Zhao HT, Damle S, Ikeda-Lee K, Kuntz S, Li J, Mohan A, Kim A, Hung G, Scheideler MA, Scherer SS, Svaren J, Swayze EE, Kordasiewicz HB. PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models. J Clin Invest. 2018 Jan 2;128(1):359-368.
Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of peripheral myelin protein 22 (PMP22) and is the most common hereditary peripheral neuropathy. CMT1A is characterized by demyelination and axonal loss, which underlie slowed motor nerve conduction velocity (MNCV) and reduced compound muscle action potentials (CMAP) in patients. There is currently no known treatment for this disease. Here, we show that antisense oligonucleotides (ASOs) effectively suppress PMP22 mRNA in affected nerves in 2 murine CMT1A models. Notably, initiation of ASO treatment after disease onset restored myelination, MNCV, and CMAP almost to levels seen in WT animals. In addition to disease-associated gene expression networks that were restored with ASO treatment, we also identified potential disease biomarkers through transcriptomic profiling. Furthermore, we demonstrated that reduction of PMP22 mRNA in skin biopsies from ASO-treated rats is a suitable biomarker for evaluating target engagement in response to ASO therapy. These results support the use of ASOs as a potential treatment for CMT1A and elucidate potential disease and target engagement biomarkers for use in future clinical trials.
Shy ME. Antisense oligonucleotides offer hope to patients with Charcot-Marie-Tooth disease type 1A. J Clin Invest. 2018 Jan 2;128(1):110-112.
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common heritable peripheral neuropathy and results from a duplication on chromosome 17 that results in an extra copy and increased dosage of peripheral myelin protein 22 (PMP22). Zhao et al., in this issue of the JCI, successfully utilized antisense oligonucleotides (ASOs) to reduce PMP22 and ameliorated neuropathy in both mouse and rat models of CMT1A. These data confirm that strategies to reduce PMP22 have potential as effective therapeutic approaches for CMT1A and lay the groundwork for clinical trials in humans afflicted with this chronic, debilitating neurodegenerative disease.
Targeted antisense oligonucleotide (ASO) successfully restored myelination and reversed many of the deficits associated with Charcot-Marie-Tooth type 1A in two animal models of the disease.
The findings, which were published in the January 2 issue of the Journal of Clinical Investigation (JCI), were heralded by independent CMT experts as a breakthrough in a possible treatment to slow or even prevent symptoms of the genetic disease that damages peripheral nerves and causes muscle weakness, sensory loss, and disability.
The lead authors of the study are staff scientists at Ionis Pharmaceuticals, a biotech company developing ASOs to fight rare diseases. The company reached out to CMT experts around the country to collaborate on the project.
CMT1A is caused by a duplication of the peripheral myelin protein 22 gene (PMP22). This extra copy of PMP22 leads to a higher level of the protein, which damages peripheral nerves.
Hien Tran Zhao, PhD, a senior scientist at Ionis and first author on the paper, said that their team found that ASOs delivered systemically can target Schwann cells. ASOs use engineered segments of DNA to target specific messenger RNAs, thereby reducing the expression of the protein they encode, she explained…
Dr. Zhao said that there was a lot of basic science suggesting that suppressing the target gene would be beneficial. “What was surprising,” she added, “was how dramatic the effect was. All aspects of the disease we tested were ameliorated.”
She said that the team is now working to identify compounds suitable for clinical development. “The compounds used here were tool compounds identified from a small screen. We are also working to flesh out the biomarkers and make sure they are all ready to go for a phase 1 study.”
Human studies pose a challenge, she acknowledged. “In the animal models, we didn't see an obvious limit to the benefit from ASO-mediated PMP22 lowering,” she explained. “However, there are additional questions to ask when looking to treat the disease in humans with antisense, such as how late in the disease will intervention be helpful. Also, too much loss of a PMP22 gene can cause hereditary neuropathy with liability to pressure palsy. We have to be aware of that as we design our study.” It will be critical to get the right levels of PMP22 expression, the scientists said.
“Our data tell us that CMT1A, at least in models, is reversible. Both the myelination deficit and functional deficits can be fixed. It also doesn't take much suppression to see a benefit,” Dr. Zhao said. “This makes sense since three copies of PMP22 causes disease, but two copies do not. The human genetics suggests that a 33 percent decrease in PMP22 will bring a person back to normal levels. Our data in animal models and the human genetics make me cautiously optimistic that we could prevent disease in patients if treated early, and potentially reverse some aspects of this disease. Of course, we will need to complete the clinical trials to know if these findings hold true in humans.”…
“This study moves CMT1A into the category of a treatable disorder, although it has to be extended into patients,” said Michael E. Shy, MD, FAAN, professor of neurology, pediatrics and physiology, director of neurogenetics, and director of neuromuscular diseases at the Carver College of Medicine at the University of Iowa. “This is a major advance in the field. If we can turn down PMP22 we can have a way to treat this disease,” said Dr. Shy, who wrote an accompanying editorial in the Journal of Clinical Investigation.
Dr. Shy said that he was surprised to see changes in nerve conduction velocities. “The thought was that even if you improve demyelination, that nerve conduction velocities don't really change. In this study, the velocities returned to normal.”
“This is quite an exciting study,” added Peter J. Dyck, MD, FAAN, director of the Peripheral Nerve Research Laboratory at Mayo Clinic in Rochester, MN. “The hope is that it can be directly applicable to patients. I think it can. For humans, the trick is to know when to start the treatment and how much to knock down PMP22.”
Dr. Dyck worked on the original description of the CMT1A phenotype in the 1960s. He and others believe that ASOs should be given as soon as the condition is identified.
“Early detection and treatment hopefully will preserve neural function,” he added. “If treatment is delayed until considerable dying back of nerve fibers has occurred, even efficacious treatment may not be able to remedy distal limb weakness and sensory loss.”