“…7 A–D), indicating that CB-5083 is well tolerated and the suppressive effect on PDE6 and retinal function is reversible. Our earlier investigation in WT and VCP R155H/+ mice led to the same conclusion [ 40 ]. Fig.…”
Section: Resultssupporting
confidence: 74%
“…In rodent models of VCP disease, cytoplasmic accumulation of TDP-43 is observed widely across brain regions [ 24 , 30 , 34 , 38 ]. Even though CB-5083 bioavailability in the brains is one-third of the levels in the circulating blood [ 40 ], we wanted to assess if CB-5083 treatment for 5 months could modulate these important disease phenotypes in VCP R155H/R155H mice. TDP-43 expression in the vehicle-treated VCP R155H/R155H mice at 7 months was not significantly altered in the brain and the spinal cord compared to the wildtype controls (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Based on our findings that VCP inhibitor CB-5083 is beneficial in improving muscle pathology, we propose that correcting the enzyme hyperactivity could be therapeutic in patients. Additionally, we interpret the lack of a significant effect of CB-5083 in the spinal cord or the brain as due to low CNS bioavailability [ 40 ]. Therefore, it will be valuable to examine the effect of future VCP inhibitors that have improved CNS penetrance.…”
Background
Pathogenic gain of function variants in Valosin-containing protein (VCP) cause a unique disease characterized by inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia (also known as Multisystem proteinopathy (MSP)). Previous studies in drosophila models of VCP disease indicate treatment with VCP inhibitors mitigates disease pathology. Earlier-generation VCP inhibitors display off-target effects and relatively low therapeutic potency. New generation of VCP inhibitors needs to be evaluated in a mouse model of VCP disease. In this study, we tested the safety and efficacy of a novel and potent VCP inhibitor, CB-5083 using VCP patient-derived myoblast cells and an animal model of VCP disease.
Methods
First, we analyzed the effect of CB-5083 in patient-derived myoblasts on the typical disease autophagy and TDP-43 profile by Western blot. Next, we determined the maximum tolerated dosage of CB-5083 in mice and treated the 2-month-old VCPR155H/R155H mice for 5 months with 15 mg/kg CB-5083. We analyzed motor function monthly by Rotarod; and we assessed the end-point blood toxicology, and the muscle and brain pathology, including autophagy and TDP-43 profile, using Western blot and immunohistochemistry. We also treated 12-month-old VCPR155H/+ mice for 6 months and performed similar analysis. Finally, we assessed the potential side effects of CB-5083 on retinal function, using electroretinography in chronically treated VCPR155H/155H mice.
Results
In vitro analyses using patient-derived myoblasts confirmed that CB-5083 can modulate expression of the proteins in the autophagy pathways. We found that chronic CB-5083 treatment is well tolerated in the homozygous mice harboring patient-specific VCP variant, R155H, and can ameliorate the muscle pathology characteristic of the disease. VCP-associated pathology biomarkers, such as elevated TDP-43 and p62 levels, were significantly reduced. Finally, to address the potential adverse effect of CB-5083 on visual function observed in a previous oncology clinical trial, we analyzed retinal function in mice treated with moderate doses of CB-5083 for 5 months and documented the absence of permanent ocular toxicity.
Conclusions
Altogether, these findings suggest that long-term use of CB-5083 by moderate doses is safe and can improve VCP disease-associated muscle pathology. Our results provide translationally relevant evidence that VCP inhibitors could be beneficial in the treatment of VCP disease.
“…7 A–D), indicating that CB-5083 is well tolerated and the suppressive effect on PDE6 and retinal function is reversible. Our earlier investigation in WT and VCP R155H/+ mice led to the same conclusion [ 40 ]. Fig.…”
Section: Resultssupporting
confidence: 74%
“…In rodent models of VCP disease, cytoplasmic accumulation of TDP-43 is observed widely across brain regions [ 24 , 30 , 34 , 38 ]. Even though CB-5083 bioavailability in the brains is one-third of the levels in the circulating blood [ 40 ], we wanted to assess if CB-5083 treatment for 5 months could modulate these important disease phenotypes in VCP R155H/R155H mice. TDP-43 expression in the vehicle-treated VCP R155H/R155H mice at 7 months was not significantly altered in the brain and the spinal cord compared to the wildtype controls (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Based on our findings that VCP inhibitor CB-5083 is beneficial in improving muscle pathology, we propose that correcting the enzyme hyperactivity could be therapeutic in patients. Additionally, we interpret the lack of a significant effect of CB-5083 in the spinal cord or the brain as due to low CNS bioavailability [ 40 ]. Therefore, it will be valuable to examine the effect of future VCP inhibitors that have improved CNS penetrance.…”
Background
Pathogenic gain of function variants in Valosin-containing protein (VCP) cause a unique disease characterized by inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia (also known as Multisystem proteinopathy (MSP)). Previous studies in drosophila models of VCP disease indicate treatment with VCP inhibitors mitigates disease pathology. Earlier-generation VCP inhibitors display off-target effects and relatively low therapeutic potency. New generation of VCP inhibitors needs to be evaluated in a mouse model of VCP disease. In this study, we tested the safety and efficacy of a novel and potent VCP inhibitor, CB-5083 using VCP patient-derived myoblast cells and an animal model of VCP disease.
Methods
First, we analyzed the effect of CB-5083 in patient-derived myoblasts on the typical disease autophagy and TDP-43 profile by Western blot. Next, we determined the maximum tolerated dosage of CB-5083 in mice and treated the 2-month-old VCPR155H/R155H mice for 5 months with 15 mg/kg CB-5083. We analyzed motor function monthly by Rotarod; and we assessed the end-point blood toxicology, and the muscle and brain pathology, including autophagy and TDP-43 profile, using Western blot and immunohistochemistry. We also treated 12-month-old VCPR155H/+ mice for 6 months and performed similar analysis. Finally, we assessed the potential side effects of CB-5083 on retinal function, using electroretinography in chronically treated VCPR155H/155H mice.
Results
In vitro analyses using patient-derived myoblasts confirmed that CB-5083 can modulate expression of the proteins in the autophagy pathways. We found that chronic CB-5083 treatment is well tolerated in the homozygous mice harboring patient-specific VCP variant, R155H, and can ameliorate the muscle pathology characteristic of the disease. VCP-associated pathology biomarkers, such as elevated TDP-43 and p62 levels, were significantly reduced. Finally, to address the potential adverse effect of CB-5083 on visual function observed in a previous oncology clinical trial, we analyzed retinal function in mice treated with moderate doses of CB-5083 for 5 months and documented the absence of permanent ocular toxicity.
Conclusions
Altogether, these findings suggest that long-term use of CB-5083 by moderate doses is safe and can improve VCP disease-associated muscle pathology. Our results provide translationally relevant evidence that VCP inhibitors could be beneficial in the treatment of VCP disease.
“…However, these trials were discontinued and terminated due to adverse effects on vision resulting from inhibition of phosphodiesterase-6 (PDE6). Nevertheless, chronic administration of CB-5083 did not cause permanent retinal damage, which suggested a decrease in CB-5083 doses, and the re-evaluation of this compound as a clinical agent might be appropriate [144].…”
Section: Cb-5083mentioning
confidence: 99%
“…Another interesting point pertains to the advances in the discovery of VCP/p97 inhibitors and the resistance mechanisms associated with VCP mutations, as discussed in the third and fourth sections. Although many inhibitors have been developed in recent years, only two phase I clinical trials on CB-5083 (NCT02243917 and NCT02223598) were initiated, but were terminated due to adverse effects on vision [144]. These data indicate that the design of new VCP/p97 inhibitors or derivatives of existing drugs with stronger inhibitory activity represents an interesting challenge.…”
Section: Conclusion and Future Perspectivesmentioning
Valosin-containing protein (VCP)/p97, a member of the AAA+ ATPase family, is a molecular chaperone recruited to the endoplasmic reticulum (ER) membrane by binding to membrane adapters (nuclear protein localization protein 4 (NPL4), p47 and ubiquitin regulatory X (UBX) domain-containing protein 1 (UBXD1)), where it is involved in ER-associated protein degradation (ERAD). However, VCP/p97 interacts with many cofactors to participate in different cellular processes that are critical for cancer cell survival and aggressiveness. Indeed, VCP/p97 is reported to be overexpressed in many cancer types and is considered a potential cancer biomarker and therapeutic target. This review summarizes the role of VCP/p97 in different cancers and the advances in the discovery of small-molecule inhibitors with therapeutic potential, focusing on the challenges associated with cancer-related VCP mutations in the mechanisms of resistance to inhibitors.
Human p97 is a potential drug target in oncology. Mutation‐driven drug resistance is an obstacle to the long‐term efficacy of targeted therapy. We found that the ATPase activity for one of the CB‐5083‐resistant p97 mutants was reduced, which also attenuated the degradation of K48 ubiquitinated proteins in cells. To understand how p97 mutant cells with significantly reduced ATPase activity can still grow, we discovered reduced levels of CHOP and NF‐κB activation in the p97 mutant cells and these cellular changes can potentially protect HCT116 cells from death due to lowered p97 activity. In addition, the NF‐kB inhibitor Sulforaphane reduces proliferation of CB‐5083 resistant cells and acts synergistically with CB‐5083 to block proliferation of the parental HCT116 cells. The combination of Sulforaphane and CB‐5083 may be a useful treatment strategy to combat CB‐5083 resistance.
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