Development and Validation of Two Optimized Multiplexed Serologic Assays for the 9-Valent Human Papillomavirus Vaccine Types.

Two multiplex immunoassays are routinely used to assess antibody responses in clinical trials of the 9-valent human papillomavirus (9vHPV) vaccine. The HPV6/11/16/18/31/33/45/52/58 competitive Luminex immunoassay (HPV-9 cLIA) and HPV6/11/16/18/31/33/45/52/58 total immunoglobulin G Luminex immunoassay are used for measurements of immunogenicity. Following their initial validation in 2010, both assays were redeveloped, and several parameters were optimized, including the coating concentration of virus-like particles, type of Luminex microspheres, serum sample and reference standard diluent, reference standard starting dilution and titration series, and vendor and concentration of the phycoerythrin-labeled antibodies. Validation studies evaluated the assay performance parameters, including the intra-assay precision (repeatability), intermediate precision, linearity, relative accuracy, and limits of quantitation. In addition, since maintaining a link to the original assays that were used in trials supporting vaccine licensure is critical, the assays were formally bridged to the previous assay versions by using individual patient sera from a 9vHPV vaccine clinical trial (n = 150 day 1 [prevaccination] samples; n = 100 month 7 [1 month post-last vaccine dose] and n = 100 month 36 [30 months post-last vaccine dose; antibody persistence] samples). The results of the validation studies indicate that both optimized assays are accurate, specific, and precise over their respective quantifiable ranges. There was a strong linear association between the new and previous versions of both assays. Assay serostatus cutoffs for the redeveloped assays were established based on the bridging studies and, for the HPV-9 cLIA, further refined, based on additional data from HPV vaccine clinical studies so as to align the seropositivity rates between assay versions. IMPORTANCE Assay modernization is a key aspect of vaccine life cycle management. Thus, new, reoptimized versions of two 9vHPV immunoassays have been developed and validated for use in ongoing and future HPV vaccine clinical trials. These assays are suitable for use in high-throughput testing for HPV antibodies in serum samples. Bridging to previous versions of the assays allows for the continuous monitoring of immune responses across assay versions, including in immunogenicity studies that involve new populations as well as long-term follow-up studies.

A phase 3, multicenter, randomized, double-blind, active-comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of a 4-dose regimen of V114, a 15-valent pneumococcal conjugate vaccine, in healthy infants (PNEU-PED).

BACKGROUND: Pneumococcal disease (PD) remains a major health concern with considerable morbidity and mortality in children. Currently licensed pneumococcal conjugate vaccines (PCVs) confer protection against PD caused by most vaccine serotypes, but non-vaccine serotypes contribute to residual disease. V114 is a 15-valent PCV containing all 13 serotypes in Prevnar 13™ (PCV13) and additional serotypes 22F and 33F. This pivotal phase 3 study compared safety and immunogenicity of V114 and PCV13. METHODS: 1720 healthy infants were randomized 1:1 to receive a 4-dose regimen of V114 or PCV13 concomitantly with other routine pediatric vaccines. Safety was evaluated after each dose as proportion of participants with adverse events (AEs). Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured at 1-month post-dose 3 (PD3), pre-dose 4, and 1-month post-dose 4 (PD4). IgG response rates, geometric mean concentrations (GMCs), and opsonophagocytic activity (OPA) were compared between vaccination groups. RESULTS: The proportion, maximum intensity, and duration of injection-site, systemic, and serious AEs were generally comparable between V114 and PCV13 groups. In comparison to PCV13, V114 met non-inferiority criteria for all 15 serotypes based on IgG response rates at PD3. V114 met non-inferiority criteria by IgG GMCs for all serotypes at PD3 and PD4, except for serotype 6A at PD3. V114-induced antibodies had bactericidal activity as assessed by OPA. Further, V114 met superiority criteria for shared serotype 3 and unique serotypes 22F and 33F compared to PCV13 by serotype-specific IgG GMCs at both PD3 and PD4. Immunogenicity of concomitantly administered routine pediatric vaccines was comparable in V114 and PCV13 groups. CONCLUSIONS: In healthy infants, V114 displays acceptable safety and tolerability profiles and generates comparable immune responses to PCV13. V114 also met superiority criteria for serotypes 3, 22F, and 33F. These results support use of V114 for prevention of PD as part of routine infant vaccination schedules. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03893448; EudraCT: 2018-004109-21.

Immunogenicity, Safety, and Tolerability of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Immunocompetent Adults Aged 18-49 Years With or Without Risk Factors for Pneumococcal Disease: A Randomized Phase 3 Trial (PNEU-DAY).

BACKGROUND: Adults with certain medical and behavioral factors are at increased risk for pneumococcal disease (PD). Sequential vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults in some countries. METHODS: This phase 3 trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults aged 18-49 years with or without predefined risk factors for PD (NCT03547167). Overall, 1515 participants were randomized 3:1 to receive either V114 or PCV13, followed by PPSV23. RESULTS: Most common solicited adverse events (AEs) following administration of V114 or PCV13 as well as PPSV23 were injection-site pain and fatigue. The proportion of participants with AEs was comparable in both groups. V114 and PCV13 were immunogenic based on opsonophagocytic activity (OPA) geometric mean titers (GMTs) 30 days postvaccination for all serotypes contained in each respective vaccine. OPA GMTs to the 2 unique serotypes in V114 were robust in the V114 group. PPSV23 was immunogenic for all 15 serotypes contained in V114 in both vaccination groups, including 22F and 33F. CONCLUSIONS: V114 administered alone or sequentially with PPSV23 is well tolerated and immunogenic for all 15 serotypes, including those not contained in PCV13, in immunocompetent adults aged 18-49 years with or without certain medical or behavioral risk factors for PD. CLINICAL TRIALS REGISTRATION: NCT03547167 and EudraCT 2017-004915-38.

Design of a phase III efficacy, immunogenicity, and safety study of 9-valent human papillomavirus vaccine in prevention of oral persistent infection in men.

BACKGROUND: Seven high-risk human papillomavirus (HPV) types (16/18/31/33/45/52/58) covered by the 9-valent HPV (9vHPV) vaccine cause >90% of HPV-related head and neck cancers (HNCs). An ongoing clinical trial (NCT04199689) was designed to evaluate 9vHPV vaccine efficacy against HPV oral persistent infection, a surrogate endpoint for HPV-related HNCs. METHODS: In this double-blind, placebo-controlled, international trial, men aged 20-45 years (N = 6000) are randomized 1:1 to receive 9vHPV vaccine or placebo on day 1, month 2, and month 6. The primary objective is to demonstrate whether 9vHPV vaccination reduces incidence of HPV16/18/31/33/45/52/58-related 6-month oral persistent infection. Incidence of HPV6/11-related 6-month oral persistent infection will be evaluated as a secondary endpoint. Oral rinse and gargle samples will be collected on day 1, month 7, month 12, and every 6 months thereafter for HPV detection by PCR. Primary analyses will be performed in per-protocol populations. Efficacy in this case-driven study will be analyzed upon accrual of ≥20 primary efficacy endpoint cases. Serum will be collected at day 1 and months 7, 12, 24, 36, and 42; anti-HPV antibody titers will be measured by competitive Luminex immunoassay. Data will be summarized as geometric mean titers and seropositivity rates. Injection-site and systemic adverse events (AEs) will be collected for 15 days post-any vaccination and serious AEs through 6 months after the last vaccination; deaths and vaccine-related serious AEs will be collected throughout the study. DISCUSSION: This trial is expected to generate important data regarding the potential for 9vHPV vaccine to prevent HPV-related head and neck disease.

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in Vietnamese males and females (9 to 26 years of age): an open-label, phase 3 trial.

This open-label, single-center, Phase 3 study (NCT03546842) assessed the immunogenicity and safety of the nine-valent human papillomavirus (9vHPV; HPV6/11/16/18/31/33/45/52/58) vaccine in Vietnamese males and females, with the aim to support 9vHPV vaccine licensure in Vietnam. Participants aged 9-26 years received three 9vHPV vaccine doses (Day 1, Month 2, Month 6). Serum samples were obtained on Day 1 (pre-vaccination) and at Month 7 (one month post-Dose 3) for the measurement of anti-HPV antibodies. Geometric mean titers (GMTs) and seroconversion percentages were obtained using the HPV-9 competitive Luminex immunoassay. Injection-site adverse events (AEs), systemic AEs, serious AEs (SAEs), and study discontinuations due to AEs were recorded. Of 201 participants enrolled, 200 (99.5%) received ≥1 vaccine dose. All participants who received the three-dose regimen (198/200, 98.5%) seroconverted for all 9vHPV vaccine types by Month 7. Robust anti-HPV GMT responses were also observed. Half of participants (50.5%) reported ≥1 AE; the majority were injection-site-related (45.0%) and mild (43.0%). There were no deaths, vaccine-related SAEs, or discontinuations due to AEs. Administration of three 9vHPV vaccine doses was highly immunogenic and resulted in acceptable seropositivity percentages for all vaccine HPV types. The 9vHPV vaccine was generally well tolerated among this study population.Region of origin: VietnamTrial registration: clinicaltrials.gov Identifier NCT03546842.

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27-45 years of age compared to women 16-26 years of age: An open-label phase 3 study.

BACKGROUND: Efficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16-26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27-45 versus 16-26 years of age. METHODS: This international, open-label study (NCT03158220) was conducted in women 16-45 years of age. Participants (16-26 years, n = 570 and 27-45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study. RESULTS: At month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27-45 years were compared to those in women 16-26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27-45 years to 16-26 years) was 0.60-0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27-45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16-26 years, and 85.2% and 24.1% of women 27-45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study. CONCLUSIONS: The 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27-45 years compared with women 16-26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16-26 years to women 27-45 years of age. Clinical trial registration NCT03158220.

Use of a Bile Salt Export Pump Knockdown Rat Susceptibility Model to Interrogate Mechanism of Drug-Induced Liver Toxicity.

Inhibition of the bile salt export pump (BSEP) may be associated with clinical drug-induced liver injury, but is poorly predicted by preclinical animal models. Here we present the development of a novel rat model using siRNA knockdown (KD) of Bsep that displayed differentially enhanced hepatotoxicity to 8 Bsep inhibitors and not to 3 Bsep noninhibitors when administered at maximally tolerated doses for 7 days. Bsep KD alone resulted in 3- and 4.5-fold increases in liver and plasma levels, respectively, of the sum of the 3 most prevalent taurine conjugated bile acids (T3-BA), approximately 90% decrease in plasma and liver glycocholic acid, and a distinct bile acid regulating gene expression pattern, without resulting in hepatotoxicity. Among the Bsep inhibitors, only asunaprevir and TAK-875 resulted in serum transaminase and total bilirubin increases associated with increases in plasma T3-BA that were enhanced by Bsep KD. Benzbromarone, lopinavir, and simeprevir caused smaller increases in plasma T3-BA, but did not result in hepatotoxicity in Bsep KD rats. Bosentan, cyclosporine A, and ritonavir, however, showed no enhancement of T3-BA in plasma in Bsep KD rats, as well as Bsep noninhibitors acetaminophen, MK-0974, or clarithromycin. T3-BA findings were further strengthened through monitoring TCA-d4 converted from cholic acid-d4 overcoming interanimal variability in endogenous bile acids. Bsep KD also altered liver and/or plasma levels of asunaprevir, TAK-875, TAK-875 acyl-glucuronide, benzbromarone, and bosentan. The Bsep KD rat model has revealed differences in the effects on bile acid homeostasis among Bsep inhibitors that can best be monitored using measures of T3-BA and TCA-d4 in plasma. However, the phenotype caused by Bsep inhibition is complex due to the involvement of several compensatory mechanisms.

Antibiotic-Induced Elevations of Plasma Bile Acids in Rats Independent of Bsep Inhibition.

Drug-induced liver injury (DILI) is a common toxicity observed in drug development and can lead to withdrawal of approved drugs from the market. To better understand the numerous mechanisms of DILI, recent efforts have focused on transporter inhibition, specifically liver canalicular bile salt export pump (Bsep) as one mechanism of DILI, and on the potential use of plasma bile acids as monitorable mechanism-based biomarkers of Bsep inhibition. To explore alternative mechanisms of bile acid increases in plasma, 6 antibiotic and 2 nonantibiotic drugs unlikely to be Bsep inhibitors were evaluated in rat studies. Surprisingly, all 6 antibiotics demonstrated 2- to 14-fold increases of plasma taurocholic acid (TCA). Also, unconjugated primary bile acids and secondary bile acids (both taurine-conjugated and unconjugated) were decreased in rat plasma after antibiotic treatments, but not with the nonantibiotic drugs. These results suggest alternative mechanisms of bile acids regulation such as attenuation of bacterial deconjugation of bile acids following reduction of gut microflora by antibiotics. Measurements of TCA transport in rat hepatocytes and Bsep-containing membrane vesicles suggest that inhibition of uptake into hepatocytes could also contribute to increases in plasma bile acid concentrations, while excluding inhibition of Bsep as a mechanism. These studies further demonstrate that there are several mechanisms that can lead to conjugated bile acid increases in plasma. By carefully considering the time course and magnitude of changes of individual bile acids relative to any changes seen in transaminases and bilirubin, interpretations and conclusions of the involvement of Bsep inhibition are enabled.

Treatment comparison in randomized clinical trials with nonignorable missingness: A reverse regression approach.

A common problem in randomized clinical trials is nonignorable missingness, namely that the clinical outcome(s) of interest can be missing in a way that is not fully explained by the observed quantities. This happens when the continued participation of patients depends on the current outcome after adjusting for the observed history. Standard methods for handling nonignorable missingness typically require specification of the response mechanism, which can be difficult in practice. This article proposes a reverse regression approach that does not require a model for the response mechanism. Instead, the proposed approach relies on the assumption that missingness is independent of treatment assignment upon conditioning on the relevant outcome(s). This conditional independence assumption is motivated by the observation that, when patients are effectively masked to the assigned treatment, their decision to either stay in the trial or drop out cannot depend on the assigned treatment directly. Under this assumption, one can estimate parameters in the reverse regression model, test for the presence of a treatment effect, and in some cases estimate the outcome distributions. The methodology can be extended to longitudinal outcomes under natural conditions. The proposed approach is illustrated with real data from a cardiovascular study.

On exchangeable multinomial distributions.

We derive an expression for the joint distribution of exchangeable multinomial random variables, which generalizes the multinomial distribution based on independent trials while retaining some of its important properties. Unlike de Finneti's representation theorem for a binary sequence, the exchangeable multinomial distribution derived here does not require that the finite set of random variables under consideration be a subset of an infinite sequence. Using expressions for higher moments and correlations, we show that the covariance matrix for exchangeable multinomial data has a different form from that usually assumed in the literature, and we analyse data from developmental toxicology studies. The proposed analyses have been implemented in R and are available on CRAN in the CorrBin package.

Pioglitazone increases whole body insulin sensitivity in obese, insulin-resistant rhesus monkeys.

Hyperinsulinemic-euglycemic clamps are considered the "gold standard" for assessing whole body insulin sensitivity. When used in combination with tracer dilution techniques and physiological insulin concentrations, insulin sensitization can be dissected and attributed to hepatic and peripheral (primarily muscle) effects. Non-human primates (NHPs), such as rhesus monkeys, are the closest pre-clinical species to humans, and thus serve as an ideal model for testing of compound efficacy to support translation to human efficacy. We determined insulin infusion rates that resulted in high physiological insulin concentrations that elicited maximal pharmacodynamic responses during hyperinsulinemic-euglycemic clamps. These rates were then used with [U-13C]-D-glucose, to assess and document the degrees of hepatic and peripheral insulin resistance between healthy and insulin-resistant, dysmetabolic NHPs. Next, dysmetabolic NHPs were treated for 28 days with pioglitazone (3 mg/kg) and again had their insulin sensitivity assessed, illustrating a significant improvement in hepatic and peripheral insulin sensitivity. This coincided with a significant increase in insulin clearance, and normalization of circulating adiponectin. In conclusion, we have determined a physiological clamp paradigm (similar to humans) for assessing glucose turnover in NHPs. We have also demonstrated that insulin-resistant, dysmetabolic NHPs respond to the established insulin sensitizer, pioglitazone, thus confirming their use as an ideal pre-clinical translational model to assess insulin sensitizing compounds.

A mixture of transition models for heterogeneous longitudinal ordinal data: with applications to longitudinal bacterial vaginosis data.

Markov models used to analyze transition patterns in discrete longitudinal data are based on the limiting assumption that individuals follow the common underlying transition process. However, when one is interested in diseases with different disease or severity subtypes, explicitly modeling subpopulation-specific transition patterns may be appropriate. We propose a model which captures heterogeneity in the transition process through a finite mixture model formulation and provides a framework for identifying subpopulations at different risks. We apply the procedure to longitudinal bacterial vaginosis study data and demonstrate that the model fits the data well. Further, we show that under the mixture model formulation, we can make the important distinction between how covariates affect transition patterns unique to each of the subpopulations and how they affect which subgroup a participant will belong to. Practically, covariate effects on subpopulation-specific transition behavior and those on subpopulation membership can be interpreted as effects on short-term and long-term transition behavior. We further investigate models with higher-order subpopulation-specific transition dependence.

Trajectories of kinematic risky driving among novice teenagers.

OBJECTIVES: Elevated gravitational force event rates are associated with the likelihood of a crash or near crash and provide an objective measure of risky driving. The purpose of this research is to examine the patterns over time of kinematic measures of risky driving among novice teenage drivers. METHODS: Driving data were collected from 42 newly licensed teenage drivers during the first 18 months of licensure. Data recording systems installed in participants' vehicles provided information on driving performance and driver characteristics. Latent class and logistic regression models were used to analyze trajectories of elevated gravitational-force (g-force) event rates, called kinematic risky driving, with respect to risk groups and associated factors. RESULTS: Kinematic risky driving over the 18-month study period was best characterized as two classes, a higher-risk and a lower-risk class. The rate of kinematic risky driving during the first 6 months generally maintained over 18 months. Indeed, of those classified by latent class analysis as higher risk, 88.9%, 94.4% and 94.4% had average event rates above the median in the 1st, 2nd, and 3rd 6-month periods, respectively, indicating substantial tracking over time. Friends' risky driving, friends' risky behavior, self-reported risky driving, and perceptions about risky driving and driving privileges were associated with trip-level rates of kinematic risky driving. However, none of these factors was associated with trip-level rates after stratifying by overall risk in a latent class model, although friend's risky driving was marginally significant. CONCLUSION: Kinematic risky driving tended to track over time within the lower and higher risky driving groups. Self-reported risky driving and having risky friends were predictors of kinematic risky driving rates, but these variables did not explain the heterogeneity within higher and lower classes of risky drivers.

The impact of random-effect misspecification on percentile estimation for longitudinal growth data.

Identifying unusual growth-related measurements or longitudinal patterns in growth is often the focus in fetal and pediatric medicine. For example, the goal of the ongoing National Fetal Growth Study is to develop both cross-sectional and longitudinal reference curves for ultrasound fetal growth measurements that can be used for this purpose. Current methodology for estimating cross-sectional and longitudinal reference curves relies mainly on the linear mixed model. The focus of this paper is on examining the robustness of percentile estimation to the assumptions with respect to the Gaussian random-effect assumption implicitly made in the standard linear mixed model. We also examine a random-effects distribution based on mixtures of normals and compare the two approaches under both correct and misspecified random-effects distributions. In general, we find that the standard linear mixed model is relatively robust for cross-sectional percentile estimation but less robust for longitudinal or 'personalized' reference curves based on the conditional distribution given prior ultrasound measurements. The methodology is illustrated with data from a longitudinal fetal growth study.

Candidate measures of whole plant food intake are related to biomarkers of nutrition and health in the US population (National Health and Nutrition Examination Survey 1999-2002).

Indices of overall dietary patterns are used in epidemiologic research to examine the relationship between nutrition and health. The objective of this study was to develop and validate an interpretable summary measure of dietary intake of whole plant foods (WPF; whole grains, vegetables, whole fruit, legumes, nuts, seeds) because of their similar nutritional characteristics and health effects. Six candidate WPF measures were calculated using data from subjects (age ≥ 6 years) participating in the 1999-2000 and 2001-2002 National Health and Nutrition Examination Survey. Measures differed by the inclusion or exclusion of potatoes and whether they were expressed as total intake or as a proportion of energy (4180 kJ) or mass (kg) consumed. Both standard and nontruncated (allowed to vary proportionally with intake) Healthy Eating Index-2005 (HEI-2005) scores were calculated. Regression analysis examined the associations between WPF and HEI-2005 measures, and between all diet measures and serum carotenoid concentration, serum lipids, fasting glucose, insulin, C-peptide, and C-reactive protein. Mean total WPF intake was 3.6 cup/oz equivalents, or 1.7 cup/oz equivalents per 4180 kJ and per kg. The largest R² between WPF and HEI-2005 measures was found for energy-adjusted WPF including potatoes and nontruncated HEI-2005 (R² = 0.50). All diet measures were positively related to serum carotenoids (P <.001) and were similarly related to health indicators (R² range from 0.003 to 0.16, P <.045 for regressions, indicating significant associations between WPF measures and health indicators). Whole plant food measures are interpretable indicators of dietary intake that are significantly related to nutrition and health biomarkers and may be of public health use.

Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 (Rp1) gene.

Retinitis pigmentosa (RP), a common group of human retinopathic diseases, is characterized by late-onset night blindness, loss of peripheral vision, and diminished or absent electroretinogram (ERG) responses. Mutations in the photoreceptor-specific gene RP1 account for 5-10% of cases of autosomal dominant RP. We generated a mouse model of the RP1 form of RP by targeted disruption of the mouse ortholog (Rp1) of human RP1. In Rp1(-/-) mice, the number of rod photoreceptors decreased progressively over a period of 1 year, whereas that of cone photoreceptors did not change for at least 10 months. Light and electron microscopic analysis revealed that outer segments of Rp1(-/-) rods and cones were morphologically abnormal and became progressively shorter in length. Before photoreceptor cell death, rhodopsin was mislocalized in inner segments and cell bodies of Rp1(-/-) rods. Rod ERG amplitudes of Rp1(-/-) mice were significantly smaller than those of Rp1(+/+) mice over a period of 12 months, whereas those of Rp1(+/-) mice were intermediate. The decreases in cone ERG amplitudes were slower and less severe than those in rods. These findings demonstrate that Rp1 is required for normal morphogenesis of photoreceptor outer segments and also may play a role in rhodopsin transport to the outer segments. The phenotype of Rp1 mutant mice resembles the human RP1 disease. Thus, these mice provide a useful model for studies of RP1 function, disease pathology, and therapeutic interventions.