UPF1

MeiraGTx’s gene therapy was able to rescue movement function or prevent motor neuron loss in several rodent models of amyotrophic lateral sclerosis. New data from mouse and rat studies show that MeiraGTx’s gene therapy for amyotrophic lateral sclerosis, or ALS, can repair a key cell-killing process that’s common in both genetic and sporadic forms of the disease. In a presentation Oct. 27 at the European Society of Cell and Gene Therapy conference in Brussels, the company showed that a single treatment with its gene therapy AAV-UPF1 prevented the loss of motor neurons in mouse and rat models with genetic and cellular defects seen in ALS, thereby improving clinical symptoms. The type of defect the treatment corrects is present in the vast majority of ALS patients, suggesting it could have wide-ranging benefit if validated in future studies. ALS is a progressive neurodegenerative disease where multiple aberrant cell processes destroy motor neurons. It’s more common in men than in women, though the gap closes with age, and comes in two forms: familial and sporadic. The familial form, or fALS, accounts for about 5% to 10% of cases, while the rest of patients have no obvious family history. Both types typically arise in people's late 40s through early 60s, with fALS starting slightly earlier. Though the timeline varies, patients usually progress from subtle muscle weakness to paralysis, respiratory failure and death within two to 10 years after the disease begins. There is currently no cure for ALS. Seven drugs have been approved by the FDA to treat the disease, including a new antisense oligonucleotide drug from Biogen and Ionis called tofersen, sold as Qalsody. The therapy targets a mutation in the gene SOD1, which affects about 10% to 20% of inherited or fALS patients. The SOD1 mutation leads to protein misfolding and aggregation within motor neurons, ultimately killing them. MeiraGTx’s new therapy also impacts the pathways that lead to protein misfolding and aggregation in motor neurons, but not the type that’s caused by SOD1. Instead, it targets a different cytotoxic, or cell damaging, process where a motor neuron protein called TAR DNA-binding protein 43, or TDP-43, incorrectly moves from the nucleus to the cytoplasm and builds up. While the TDP-43 pathology isn’t found in patients who have the SOD1 mutation, it is present in those who have the most common form of fALS, which is linked with the gene C9ORF72. It’s also found in nearly all patients with sporadic ALS, bringing its prevalence to more than 95% of ALS patients overall. To counteract TDP-43’s effects, MeiraGTx’s gene therapy increases the expression of the gene UPF1, which is important to RNA metabolism and several pathways that are dysregulated in ALS. Activating UPF1 seems to ameliorate the effects of TDP-43, along with other pathways leading to ALS pathology. The new data come from experiments in four models: one neonate and one adult model with reflex impairments induced by TDP-43 toxicity; a mouse model with a mutation in the C9ORF72 gene; and a mouse model with a mutation in the gene FUS, which is primarily associated with fALS but is also seen in some patients with sporadic disease. For the studies in the neonate rats with the induced TDP-43 dysfunction, the researchers measured whether AAV-UPF1 prevented them from developing forelimb impairment. Over the course of 12 weeks, forelimb function remained intact in all seven of the treated rats, while around 75% of the seven untreated rats showed impairments by Week 4. In the adult rats with induced TDP-43 dysfunction, the researchers looked at how well the treatment reduced the degree of impairments in hindlimb reflexes. While the untreated rats’ reflexes degraded to 25% of normal by Week 6 of the study—and fell further as the study progressed—the treated rats’ reflexes degraded to only about 75% of normal, even by Week 24. For the mice with genetic disease, the researchers measured whether the treatment could protect against motor neuron loss. In the FUS model, treated mice had nearly the same amount of motor neurons as controls, while the untreated mice exhibited motor neuron loss. The same was true for mice in the C9ORF72 model: The treated animals were protected from cell loss, while those that didn’t receive the treatment were not. In addition to the rodent studies, the MeiraGTx team presented data on AAV-hUPF1, a version of AAV-UPF1 that had been made smaller and more potent to optimize it for the clinic. They showed that it improved survival in human neurons derived from induced pluripotent stem cells with mutations in the TDP43 or C9ORF72 genes and rescued motor neuron loss in mice with the FUS gene mutation. Finally, the researchers also presented data on a new capsid, AAV2-retro, to deliver the ALS gene therapy as well as other neuronal indications. It was able to transduce the therapy in the brains and spinal cords of primates and also showed an effect in ALS patient-derived neurons harboring different disease-causing mutations.   MeiraGTx is continuing to optimize the vector for the clinic and plans to start studies for an investigational new drug application in 2024, presentation documents said.