Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neurology
Total Results:
23001
First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B
Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood.
PMID: 36299240
ISSN: 1525-0024
CID: 5359542
Federated learning enables big data for rare cancer boundary detection
Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing.
PMCID:9722782
PMID: 36470898
ISSN: 2041-1723
CID: 5381682
Functional Outcomes of a Comprehensive, Individualized, Person-Centered Management Program in Advanced Alzheimer"™s Disease(AD): Results from a 52-Week Randomized Controlled Trial
Background: We conducted a 28-week, single-blind, randomized, controlled trial of the efficacy of Comprehensive, Individualized, Person-Centered Management (CI-PCM) and memantine treatment (Reisberg et al., Dement Geriatr Cogn Disord, 2017) in advanced AD persons. CI-PCM and memantine was approximately 7.5 times more beneficial to AD persons on the Functional Assessment Staging Tool (FAST) (Kenowsky et. al., Alzheimer"™s and Dementia, 2017) than to AD persons who received memantine alone in the memantine FDA approval pivotal trial conducted by Reisberg et. al., (NEJM 2003). We also conducted a 24-week extension study. Herein, we report the difference in functional outcomes between the CI-PCM and Usual Community Care (UCC+FC) groups at 52-weeks on the FAST and the ADCS-ADLSev-Abv. See Figures 1 and 2. Method: After screening, 20 eligible subject-carepartner dyads were randomized equally to the CI-PCM and UCC+FC groups. All 20 dyads completed the 28-week study and entered the 24-week extension study. One subject in the UCC+FC group died during the extension study. The FAST and ADCS-ADLsev-abv were conducted at baseline, and weeks 4, 12, 28, and 52. P values were calculated using the Wilcoxon Mann Whitney test. Result: The mean FAST total score from baseline (6.6±0.1SE) to week 52 (6.5±0.01SE) showed an improvement of functional limitations in the CI-PCM group. The mean FAST total score for the UCC+FC group showed a functional decline from baseline (6.6±0.1SE) to week 52 (6.8±0.1SE), displaying a robustly significant difference between the two groups (p<0.0014). The mean ADCS-ADL-sev-abv total score for the CI-PCM group demonstrated a 20.9% improvement in functioning from baseline (15.3±2.0SE) to week 52 (18.5±2.5SE). The mean ADCS-ADL-sev-abv total score for the UCC+FC group showed a decline of 48.6% from baseline (14.8±2.1SE) to week 52 (7.6±2.3SE), indicating a significant difference between the two groups (p<0.009). Conclusion: The CI-PCM program is the only evidenced-based treatment to date that can significantly improve and reverse functional deterioration in advanced AD persons. The functional success of the CI-PCM program may primarily be attributed to care partners learning to memory coach AD persons to perform daily activities such as bathing, dressing, feeding and toileting themselves, and to become/maintain urinary and fecal continence.
SCOPUS:85144362721
ISSN: 1552-5260
CID: 5393842
Tackling the Unmet Therapeutic Needs in Nonsurgical Treatments for Epilepsy
PMID: 36066899
ISSN: 2168-6157
CID: 5332412
Normative Data and Conversion Equation for Spectral-Domain Optical Coherence Tomography in an International Healthy Control Cohort
BACKGROUND:Spectral-domain (SD-) optical coherence tomography (OCT) can reliably measure axonal (peripapillary retinal nerve fiber layer [pRNFL]) and neuronal (macular ganglion cell + inner plexiform layer [GCIPL]) thinning in the retina. Measurements from 2 commonly used SD-OCT devices are often pooled together in multiple sclerosis (MS) studies and clinical trials despite software and segmentation algorithm differences; however, individual pRNFL and GCIPL thickness measurements are not interchangeable between devices. In some circumstances, such as in the absence of a consistent OCT segmentation algorithm across platforms, a conversion equation to transform measurements between devices may be useful to facilitate pooling of data. The availability of normative data for SD-OCT measurements is limited by the lack of a large representative world-wide sample across various ages and ethnicities. Larger international studies that evaluate the effects of age, sex, and race/ethnicity on SD-OCT measurements in healthy control participants are needed to provide normative values that reflect these demographic subgroups to provide comparisons to MS retinal degeneration. METHODS:Participants were part of an 11-site collaboration within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. SD-OCT was performed by a trained technician for healthy control subjects using Spectralis or Cirrus SD-OCT devices. Peripapillary pRNFL and GCIPL thicknesses were measured on one or both devices. Automated segmentation protocols, in conjunction with manual inspection and correction of lines delineating retinal layers, were used. A conversion equation was developed using structural equation modeling, accounting for clustering, with healthy control data from one site where participants were scanned on both devices on the same day. Normative values were evaluated, with the entire cohort, for pRNFL and GCIPL thicknesses for each decade of age, by sex, and across racial groups using generalized estimating equation (GEE) models, accounting for clustering and adjusting for within-patient, intereye correlations. Change-point analyses were performed to determine at what age pRNFL and GCIPL thicknesses exhibit accelerated rates of decline. RESULTS:The healthy control cohort (n = 546) was 54% male and had a wide distribution of ages, ranging from 18 to 87 years, with a mean (SD) age of 39.3 (14.6) years. Based on 346 control participants at a single site, the conversion equation for pRNFL was Cirrus = -5.0 + (1.0 × Spectralis global value). Based on 228 controls, the equation for GCIPL was Cirrus = -4.5 + (0.9 × Spectralis global value). Standard error was 0.02 for both equations. After the age of 40 years, there was a decline of -2.4 μm per decade in pRNFL thickness ( P < 0.001, GEE models adjusting for sex, race, and country) and -1.4 μm per decade in GCIPL thickness ( P < 0.001). There was a small difference in pRNFL thickness based on sex, with female participants having slightly higher thickness (2.6 μm, P = 0.003). There was no association between GCIPL thickness and sex. Likewise, there was no association between race/ethnicity and pRNFL or GCIPL thicknesses. CONCLUSIONS:A conversion factor may be required when using data that are derived between different SD-OCT platforms in clinical trials and observational studies; this is particularly true for smaller cross-sectional studies or when a consistent segmentation algorithm is not available. The above conversion equations can be used when pooling data from Spectralis and Cirrus SD-OCT devices for pRNFL and GCIPL thicknesses. A faster decline in retinal thickness may occur after the age of 40 years, even in the absence of significant differences across racial groups.
PMID: 36049213
ISSN: 1536-5166
CID: 5337812
Clinical Implications of Internal Carotid Arterial Tortuosity in Patients with White Matter Hyperintensities
Background: White matter hyperintensities (WMHs) are observed frequently on MRI in elderly and associated with cognitive dysfunction. Many studies focused on intracranial small vessel disease (SVD), however, few studies linked WMHs with changes of extracranial large feeding arteries. We aimed to investigate the effects of internal carotid artery (ICA) tortuosity changes through quantitative MR Angiography. Method: Fifty-seven patients (age: 72.98±5.62; 32 females/25 males) with WMHs were included. WMHs lesions were semi-automatically segmented on FLAIR images. ICAs were segmented on the TOF images to generate tortuosity quantitative metrics, including tortuosity index (TI), inflection count metric (ICM), and ICA angle (Figure 1). According to the Fazekas scores, patients were categorized into mild, moderate and severe groups as summarized in Table 1. One-way ANOVA analyses were applied to reveal the difference of averaged bilateral ICAs' tortuosity measurements. Pearson's correlation coefficients were calculated to quantitatively investigate the relationship between tortuosity and volumes of lesions that are apart from the ventricle in subcortical white matter, i.e., deep white matter lesions (DWMLs), as well as the lesions attached with the ventricular system, i.e., periventricular white matter lesions (PVWMLs). Result: Patients with higher Fazekas scores have higher TI and ICM, indicating higher tortuosity (Figure 2). The correlation results showed that TI and ICM were positively correlated with DWMLs volumes (r = 0.33, P< 0.05; r = 0.4, P< 0.01), however, they did not show associations with PVWMLs. While there's no correlation between averaged bilateral ICA angles and DWMLs or PVWMLs, we found significant correlations between left ICA angles and DWML volumes on left brain (r =0.56, P < 0.005) as well as between right ICA angles and DWML volumes on right brain (r = 0.49, P < 0.05) (Figure 3). Conclusion: Tortuosity measurements derived from TOF images showed that subjects with higher degree of ICA tortuosity had higher lesion volumes of DWMLs not PVWMLs, indicating DWMLs may have different etiologies such as ischemic origin. The findings also highlight the importance of ICA angle as a risk factor for WMHs development which might be associated with the local hemodynamic shear stress at the bulb, where the ICA plaques are often developed.
SCOPUS:85144449727
ISSN: 1552-5260
CID: 5393902
Journal of the National Comprehensive Cancer Network : JNCCN. 2022:20(12):1363-1369.DOI: 10.6004/jnccn.2022.7093
Current Role and Future Potential of CSF ctDNA for the Diagnosis and Clinical Management of Pediatric Central Nervous System Tumors
Most pediatric central nervous system (CNS) tumors are located in eloquent anatomic areas, making surgical resection and, in some cases, even biopsy risky or impossible. This diagnostic predicament coupled with the move toward molecular classification for diagnosis has exposed an urgent need to develop a minimally invasive means to obtain diagnostic information. In non-CNS solid tumors, the detection of circulating tumor DNA (ctDNA) in plasma and other bodily fluids has been incorporated into routine practice and clinical trial design for selection of molecular targeted therapy and longitudinal monitoring. For primary CNS tumors, however, detection of ctDNA in plasma has been challenging. This is likely related at least in part to anatomic factors such as the blood-brain barrier. Due to the proximity of primary CNS tumors to the cerebrospinal fluid (CSF) space, our group and others have turned to CSF as a rich alternative source of ctDNA. Although multiple studies at this time have demonstrated the feasibility of CSF ctDNA detection across multiple types of pediatric CNS tumors, the optimal role and utility of CSF ctDNA in the clinical setting has not been established. This review discusses the work-to-date on CSF ctDNA liquid biopsy in pediatric CNS tumors and the associated technical challenges, and reviews the promising opportunities that lie ahead for integration of CSF ctDNA liquid biopsy into clinical care and clinical trial design.
PMCID:10050207
PMID: 36509077
ISSN: 1540-1413
CID: 5770472
Updates on efficacy and safety outcomes of new and emerging disease modifying therapies and stem cell therapy for Multiple Sclerosis: A review
Multiple Sclerosis (MS) is a chronic neurodegenerative autoimmune disorder of the central nervous system (CNS) and the most common cause of serious physical disability in working-age adults. Drug development and research in this field have rapidly evolved over the past two decades, leading to the broad array of treatment options available today. These disease-modifying therapies (DMTs) work through distinct mechanisms of action and exhibit varying safety and efficacy profiles to help manage symptoms and reduce exacerbations in MS patients. Our extensive understanding of this condition has also led to novel approaches, such as the discovery of specific biomarkers that allow us to monitor the therapeutic response towards DMTs. The development of new DMTs continues to progress quickly today, and it can be difficult for clinicians to remain up to date on the most recent advancements and new treatment options for their patients. In this comprehensive review, we provide an outline of current MS medications in the pipeline including emerging DMTs and stem cell therapy, as well as the unique characteristics of these medications, including their indications, pharmacokinetic effects, and the relevant advancements.
PMID: 36057173
ISSN: 2211-0356
CID: 5843552
A new classification for diagnosis of optic neuritis
PMID: 36179755
ISSN: 1474-4465
CID: 5334682
Journal of prevention of Alzheimer's disease. 2022:Conference:(15th):S81-S82.DOI: 10.14283/jpad.2022.97
PEPINEMAB, A SEMA4D BLOCKING ANTIBODY, IS A NOVEL POTENTIAL TREATMENT for NEURODEGENERATIVE DISEASE: CLINICAL PROOF of CONCEPT in PHASE 2 HD STUDY SUPPORTS CLINICAL DEVELOPMENT in AN ONGOING PHASE 1/2 AD STUDY [Meeting Abstract]
Background: Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin receptors. SEMA4D is upregulated in neurons during Huntington's Disease (HD) and alzheimer's Disease (AD) progression and triggers astrocytes that express plexin-B1/B2 receptor to undergo reactive gliosis with concomitant loss of normal astrocyte functions1. Drivers of glial cell activation represent novel targets to modify progression of neurodegenerative pathology. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in the SIGNAL-HD (NCT02481674) Phase 2 trial2 as well as in preclinical models of HD and AD. These studies provided clinical rationale for the ongoing Phase 1/2 SIGNAL-AD study (NCT04381468).
Objective(s): Present the updated safety, efficacy, and biomarker data from the completed SIGNAL-HD trial2. In addition, describe how neuroimaging and subgroup analysis of the clinical HD results provide further rationale for investigation in AD, and present the trial design, enrollment status, and updated blinded safety data for the Phase 1b/2a double-blind, randomized, placebO'Controlled SIGNAL-AD trial.
Method(s): The SIGNAL-HD phase 2 study included 301 subjects with late prodromal (LP) and early manifest (EM) HD. Subjects were treated with monthly infusions of pepinemab for at least 18 months and evaluated for safety and a variety of clinical parameters including cognition (HD-CAB). Imaging endpoints included structural MRI to assess brain atrophy and FDG-PET to assess brain metabolism. The SIGNAL-AD study is in progress and is planned to enroll up to 40 subjects with early AD treated for approximately 1 year. Objectives include safety, change in brain metabolism via FDG-PET, and clinical endpoints including the alzheimer's Disease Assessment Scale - cognition (ADAS-cog) and Clinical Dementia Rating Scale - sum of boxes (CDR-SB).
Result(s): In SIGNAL-HD, pepinemab was well-tolerated and was shown to cross the BBB at a concentration sufficient to engage its target. While co-primary efficacy outcome measures did not achieve statistical significance in this study, multiple exploratory and post-hoc measures indicated significant cognitive benefit and were supported by pre-specified FDG-PET imaging that indicated significant reversal of decline in metabolic activity (p>=0.05) in 15/26 brain regions of interest. Treatment effects were observed in EM but not LP subjects. In 179 EM subjects, a treatment benefit was observed in 6/6 components of the HD-CAB cognitive assessment battery, with a significant treatment effect on the HD-CAB composite index (p=0.007). Post-hoc analysis of the HD-CAB results showed pepinemab treatment preserved the ability of EM subjects to learn from experience during sequential administration of HD-CAB and that the cognitive treatment benefit was greater in subjects that were more cognitively impaired at baseline, as judged by Montreal Cognitive Assessment (MoCA) score <26 vs. >=26. The largest metabolic decline in HD is observed in caudate and putamen. It is, therefore, striking that a treatment effect on FDG-PET SUVR was not observed in caudate and putamen of either EM or LP subjects. Since degeneration of medium spiny neurons in striatum is an early event in prodromal HD that continues following motor diagnosis, this could account for reduced glucose utilization that is not SEMA4D-dependent and, therefore, not affected by pepinemab treatment. Our data support an important glial contribution to glucose utilization in other brain regions that is reduced by reactive gliosis and restored by pepinemab treatment. This suggests distinct early and late stages of pathology during disease progression. The ongoing blinded SIGNAL-AD trial has enrolled approximately half of the 40 planned subjects, and top line data for a full year of randomized, double-blind treatment is anticipated in Q1 2024. It will be of particular interest to determine whether metabolic changes in the entorhinal cortex, a region of early degeneration in AD, are less SEMA4D-dependent than for other cortical regions that degenerate somewhat later in disease progression.
Conclusion(s): SIGNAL-HD showed a favorable safety profile and positive trends in cognition and imaging endpoints that encourage continued development in both HD and AD. The Phase 1b/2a study in AD (SIGNAL-AD), is currently enrolling and initial blinded safety review has suggested pepinemab is well tolerated in AD as well
Objective(s): Present the updated safety, efficacy, and biomarker data from the completed SIGNAL-HD trial2. In addition, describe how neuroimaging and subgroup analysis of the clinical HD results provide further rationale for investigation in AD, and present the trial design, enrollment status, and updated blinded safety data for the Phase 1b/2a double-blind, randomized, placebO'Controlled SIGNAL-AD trial.
Method(s): The SIGNAL-HD phase 2 study included 301 subjects with late prodromal (LP) and early manifest (EM) HD. Subjects were treated with monthly infusions of pepinemab for at least 18 months and evaluated for safety and a variety of clinical parameters including cognition (HD-CAB). Imaging endpoints included structural MRI to assess brain atrophy and FDG-PET to assess brain metabolism. The SIGNAL-AD study is in progress and is planned to enroll up to 40 subjects with early AD treated for approximately 1 year. Objectives include safety, change in brain metabolism via FDG-PET, and clinical endpoints including the alzheimer's Disease Assessment Scale - cognition (ADAS-cog) and Clinical Dementia Rating Scale - sum of boxes (CDR-SB).
Result(s): In SIGNAL-HD, pepinemab was well-tolerated and was shown to cross the BBB at a concentration sufficient to engage its target. While co-primary efficacy outcome measures did not achieve statistical significance in this study, multiple exploratory and post-hoc measures indicated significant cognitive benefit and were supported by pre-specified FDG-PET imaging that indicated significant reversal of decline in metabolic activity (p>=0.05) in 15/26 brain regions of interest. Treatment effects were observed in EM but not LP subjects. In 179 EM subjects, a treatment benefit was observed in 6/6 components of the HD-CAB cognitive assessment battery, with a significant treatment effect on the HD-CAB composite index (p=0.007). Post-hoc analysis of the HD-CAB results showed pepinemab treatment preserved the ability of EM subjects to learn from experience during sequential administration of HD-CAB and that the cognitive treatment benefit was greater in subjects that were more cognitively impaired at baseline, as judged by Montreal Cognitive Assessment (MoCA) score <26 vs. >=26. The largest metabolic decline in HD is observed in caudate and putamen. It is, therefore, striking that a treatment effect on FDG-PET SUVR was not observed in caudate and putamen of either EM or LP subjects. Since degeneration of medium spiny neurons in striatum is an early event in prodromal HD that continues following motor diagnosis, this could account for reduced glucose utilization that is not SEMA4D-dependent and, therefore, not affected by pepinemab treatment. Our data support an important glial contribution to glucose utilization in other brain regions that is reduced by reactive gliosis and restored by pepinemab treatment. This suggests distinct early and late stages of pathology during disease progression. The ongoing blinded SIGNAL-AD trial has enrolled approximately half of the 40 planned subjects, and top line data for a full year of randomized, double-blind treatment is anticipated in Q1 2024. It will be of particular interest to determine whether metabolic changes in the entorhinal cortex, a region of early degeneration in AD, are less SEMA4D-dependent than for other cortical regions that degenerate somewhat later in disease progression.
Conclusion(s): SIGNAL-HD showed a favorable safety profile and positive trends in cognition and imaging endpoints that encourage continued development in both HD and AD. The Phase 1b/2a study in AD (SIGNAL-AD), is currently enrolling and initial blinded safety review has suggested pepinemab is well tolerated in AD as well
EMBASE:639873524
ISSN: 2426-0266
CID: 5512772
