing. They can originate from the process or the starting materials. Cramer categorised impurities into four classes, with Class 4 requiring the most attention due to potential toxicity. The process involves setting specifications and batch release documents to ensure quality control.