ABSTRACT
Exposure-response analyses of venetoclax in combination with bortezomib and dexamethasone in previously treated patients with multiple myeloma (MM) were performed on a phase Ib venetoclax dose-ranging study. Logistic regression models were utilized to determine relationships, identify subpopulations with different responses, and optimize the venetoclax dosage that balanced both efficacy and safety. Bortezomib refractory status and number of prior treatments were identified to impact the efficacy response to venetoclax treatment. Higher venetoclax exposures were estimated to increase the probability of achieving a very good partial response (VGPR) or better through venetoclax doses of 1,200 mg. However, the probability of neutropenia (grade ≥3) was estimated to increase at doses >800 mg. Using a clinical utility index, a venetoclax dosage of 800 mg daily was selected to optimally balance the VGPR or better rates and neutropenia rates in MM patients administered 1-3 prior lines of therapy and nonrefractory to bortezomib.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Maximum Tolerated Dose , Multiple Myeloma/drug therapy , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Dexamethasone/therapeutic use , Dose-Response Relationship, Drug , Drug Dosage Calculations , Humans , Logistic Models , Neutropenia/chemically induced , Sulfonamides/administration & dosageABSTRACT
A posterior segment approach for cell transplantation or injection into the subretinal space of the dog has been developed. Controlled penetration to the subretinal space was achieved using a 29-gauge injection cannula, either blunted or with a 30 degrees sharpened bevel, and partially ensheathed with moveable plastic tubing. Depending on the injection volume used, the retina detached, and the fluid was reabsorbed within 1-3 weeks, although for smaller volumes the retina reattached within a matter of days. The optimal injection volume used was between 100 and 150 microl, or two injections of 55 microl each. By ophthalmoscopy following the surgery, it was possible to serially monitor the injection site and retinal bleb through fundus photography. Light microscopy demonstrates the distribution of stable, viable RPE cells in the subretinal space up to 6 months. The transplantation technique developed for the dog is atraumatic and free from any major surgical or clinical complications. It can be readily used to deliver cells or fluids to localized regions of the subretinal space.
Subject(s)
Cell Transplantation/methods , Pigment Epithelium of Eye/transplantation , Retinitis Pigmentosa/therapy , Animals , Dogs , Injections , Models, Animal , Ophthalmoscopy , Pigment Epithelium of Eye/cytologyABSTRACT
PURPOSE: To develop an effective therapy for treating glycosaminoglycan (GAG) storage in mucopolysaccharidosis VII (MPS VII) retinal pigment epithelium (RPE) in vitro using adenoviral vector mediated human beta-glucuronidase cDNA (Ad-GUSB) transfer. METHODS: Ad-GUSB was used to infect RPE at confluency. The transduction condition was optimized varying time of infection and number of infectious particles. The beta-glucuronidase (GUSB) activity was measured in transduced cells and media using a fluorogenic substrate. The GAG profiles were examined by metabolically labeling RPE with (35)Na(2)SO(4). RESULTS: Transduced RPE, irrespective of species or disease status, expressed a high level of beta-glucuronidase. The expressed enzyme restored normal levels of GAGs in the RPE cells of homozygous affected MPS VII dogs by metabolizing stored GAGs. The over-expressed enzyme (>10 000 nmoles/hr/mg) failed to restore normal level of GAGs. A high level of GUSB expression was maintained in vitro at least nine weeks. CONCLUSIONS: Adenoviral vector could mediate transfer of GUSB in MPS VII affected RPE and RPE of various species, and the expression was observed to be stable in vitro. However, controlled expression of GUSB was essential for the metabolism of stored GAGs to achieve normal levels.
Subject(s)
Adenoviridae/genetics , DNA, Complementary/metabolism , Dog Diseases/therapy , Genetic Therapy/veterinary , Glucuronidase/genetics , Mucopolysaccharidosis VII/veterinary , Pigment Epithelium of Eye/enzymology , Animals , Cats , Dog Diseases/enzymology , Dogs , Gene Expression , Gene Transfer Techniques/veterinary , Genetic Vectors , Glycosaminoglycans/metabolism , Mucopolysaccharidosis VII/enzymology , Mucopolysaccharidosis VII/therapyABSTRACT
Age related changes in the activity of lysosomal enzymes have been studied in the cultured human retinal pigment epithelium cells collected from 26-85 year old donors. Among four such enzymes studied, activities of cathepsin D and beta-glucuronidase increased with the age of the donors while no notable change in activity of arylsulfatase B and alpha-mannosidase was observed. Kinetic parameters of beta-glucuronidase was measured in retinal pigment epithelium cells isolated from donors of different ages. Similar kinetic parameters for beta-glucuronidase at different ages suggest that the observed increase in the activity of the enzyme with age is not due to post-translational modification of the enzyme. Western blot analysis provides evidence for increased synthesis of beta-glucuronidase with aging. Relative proportions of glycosaminoglycans, the natural substrates of beta-glucuronidase and arylsulfatase B, in the retinal pigment epithelium altered with the age of the donors. A significant decrease of dermatan sulfate levels with aging correlates well with the observed increase in the level of beta-glucuronidase activity.