Dataset Information

Systemic Safety of a Recombinant AAV8 Vector for Human Cocaine Hydrolase Gene Therapy: A Good Laboratory Practice Preclinical Study in Mice.

ABSTRACT: Cocaine addiction continues to impose major burdens on affected individuals and broader society but is highly resistant to medical treatment or psychotherapy. This study was undertaken with the goal of Food and Drug Administration (FDA) permission for a first-in-human clinical trial of a gene therapy for treatment-seeking cocaine users to become and remain abstinent. The approach was based on intravenous administration of AAV8-hCocH, an adeno-associated viral vector encoding a modified plasma enzyme that metabolizes cocaine into harmless by-products. To assess systemic safety, we conducted "Good Laboratory Practice" (GLP) studies in cocaine-experienced and cocaine-naive mice at doses of 5E12 and 5E13 vector genomes/kg. Results showed total lack of viral vector-related adverse effects in all tests performed. Instead, mice given one injection of AAV8-hCocH and regular daily injections of cocaine had far less tissue pathology than cocaine-injected mice with no vector treatment. Biodistribution analysis showed the vector located almost exclusively in the liver. These results indicate that a liver-directed AAV8-hCocH gene transfer at reasonable dosage is safe, well tolerated, and effective. Thus, gene transfer therapy emerges as a radically new approach to treat compulsive cocaine abuse. In fact, based on these positive findings, the FDA recently accepted our latest request for investigational new drug application (IND 18579).

SUBMITTER: Chen VP

PROVIDER: S-EPMC6985763 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Systemic Safety of a Recombinant AAV8 Vector for Human Cocaine Hydrolase Gene Therapy: A Good Laboratory Practice Preclinical Study in Mice.

Chen Vicky Ping VP Gao Yang Y Geng Liyi L Steele Mike M Jenks Nathan N Peng Kah-Whye KW Brimijoin Stephen S

Human gene therapy 20191219 1-2

Cocaine addiction continues to impose major burdens on affected individuals and broader society but is highly resistant to medical treatment or psychotherapy. This study was undertaken with the goal of Food and Drug Administration (FDA) permission for a first-in-human clinical trial of a gene therapy for treatment-seeking cocaine users to become and remain abstinent. The approach was based on intravenous administration of AAV8-hCocH, an adeno-associated viral vector encoding a modified plasma en ...[more]

PMID: 31650869

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Project description:X-linked retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding the protein retinoschisin (RS1) and one of the most common causes of macular degeneration in young men. Currently, no FDA-approved treatments are available for XLRS and a replacement gene therapy could provide a promising strategy. We have developed a novel gene therapy approach for XLRS, based on the administration of AAV8-scRS/IRBPhRS, an adeno-associated viral vector coding the human RS1 protein, via the intravitreal route. On the basis of our prior study in an Rs1-KO mouse, this construct transduces efficiently all the retinal layers, resulting in an RS1 expression similar to that observed in the wild-type and improving retinal structure and function. In support of a clinical trial, we carried out a study to evaluate the ocular safety of intravitreal administration of AAV8-scRS/IRBPhRS into 39 New Zealand White rabbits. Two dose levels of vector, 2e(10) and 2e(11) vector genomes per eye (vg/eye), were tested and ocular inflammation was monitored over a 12-week period by serial ophthalmological and histopathological analysis. A mild ocular inflammatory reaction, consisting mainly of vitreous infiltrates, was observed within 4 weeks from injection, in both 2e(10) and 2e(11) vg/eye groups and was likely driven by the AAV8 capsid. At 12-week follow-up, ophthalmological examination revealed no clinical signs of vitreitis in either of the dose groups. However, while vitreous inflammatory infiltrate was significantly reduced in the 2e(10) vg/eye group at 12 weeks, some rabbits in the higher dose group still showed persistence of inflammatory cells, histologically. In conclusion, intravitreal administration of AAV8-scRS/IRBPhRS into the rabbit eye produces a mild and transient intraocular inflammation that resolves, at a 2e(10) vg/eye dose, within 3 months, and does not cause irreversible tissue damages. These data support the initiation of a clinical trial of intravitreal administration of AAV8-scRS/IRBPhRS in XLRS patients.

Project description:Background: With increasing insecticide resistance in malaria-endemic countries there is an urgent need for safe and effective novel vector control products. To improve the capacity of facilities that test insecticides in sub-Saharan Africa, a programme is supporting seven facilities towards Good Laboratory Practice (GLP) certification, the globally recognized standard for quality management system (QMS) for the conduct of non-clinical and environmental studies. The World Health Organization (WHO) GLP Handbook provides guidance on a stepwise approach to implement a GLP compliant QMS. This study assesses auditor GLP checklists and timings outlined in the WHO GLP Handbook in the real-life context of a Tanzanian insecticide-testing facility, evaluating their implementation in this context. Methods and Principle Findings: We conducted document review and semi-structured interviews with staff at all levels of the test facility to explore factors that influenced progress towards GLP certification. We found that while auditor GLP checklists underemphasised computer systems, they were otherwise broadly applicable. Factors that delayed time to completion of GLP certification included the need for extensive infrastructure improvements, the availability of regional expertise related to GLP, the capacity of national and regional external systems and services to meet GLP compliance requirements, and training development required for Standard Operating Procedure implementation. Conclusion: The standards required for full GLP compliance are rigorous, with an expected completion timeline to implementation of 24 months. This study shows that in low and middle-income countries this timeline may be unrealistic due to challenges related to infrastructure development and lack of regional capacity and expertise. We recommend a comprehensive gap analysis when starting a project, including these areas which are beyond those recommended by the WHO GLP Handbook. These challenges can be successfully overcome and the experience in Tanzania provides key lessons for other facilities seeking GLP certification or the development of similar QMS.

Project description:BackgroundLimited health research capacities (HRC) undermine a country's ability to identify and adequately respond to local health needs. Although numerous interventions to strengthen HRC have been conducted in Africa, there is a need to share the lessons learnt by funding organizations, institutes and researchers. The aim of this report is to identify best practices in HRC strengthening by describing a training programme conducted between 2016 and 2017 at the Saint Joseph's Catholic Hospital (SJCH) in Monrovia (Liberia).MethodsA call for trainees was launched at the SJCH, the Liberia Medicines and Health Products Regulatory Authority (LMHRA), the Ministry of Health and Social Welfare, the Mother Pattern College of Health Sciences (MPCHS) and community members. Selected trainees participated in four workshops on Good Clinical Laboratory Practice (GCLP), standard operating procedures (SOP) and scientific communication, as well as in a 5-months eLearning mentoring programme. After the training, a collectively-designed research project on malaria was conducted.ResultsTwenty-one of the 28 trainees (14 from the SJCH, 3 from LMHRA, one from MPCHS, and 10 community representatives) completed the programme satisfactorily. Pre- and post-training questionnaires completed by 9 of the trainees showed a 14% increase in the percentage of correct answers. Trainees participated in a mixed-methods cross-sectional study of Plasmodium falciparum infection among pregnant women at the SJCH. Selected trainees disseminated activities and research outcomes in three international meetings and three scientific publications.ConclusionThis training-through-research programme successfully involved SJCH staff and community members in a practical research exercise on malaria during pregnancy. The challenge is to ensure that the SJCH remains active in research. Harmonization of effectiveness indicators for HRC initiatives would strengthen the case for investing in such efforts.

Dataset Information

Systemic Safety of a Recombinant AAV8 Vector for Human Cocaine Hydrolase Gene Therapy: A Good Laboratory Practice Preclinical Study in Mice.

Publications

Systemic Safety of a Recombinant AAV8 Vector for Human Cocaine Hydrolase Gene Therapy: A Good Laboratory Practice Preclinical Study in Mice.

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