Safety of AAV-Based Gene Therapies for Rare Diseases: A Systematic Review and Meta-analysis
Name:
Dr. Nirma Vadlamudi
Email
nvadlamudi@ufl.edu
Phone
(352) 273-8502
Faculty Department/Division
Pharmaceutical Outcome and Policy
This project is primarily:
Literature Review
Research Project Description:
• Background & Significance
Gene therapies using adeno-associated virus (AAV) vectors have transformed treatment prospects for rare genetic disorders. However, emerging safety concerns highlight the need for a systematic synthesis of evidence. A comprehensive systematic review and meta-analysis can clarify the nature, frequency, and severity of safety events reported across clinical and preclinical AAV-based therapeutic studies. This will provide a guidance for the use of these treatments.
- Specific Aims
- Primary Aims: Characterize safety events reported in clinical and preclinical studies of AAV-based therapeutics for rare diseases, including the type, frequency, and severity of adverse outcomes.
- Secondary Aims: Identify recurring safety patterns and mechanisms, with emphasis on vector-related toxicity, immune responses, and potential off-target effects.
- We hypothesize that AAV-based gene therapies for rare diseases are associated with a reproducible pattern of safety events, such as immune-mediated reactions and vector-related toxicities. The frequency and severity of these events varies systematically by factors such as dose, route of administration, and patient population.
- Methods
We will conduct a systematic literature review and meta-analysis of clinical trials and preclinical studies of AAV-based therapeutics for rare diseases. Evidence will be gathered from published studies and supplemented with data from registries and regulatory reports. Extracted outcomes will focus on safety events, including vector-related toxicity, immune-mediated adverse events, and off-target effects. Results will be quantitatively synthesized to estimate pooled safety event frequencies and explore patterns across study types and therapeutic contexts. Prespecified subgroup analyses will be used to evaluate whether safety profiles vary by key factors such as dose, route of administration, capsid/serotype, indication, and patient population (pediatric vs adult). - Role of Medical Student
The medical student will serve as the project lead for a systematic review and meta-analysis evaluating safety events associated with AAV-based gene therapies for rare diseases. Under faculty mentorship, the student will conduct the literature search and manage the review workflow, develop and pilot a structured data extraction form, oversee double-extraction and data verification, and perform risk-of-bias assessments appropriate to each study design. The student will also help prepare analysis-ready datasets, contribute to narrative synthesis, and draft the study protocol and key sections of the manuscript. Authorship will follow standard scholarly criteria, with the student positioned for lead authorship based on contribution, and the opportunity to present the work at a scientific conference. - References
Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019;18(5):358-378. doi:10.1038/s41573-019-0012-9
Han Z, Yi X, Li J, Liao D, Gao G, Ai J. Efficacy and Safety of Adeno-Associated Virus-Based Clinical Gene Therapy for Hemophilia: A Systematic Review and Meta-Analysis. Hum Gene Ther. 2024;35(3-4):93-103. doi:10.1089/hum.2023.208
Naso MF, Tomkowicz B, Perry WL 3rd, Strohl WR. Adeno-Associated Virus (AAV) as a Vector for Gene Therapy. BioDrugs. 2017 Aug;31(4):317-334. doi: 10.1007/s40259-017-0234-5. PMID: 28669112; PMCID: PMC5548848.
Notarte KI, Catahay JA, Macasaet R, et al. Infusion reactions to adeno-associated virus (AAV)-based gene therapy: Mechanisms, diagnostics, treatment and review of the literature. J Med Virol. 2023;95(12):e29305. doi:10.1002/jmv.29305
Does this project have an international component or travel?
No
If your project has an international component please give details (where, when, data collection involved, etc.):
N/A
Trends in the Incidence of Young-Onset Colorectal Cancer with a Focus on Years Approaching Screening Age: A Commercial Claims Data Study in United States
Name:
Dr. Nirma Vadlamudi
Email
nvadlamudi@ufl.edu
Phone
(352) 273-8502
Faculty Department/Division
Pharmaceutical Outcomes and Policy
This project is primarily:
Clinical
Research Project Description:
Background and Significance.
Colorectal cancer is the 2nd leading cause of cancer death in the United States. National surveillance data show CRC incidence and mortality remain substantial, with age-adjusted incidence around the high 30s per 100,000 and death rates in the low teens per 100,000 in recent years. Despite long-term declines in CRC mortality that are often attributed to improvements in screening and treatment, CRC continues to account for tens of thousands of deaths annually.
International reports indicate that early-onset CRC is increasing across many jurisdictions, and its growing contribution to the overall CRC burden has raised concerns about missed opportunities for prevention and timely diagnosis in younger adults who historically fell outside routine screening recommendations. In addition, age-specific analyses have demonstrated a notable “threshold” phenomenon around the traditional screening initiation age, with steep increases in observed CRC incidence from age 49 to 50. This highlights how screening uptake and diagnostic intensity may influence measured incidence near eligibility cutoffs.
This study will generate updated, claims-based evidence on CRC incidence and young-onset CRC trends among adults aged 18–60 years from 2005–2023. By estimating age-specific and age-standardized incidence rates within a continuously enrolled population, the study will provide actionable benchmarks for clinicians, payers, and policymakers on where CRC burden is rising most rapidly and how incidence patterns differ across the pre-screening and screening-adjacent age ranges (e.g., 45–49 vs ≥50). These estimates are directly relevant to evaluating the public health rationale for earlier screening and to anticipating healthcare resource needs (endoscopy capacity, oncology services) as early-onset disease becomes a larger fraction of CRC diagnoses.
Specific Aims.
Primary Aims: Estimate age-specific and age-standardized CRC incidence (2005–2023) by calculating annual incidence rates of incident CRC among adults aged 18–60 overall and by single-year age.
Secondary Aims: (1) Characterize temporal trends in young-onset CRC (ages 18–49) (2) Evaluate heterogeneity by sex and tumor site and assess screening-threshold patterns.
We hypothesize that CRC incidence patterns in MarketScan from 2005–2023 will demonstrate rising young-onset incidence, heterogeneity by sex and tumor site, and detectable inflection points around screening-related ages (around age 45 to 50).
Methods.
We will use IBM MarketScan Commercial claims data from 2005–2023. The study population will include individuals aged 18–60 years with continuous enrollment for at least 12 months before cohort entry. Incident colorectal cancer (CRC) will be identified using ICD-9-CM (153, 154) /ICD-10-CM (C18, C19, C20, C21) diagnosis codes corresponding to colon, rectosigmoid, and rectal cancer. The index date will be defined as the first record qualifying CRC diagnosis code. Young-onset CRC will be defined as index diagnosis before age 50 years. Follow-up will end with disenrollment from the health plan or end of data availability.
Primary analyses will estimate overall and age-specific CRC incidence rates (IRs) per 100,000 person-years among continuously enrolled MarketScan members from 2005–2023. Annual IRs will be calculated for adults aged 20–60 years overall and by single-year age increments to characterize age-specific patterns in incidence. We will also summarize descriptive characteristics (e.g., age at diagnosis, sex, cancer site) for all incident CRC cases diagnosed between ages 20 and 60 years. To evaluate changes across adjacent ages, we will compute the percentage increase in incidence and incidence rate ratios (IRRs) for each 1-year age increment. All primary analyses will be conducted overall and stratified by sex and cancer site (colon vs rectum/rectosigmoid).
Secondary analyses will focus on young-onset CRC (yCRC), defined as CRC diagnosed at ages 18–49 years. We will evaluate temporal trends in yCRC incidence from 2005–2023 and report descriptive statistics for incident yCRC cases. Joinpoint regression will be used to model changes in incidence over time and estimate annual percent change (APC) across one or more calendar-time segments; APC will be derived as exp(β) − 1 from the fitted log-linear model. Joinpoint analyses will be conducted overall and stratified by sex, cancer site, and age group (18–29, 30–39, and 40–49).
Role of Medical Student.
The medical student will contribute to (1) developing clinically grounded CRC case definitions and code lists (including ICD-9/ICD-10 mappings and site classification), (2) refining the analytic plan and sensitivity analyses using clinical insight, (3) supporting data analysis and quality checks (e.g., face-validity review of age- and site-specific incidence patterns), and (4) interpreting findings and leading dissemination through an abstract/poster and draft manuscript sections. The student will have the opportunity for authorship on presentations and manuscripts resulting from this work, consistent with their contributions.
Ethics Approval: The University of Florida reviewed this study and determined it was exempt from ethics approval.
References:
- National Cancer Institute. SEER Cancer Stat Facts: colorectal cancer. Accessed on 05 January 2026. Available from: https://seer.cancer.gov/statfacts/html/colorect.html.
- Abualkhair WH, Zhou M, Ahnen D, Yu Q, Wu XC, Karlitz JJ. Trends in Incidence of Early-Onset Colorectal Cancer in the United States Among Those Approaching Screening Age. JAMA Netw Open. 2020 Jan 3;3(1):e1920407.
- Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-164.
- American Cancer Society. Cancer Facts & Figures 2021. Atlanta: American Cancer Society; 2021.
Gupta S. Screening for Colorectal Cancer. Hematol Oncol Clin North Am. 2022 Jun;36(3):393-414. - Howren A, Sayre EC, Loree JM, Gill S, Brown CJ, Raval MJ, Farooq A, De Vera MA. Trends in the Incidence of Young-Onset Colorectal Cancer With a Focus on Years Approaching Screening Age: A Population-Based Longitudinal Study. J Natl Cancer Inst. 2021 Jul 1;113(7):863-868.