While there has been good progress in understanding the genetic causes of hereditary neuropathies, treatment options for affected individuals are limited to the management of symptoms and surgery in severe cases. The majority of these neuropathies are linked with Peripheral Myelin Protein 22 (PMP22) and include Charcot-Marie-Tooth disease type 1A (CMT1A) and Dejerine-Sottas Syndrome (DSS). CMT1A is most frequently associated with duplication of the PMP22 gene, whereas less common forms of CMT1A and DSS are associated with single amino acid substitutions in PMP22. Importantly, both of these neuropathies are genotypically and phenotypically faithfully modeled in mice. The transgenic C22 mouse models CMT1A, while the spontaneous Trembler J (TrJ) represents severe CMT1A and early-onset DSS. Although therapies for CMT1A and DSS neuropathies are not available, the mouse models have been critical in the identification of pathogenic mechanisms and initial preclinical assessments of novel therapies. Studies from my laboratory with these models and human nerve biopsies revealed the presence of both mutant TrJ-PMP22 and overproduced wild type (Wt) PMP22 within the Schwann cell cytoplasm, indicating altered trafficking of this myelin protein. This discovery led us to hypothesize that protein quality contrl mechanisms, including the chaperone pathway could be compromised in the pathogenesis of PMP22-linked neuropathies. Indeed, we demonstrated that enhancing the heat shock response with the compound EC137, an HSP90 inhibitor, dramatically improves myelination in models of CMT1A and DSS neuropathies. The goal of the current proposal is to obtain in vivo efficacy data on two identified FDA-approved enhancers of the chaperone pathway (AUY922 and BIIB021) in C22 and TrJ neuropathic mice. Preliminary studies indicate that both compounds support Schwann cell viability in vitro and enhance chaperone expression when used at 100-250 nM. In myelinating explant cultures from neuropathic mice both BIIB021 and AUY922 enhanced myelin synthesis. Furthermore, AUY922 significantly improved rotarod performance and muscle force contraction in C22 neuropathic mice when administered at 2 mg/kg, twice a week for 18 weeks. To substantiate these preliminary results in the C22 model, and to establish whether this approach is viable for DSS, additional rigorous preclinical studies are necessary.
Aims 1 -4 of the proposal define rigorous preclinical studies with AUY922 and BIIB021 in both the C22 and TrJ mice. Working with two distinct genetic forms of the disease will determine if targeting the chaperone pathway could provide benefits for a broad group of CMT patients. Since the proposed candidate therapeutics are already FDA-approved for indications in cancer at much higher doses than our studies predict would be needed in neuropathic patients, if positive, the current study will provide the foundation for subsequent clinical studies in humans.
Charcot-Marie-Tooth (CMT) neuropathies are common among the population yet treatment options are not available. The current project will test identified candidate therapeutics for in vivo efficacy in reversing myelin and functional deficits n mouse models of CMT.
| Moloney, Christina; Rayaprolu, Sruti; Howard, John et al. (2016) Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype. Acta Neuropathol Commun 4:122 |
| Zhou, Ye; Notterpek, Lucia (2016) Promoting peripheral myelin repair. Exp Neurol 283:573-80 |
