Biomedical subjects

Joseph C Glorioso

Publications and source records attributed to Joseph C Glorioso.

At least 19 recordsLinked to original sources

PubMed2025

Biosafety and efficacy of Kv7 activating rdHSV-CA8∗ analgesic gene therapy for chronic pain via the intra-articular route in mice.

Chronic pain remains a global health challenge, often resistant to available treatments with socioeconomic and psychological burdens. All chronic pain is believed due to neuronal signaling imbalances, resulting in increased excitability. Gene therapy represents a promising molecular therapy targeting molecular pain processing pathways, by offering precise, localized, long-lasting neuromodulation while minimizing systemic exposure and side effects. In model systems, replication-defective, disease-free, herpes simplex virus (rdHSV) gene therapy expressing an analgesic carbonic anhydrase-8 (CA8∗) peptide variant corrects somatosensory hyperexcitability by activating Kv7 voltage-gated potassium channels, produces profound, long-lasting analgesia and treats chronic pain from knee osteoarthritis (OA). In these studies, we provide the first non-glucagon-like peptide (GLP) biosafety, efficacy, biodistribution, shedding, and histopathology examination of this rdHSV-CA8∗. Naive mice were examined for clinical safety, biodistribution across all major tissues, knee histopathology, and analgesic efficacy via the intra-articular knee route of administration. We observed no signs of persistent toxicity, viral genomes remained where they were injected, and there was no evidence of shedding. Profound analgesia persisted for 6 months without functional impairments. These initial biosafety and efficacy data support further development of rdHSV-CA8∗ for treating chronic knee pain due to moderate to severe OA.

Animals↗

PubMed2012

Immunosuppression decreases inflammation and increases AAV6-hSERCA2a-mediated SERCA2a expression.

The calcium pump SERCA2a (sarcoplasmic reticulum calcium ATPase 2a), which plays a central role in cardiac contraction, shows decreased expression in heart failure (HF). Increasing SERCA2a expression in HF models improves cardiac function. We used direct cardiac delivery of adeno-associated virus encoding human SERCA2a (AAV6-hSERCA2a) in HF and normal canine models to study safety, efficacy, and the effects of immunosuppression. Tachycardic-paced dogs received left ventricle (LV) wall injection of AAV6-hSERCA2a or solvent. Pacing continued postinjection for 2 or 6 weeks, until euthanasia. Tissue/serum samples were analyzed for hSERCA2a expression (Western blot) and immune responses (histology and AAV6-neutralizing antibodies). Nonpaced dogs received AAV6-hSERCA2a and were analyzed at 12 weeks; a parallel cohort received AAV-hSERCA2a and immunosuppression. AAV-mediated cardiac expression of hSERCA2a peaked at 2 weeks and then declined (to ~50%; p<0.03, 6 vs. 2 weeks). LV end diastolic and end systolic diameters decreased in 6-week dogs treated with AAV6-hSERCA2a (p<0.05) whereas LV diameters increased in control dogs. Dogs receiving AAV6-hSERCA2a developed neutralizing antibodies (titer ≥1:120) and cardiac cellular infiltration. Immunosuppression dramatically reduced immune responses (reduced inflammation and neutralizing antibody titers <1:20), and maintained hSERCA2a expression. Thus cardiac injection of AAV6-hSERCA2a promotes local hSERCA2a expression and improves cardiac function. However, the hSERCA2a protein level is reduced by host immune responses. Immunosuppression alleviates immune responses and sustains transgene expression, and may be an important adjuvant for clinical gene therapy trials.

Animals↗

PubMed2006

Characterization of soluble glycoprotein D-mediated herpes simplex virus type 1 infection.

Herpes simplex virus type 1 (HSV-1) entry into permissive cells involves attachment to cell-surface glycosaminoglycans (GAGs) and fusion of the virus envelope with the cell membrane triggered by the binding of glycoprotein D (gD) to cognate receptors. In this study, we characterized the observation that soluble forms of the gD ectodomain (sgD) can mediate entry of gD-deficient HSV-1. We examined the efficiency and receptor specificity of this activity and used sequential incubation protocols to determine the order and stability of the initial interactions required for entry. Surprisingly, virus binding to GAGs did not increase the efficiency of sgD-mediated entry and gD-deficient virus was capable of attaching to GAG-deficient cells in the absence of sgD. These observations suggested a novel binding interaction that may play a role in normal HSV infection.

Animals↗

PubMed2006

Inactivation of herpes simplex type 1 gene vector on immobilized metal affinity chromatography: oxidative damage by hydroxyl free radicals and its prevention.

Metal catalyzed oxidation (MCO), which typically involves oxygen free radical generation, is an important pathway that leads to the deterioration of many biological molecules in solution. The occurrence of MCO in immobilized metal affinity chromatography (IMAC) systems and its potential for inactivating biological products has not been well recognized. In this study, we report the inactivation of herpes simplex virus type 1 (HSV-1) gene therapy vector on immobilized cobalt affinity chromatography. We observed that purification of KgBHAT, an HSV-1 mutant bearing cobalt affinity tags (HAT) on the surface, on an IDA-Co2+ column using crude supernatant as starting material resulted in signification loss in virus infectivity (<5% recovery). Electron spin resonance (ESR) revealed that the virus inactivation was caused by hydroxyl free radicals generated from the interactions between cellular impurities and the metal ions on the column. Inclusion of 20 mM ascorbate, a free radical scavenger, in the chromatography mobile phase effectively scavenged the hydroxyl radicals and dramatically augmented the infectivity recovery to 70%. This finding is the first demonstration of oxygen free radical-mediated biological inactivation in an actual IMAC purification and the way on how to effectively prevent it.

Chromatography, Affinity↗

PubMed2006

HSV-mediated delivery of erythropoietin restores dopaminergic function in MPTP-treated mice.

To investigate the neuroprotective effects of erythropoietin (EPO) in a rodent model of Parkinson disease, we inoculated a nonreplicating herpes simplex virus-based vector expressing EPO (vector DHEPO) into the striatum of mice 1 week prior to, or 2 weeks after, the start of continual administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (4 mg/kg intraperitoneally, 5 of 7 days) for 6 weeks. Inoculation with DHEPO prior to MPTP intoxication preserved behavioral function measured by pellet retrieval and the histological markers of tyrosine hydroxylase-immunoreactive (TH-IR) neuronal cell bodies in the substantia nigra (SN) and TH-IR and dopamine transporter-immunoreactive (DAT-IR) terminals in striatum. Inoculation of DHEPO 2 weeks into a 6-week course of MPTP resulted in improvement of behavioral function and restoration of TH-IR cells in SN and TH- and DAT-IR in the striatum. The effects of vector-produced EPO were similar in magnitude to the effects of vector-mediated expression of glial-derived neurotrophic factor in the same model. These results demonstrate that vector-mediated EPO production may be used to reverse dopaminergic neurodegeneration in the face of continued toxic insult.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2006

Presence of imidazole in loading buffer prevents formation of free radical in immobilized metal affinity chromatography and dramatically improves the recovery of herpes simplex virus type 1 gene therapy vectors.

We have recently shown that immobilized metal affinity chromatography (IMAC) is an effective technique for purification of herpes simplex virus type 1 (HSV-1) gene vector engineered to display cobalt affinity tag on the envelope. However, the tagged HSV-1 viruses were severely inactivated by oxidative hydroxyl free radicals when crude HSV-1 supernatant was applied on an immobilized cobalt column and eluted by a low pH buffer. Furthermore, we have reported that virus inactivation could be prevented by inclusion of high concentration of ascorbate in chromatographic mobile phase. In this paper we report that when elution of bound virus was attempted by inclusion of imidazole in elution buffer, rather than lowering the pH of elution buffer, similar inactivation was also observed. The results also demonstrated that virus inactivation was dramatically reduced by inclusion of 20mM imidazole in the loading buffer. Electron spin resonance (ESR) experiments suggest that imidazole prevents hydroxyl free radical generation from the cobalt complexes. This is the first report describing the role of imidazole in preventing free radical formation in an IMAC column. From a practical stand point, our results imply that inclusion of appropriate amount of imidazole in the loading buffer is an effective strategy for improving the recovery yield of active products and for enhancing product quality during IMAC purification.

Amino Acid Sequence↗

PubMed2006

HSV-mediated expression of interleukin-4 in dorsal root ganglion neurons reduces neuropathic pain.

BACKGROUND: To examine the role of inflammatory mediators in neuropathic pain, we used a replication-defective genomic herpes simplex virus (HSV)-based vector containing the coding sequence for the anti-inflammatory peptide interleukin (IL)-4 under the transcriptional control of the HSV ICP4 immediate early promoter, vector S4IL4, to express IL-4 in dorsal root ganglion (DRG) neurons in vivo. RESULTS: Subcutaneous inoculation of S4IL4 in the foot transduced lumbar DRG to produce IL-4. Transgene-mediated expression of IL-4 did not alter thermal latency or tactile threshold in normal animals, but inoculation of S4IL4 1 week after spinal nerve ligation (SNL) reduced mechanical allodynia and reversed thermal hyperalgesia resulting from SNL. Inoculation of S4IL4 1 week before SNL delayed the development of thermal hyperalgesia and tactile allodynia, but did not prevent the ultimate development of these manifestations of neuropathic pain. S4IL4 inoculation suppressed non-noxious-induced expression of c-Fos immunoreactivity in dorsal horn of spinal cord and reversed the upregulation of spinal IL-1beta, PGE2, and phosphorylated-p38 MAP kinase, characteristic of neuropathic pain. CONCLUSION: HSV-mediated expression of IL-4 effectively reduces the behavioral manifestations of neuropathic pain, and reverses some of the biochemical and histologic correlates of neuropathic pain at the spinal level.

Animals↗

PubMed2006

Tumor necrosis factor-alpha contributes to below-level neuropathic pain after spinal cord injury.

OBJECTIVE: Our objective was to elucidate the mechanisms responsible for below-level pain after partial spinal cord injury (SCI). METHODS: We used lateral hemisection to model central neuropathic pain and herpes simplex viral (HSV) vector-mediated transfer of the cleaved soluble receptor for tumor necrosis factor-alpha (TNF-alpha) to evaluate the role of TNF-alpha in the pathogenesis of below-level pain. RESULTS: We found activation of microglia and increased expression of TNF-alpha below the level of the lesion in the lumbar spinal cord after T13 lateral hemisection that correlated with emergence of mechanical allodynia in the hind limbs of rats. Lumbar TNF-alpha had an apparent molecular weight of 27 kDa, consistent with the full-length transmembrane form of the protein (mTNF-alpha). Expression of the p55 TNF soluble receptor (sTNFRs) by HSV-mediated gene transfer resulted in reduced pain behavior and a decreased number of ED1-positive cells, as well as decreased phosphorylation of the p38 MAP kinase (p-p38) and diminished expression of mTNF-alpha in the dorsal horn. INTERPRETATION: These results suggest that expression of mTNF-alpha after injury is related to development of pain, and that reverse signaling through mTNF-alpha by sTNFR at that level reduces cellular markers of inflammatory response and pain-related behavior.

Animals↗

PubMed2006

Soluble V domain of Nectin-1/HveC enables entry of herpes simplex virus type 1 (HSV-1) into HSV-resistant cells by binding to viral glycoprotein D.

Interaction of herpes simplex virus (HSV) glycoprotein D (gD) with specific cellular receptors is essential for HSV infection of susceptible cells. Virus mutants that lack gD can bind to the cell surface (attachment) but do not enter, implying that interaction of gD with its receptor(s) initiates the postattachment (entry) phase of HSV infection. In this report, we have studied HSV entry in the presence of the gD-binding variable (V) domain of the common gD receptor nectin-1/HveC to determine whether cell association of the gD receptor is required for HSV infection. In the presence of increasing amounts of the soluble nectin-1 V domain (sNec1(123)), increasing viral entry into HSV-resistant CHO-K1 cells was observed. At a multiplicity of 3 in the presence of optimal amounts of sNec1(123), approximately 90% of the cells were infected. The soluble V domain of nectin-2, a strain-specific HSV entry receptor, promoted entry of the HSV type 1 (HSV-1) Rid-1 mutant strain, but not of wild-type HSV-1. Preincubation and immunofluorescence studies indicated that free or gD-bound sNec1(123) did not associate with the cell surface. sNec1(123)-mediated entry was highly impaired by interference with the cell-binding activities of viral glycoproteins B and C. While gD has at least two functions, virus attachment to the cell and initiation of the virus entry process, our results demonstrate that the attachment function of gD is dispensable for entry provided that other means of attachment are available, such as gB and gC binding to cell surface glycosaminoglycans.

Animals↗

PubMed2005

Gene transfer of glutamic acid decarboxylase reduces neuropathic pain.

We tested whether transfer of the gene coding for glutamic acid decarboxylase to dorsal root ganglion using a herpes simplex virus vector to achieve release of GABA in dorsal horn would attenuate nociception in this condition. Subcutaneous inoculation of a replication-defective herpes simplex virus vector expressing glutamic acid decarboxylase (vector QHGAD67) 7 days after selective L5 spinal nerve ligation reversed mechanical allodynia and thermal hyperalgesia; the antiallodynic effect lasted 6 weeks and was reestablished by reinoculation. QHGAD67 inoculation also suppressed induction of c-Fos and phosphorylated extracellular signal-regulated kinase 1 and 2 in the spinal cord.

Animals↗

PubMed2005

Enhanced efficacy of conditionally replicating herpes simplex virus (G207) combined with 5-fluorouracil and surgical resection in peritoneal cancer dissemination models.

BACKGROUND: The therapeutic efficacy of G207, a replication-competent herpes simplex virus, for malignancies is increased when combined with certain chemotherapies, but the mechanism is unclear and the interaction between G207 and surgical resection has not been extensively studied. The goals of the current study were to examine the performance of combination treatments for peritoneal disseminated cancers and to explore the mechanism of effective combinations. METHODS: Hamsters and SCID and BALB/c mice harboring peritoneal dissemination of gallbladder, gastric or colon cancer cells were treated with G207, 5-fluorouracil (5FU), or surgical resection alone, or G207 combined with 5FU or surgery. Animal survival, antiviral immunity, intratumoral ribonucleotide reductase activity, and viral spread were compared between the groups. RESULTS: The combination of G207 and 5FU prolonged the survival of hamsters bearing peritoneal dissemination of gallbladder cancer compared with the controls, G207 alone and 5FU alone. 5FU did not suppress the production of neutralizing antibodies against G207, but increased ribonucleotide reductase activity and viral spread in subcutaneous gallbladder tumors. The enhanced efficacy of the combination treatment was also observed in immunodeficient mice with disseminated gastric cancer. Although surgical resection did not significantly prolong animal survival or increase the intratumoral activity of ribonucleotide reductase, long-term survivors emerged from groups of animals treated with surgical resection and G207 for gallbladder and colon disseminated cancers. CONCLUSIONS: These results indicate that the increased activity of ribonucleotide reductase in tumors mediated by 5FU and the decreased tumor burden resulting from surgical resection may enhance the therapeutic efficacy of oncolytic herpes virus for peritoneal disseminated cancer.

Animals↗

PubMed2005

Herpes simplex virus targeting to the EGF receptor by a gD-specific soluble bridging molecule.

Herpes simplex virus 1 (HSV-1) enters cells via initial binding of envelope glycoproteins (g) C and B to cell-surface glycosaminoglycans (GAGs) and subsequent membrane fusion involving envelope gD, gB, and gH/gL. Current insights suggest that the fusion process is initiated by interaction of gD with a cognate cellular receptor, such as the widely distributed cell adhesion molecule nectin-1. To redirect the tropism of HSV-1, we have generated a soluble adapter protein (P-V528LH) comprising the gD-binding variable domain of nectin-1 fused to a single-chain antibody (528LH) recognizing the EGF receptor. The adapter molecule enabled HSV-1 entry into naturally nonpermissive CHO cells expressing the human EGF receptor, but not into CHO cells lacking the receptor, and entry was not observed when the antibody portion of the adapter was replaced with an antibody of different specificity. Adapter-mediated entry increased with the viral dose and was nearly as efficient as direct viral entry into nectin-1-bearing CHO cells. Entry depended on viral gD and was diminished in the absence of cellular GAGs. These experiments represent the first demonstration that a soluble molecule can direct HSV infection via a new receptor, supporting the possible utility of this approach for HSV retargeting.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Long-term neuroprotection achieved with latency-associated promoter-driven herpes simplex virus gene transfer to the peripheral nervous system.

We examined the ability of the herpes simplex virus (HSV) latency-associated promoter (LAP2) to drive biologically relevant prolonged transgene expression in the peripheral nervous system. Rat dorsal root ganglia were transduced in vivo by subcutaneous inoculation of replication-incompetent HSV-based vectors containing nerve growth factor (NGF) or neurotrophin-3 (NT-3) under the control of LAP2 (vectors SLN and QLNT3, respectively) and vector SHN expressing NGF under the control of the human cytomegalovirus immediate early promoter. Twenty-four weeks later a pure sensory neuropathy was induced by overdose of pyridoxine (PDX), and the animals were assessed 6 months after inoculation. Inoculation of SLN, but not SHN, attenuated the nerve damage caused by PDX and protected foot sensory amplitude, H-wave amplitude, and behavioral measures of proprioceptive function. QLNT3 was more effective than SLN in preserving the largest myelinated fibers from degeneration. These results indicate that expression of NGF or NT-3 driven by LAP2 is sufficient to prevent the development of neuropathy 6 months after vector inoculation in rats.

Animals↗

PubMed2005

Combination gene therapy for glioblastoma involving herpes simplex virus vector-mediated codelivery of mutant IkappaBalpha and HSV thymidine kinase.

To improve the effectiveness of herpes simplex virus (HSV) thymidine kinase/ganciclovir (HSV-tk/GCV) suicide gene therapy, the replication-defective HSV vector TOIkappaB expressing both HSV-TK and a mutant form of the NF-kappaB inhibitor IkappaBalpha (IkappaBalphaM) was developed. TOIkappaB was constructed by recombining the IkappaBalphaM gene into the U(L)41 locus of a replication-defective lacZ expression vector, TOZ.1. Expression of IkappaBalphaM was confirmed by Western blotting, and the ability of the mutant protein to inhibit NF-kappaB nuclear translocation was examined by electrophoretic mobility shift assay. In human glioblastoma U-87MG cells, the p50/p50 dimer of NF-kappaB was already translocated to the nucleus without receptor-dependent signaling by TNF-alpha. Following infection with TOIkappaB, nuclear translocation of NF-kappaB in U-87MG cells was significantly inhibited and caspase-3 activity increased compared with TOZ.1-infected cells. The cytotoxicity of TOIkappaB for U-87MG cells was investigated by colorimetric MTT assay. At an MOI of 3, TOIkappaB infection killed 85% of the cells compared to 20% killed by TOZ.1 infection. In the presence of GCV, these numbers increased to 95-100% for TOIkappaB and 80-85% for TOZ.1. TOIkappaB neurotoxicity measured on cultured murine neurons was relatively low and similar to that of TOZ.1. The survival of nude mice implanted into the brain with U-87MG tumor cells was markedly prolonged by intratumoral TOIkappaB injection and GCV administration. Survival of TOIkappaB+GCV group was significantly longer (P<.02, Wilcoxon test) than for the control groups (TOZ.1 or TOIkappaB only, PBS or PBS+GCV). These results suggest that IkappaBalphaM expression may be a safe enhancement of replication-defective HSV-based suicide gene therapy in vitro and in vivo.

Animals↗

PubMed2005

Improvement in erectile dysfunction after neurotrophic factor gene therapy in diabetic rats.

PURPOSE: Erectile dysfunction (ED) is a common but difficult to treat complication of diabetes mellitus (DM). We have previously reported herpes simplex virus (HSV) vector mediated delivery of nerve growth factor into the bladder to treat diabetic cystopathy and neurotrophin-3 (NT3) gene transfer for pyridoxine treatment. Nerve growth factor and NT3 are neurotrophic factors that may protect nerves from mechanical and metabolic damage. We investigated the effects of HSV mediated delivery of NT3 for the treatment of diabetic ED. MATERIALS AND METHODS: Male Sprague-Dawley rats weighing 300 to 400 gm were injected with 65 mg/kg streptozotocin to induce DM. After 4 weeks 20 microl containing 5 x 10 pfu replication defective HSV vector expressing lacZ (6 rats) or NT3 (6) were injected directly into the cavernous nerve sheath with a 30 gauge needle. Four weeks later the animals underwent measurement of intracavernous pressure under electrical stimulation (20 Hz, 0.5 millisecond and 10 V) of the cavernous nerve. Staining for lacZ and neuronal nitric oxide synthase in the major pelvic ganglia was also performed. RESULTS: beta-Galactosidase staining revealed lacZ positive neurons in the major pelvic ganglia. Maximal intracavernous pressure induced by electrical stimulation showed statistically significant mean values +/- SEM of 15.1 +/- 2.1 and 43.8 +/- 11.1 cm H2O in the lacZ and NT3 vector injected groups, respectively (p = 0.03). The mean number of neuronal nitric oxide synthase positive neurons per section in the NT3 group was significantly higher than that in the lacZ control group at 3.33 +/- 0.23 and 0.64 +/- 0.14 neurons per high power field, respectively (p < 0.001). CONCLUSIONS: We report that gene therapy for the treatment of diabetic ED is feasible with HSV vectors. NT3 gene therapy may be applicable for the treatment of ED induced by DM.

Animals↗

PubMed2005

Equine herpesvirus 1 utilizes a novel herpesvirus entry receptor.

The well-described herpesvirus entry receptors HveA (TNFRSF14), HveB (nectin 2), and HveC (nectin 1) have been shown to mediate the entry of alphaherpesviruses. Our findings showed that the alphaherpesvirus equine herpesvirus 1 (EHV-1) efficiently entered and replicated in CHO-K1 cells that lack the entry receptors HveA, HveB, and HveC, demonstrating that EHV-1 utilizes a unique entry receptor. As with other alphaherpesviruses, efficient EHV-1 entry was dependent on glycoprotein D and cell surface glycosaminoglycans.

Animals↗

PubMed2005

Replication-defective genomic HSV gene therapy vectors: design, production and CNS applications.

Herpes simplex virus (HSV) is a neurotropic double-stranded DNA virus. In an unmodified form it is a human pathogen, causing recurrent cold sores, keratitis and, rarely, severe encephalitis. Elimination of pathogenic functions results in the generation of a valuable gene transfer vector for neurological applications. Replication-defective genomic HSV-based vectors are highly infectious, and efficiently transduce and express transgenes in a broad range of both dividing and non-dividing cells. Clinically relevant yields of clinical grade vector can be produced by growth in cell lines that complement the viral functions that are deleted in the vectors to eliminate pathogenicity. The viral genome is over 150 kb in length and many of the viral genes may be deleted without compromising viral growth in vitro, and therefore large or multiple transgenes can be accommodated within the vectors. The wild-type virus adopts a lifelong latent state in neurons of sensory ganglia. This property can be exploited in the generation of vectors to allow long-term transgene expression in neurons. In this review, we summarize recent progress in the areas of vector development and vector production, and in developing gene transfer therapeutics to treat malignant glioma.

Animals↗

PubMed2004

The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease.

Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXR), decrease amyloid beta (Abeta) secretion in vitro. The effect was attributed primarily to the ATP-binding cassette transporter A1 (ABCA1) transcriptionally up-regulated by ligand-activated LXRs. We now examined the effect of the synthetic LXR ligand T0901317, which can be used in vivo, on Abeta production in vitro and in APP23 transgenic mice. T0901317 applied to a variety of in vitro models, including immortalized fibroblasts from Tangier patients, and primary embryonic mouse neurons caused a concentration-dependent decrease in Abeta secretion, and this effect was increased by the addition of apolipoprotein A-I. The inhibition of Abeta production by T0901317 was cell-type specific, being more prominent in primary neurons than in non-neuronal cells. Tangier fibroblasts lacking a functional ABCA1 secreted more Abeta than control fibroblasts, thus demonstrating the role of ABCA1 in amyloid precursor protein (APP) processing and Abeta generation. T0901317 treatment of 11-week-old APP23 mice for 6 days showed a significant increase in ABCA1 expression and a decrease in the ratio of soluble APP (sAPP)beta- to sAPPalpha-cleavage products. Most importantly, the treatment caused a statistically significant reduction in the levels of soluble Abeta40 and of Abeta42 in the brain these mice. Our experiments demonstrate that T0901317 decreases amyloidogenic processing of APP in vitro and in vivo, thus supporting the search for potent and specific LXR ligands with properties allowing therapeutic application.

Alzheimer Disease↗