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Cellular & Gene Therapy Guidances (Food and Drug Administration)

 

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Human Genome Editing: FDA Draft Guidance Summary

Consideration for Developing Gene Editing Product  1. Genome Editing Methods: Genome editing can be achieved through nuclease-dependent or nuclease-independent methods. Nuclease-dependent methods involve introducing site-specific breaks in DNA using technologies like zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), modified-homing endonucleases, and CRISPR-associated (Cas) nucleases. These breaks can lead to modification of the DNA sequence at the cleavage site. Nuclease-independent methods can change DNA sequences without cleaving the DNA and include techniques like base editing and synthetic triplex-forming peptide nucleic acids. The choice of GE technology should consider factors such as the mechanism of action, the ability to target specific DNA sequences, and the potential to optimize components for efficiency, specificity, or stability. 2. Type and Degree of Genomic Modification: Different GE approaches rely on DNA repair pathways such a...
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Stem loop RT-PCR for Detection of siRNA in Animal Tissues

Step Loop RT-PCR for Detection of Small Interfering RNA (siRNA) The recent publications described a novel used the novel method for the detection of siRNAs using a TaqMan®-based approach. This approach utilizes similar strategy that has been used for microRNA detection. The approach is illustrated in below.  In brief, the RT step occurs in the presence of a stem-loop RT primer that is complementary to the last 6–10 bases of the 3′ end of the antisense strand of the target siRNA. The stem-loop primer contains an additional universal sequence at the 5′ end that facilitates a TaqMan-based detection strategy in the subsequent qPCR step. As in the case of microRNA, the forward primer for qPCR is sequence-specific for the target siRNA. For sequence compositions that yield a low predicted melting temperature (Tm), the forward primer is designed as a tailed primer to help increase Tm. Stem Loop PCR for SiRNA Detection Step 1: Preparation of liver and plasma samples for the quanti...
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ICH Q8 (R2) Pharmaceutical development (CHMP/ICH/167068/04)

 ICH Q8 (R2) is a guideline titled "Pharmaceutical Development" (CHMP/ICH/167068/04). This guideline is part of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and provides recommendations for the pharmaceutical development of medicinal products. It offers a structured approach to the development of pharmaceutical products to ensure their quality, safety, and efficacy. Here's an elaboration of ICH Q8 (R2): 1. Purpose of ICH Q8 (R2): The primary purpose of ICH Q8 (R2) is to provide a systematic and science-based approach to pharmaceutical development. The guideline aims to facilitate the design and development of high-quality pharmaceutical products that meet the needs of patients and regulatory authorities. 2. Scope: ICH Q8 (R2) applies to the development of all types of pharmaceutical products, including small molecules, biotechnological products, and other complex medicinal products. 3. Pharmaceutical Develop...
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Cell-Mediated Immunity in AAV Gene Therapy

Cell-mediated immunity (CMI) plays a significant role in the effectiveness and safety of AAV (Adeno-Associated Virus) gene therapy. Understanding the impact of CMI is crucial for optimizing therapeutic outcomes and managing potential adverse effects. Here’s a detailed overview of the impact of CMI on AAV gene therapy: 1. Mechanisms of Cell-Mediated Immunity in AAV Gene Therapy T-Cell Activation : After administration of an AAV vector, T cells can recognize the AAV capsid proteins or the transgene product as foreign antigens, leading to their activation. This can involve both CD4+ helper T cells and CD8+ cytotoxic T cells. Cytokine Production : Activated T cells produce cytokines (e.g., IFN-γ, TNF-α) that can enhance the immune response. These cytokines can influence the activation and proliferation of other immune cells, including B cells and macrophages. 2. Impact on Efficacy of AAV Gene Therapy Enhanced Antigen Presentation : CMI can improve the presentation of transgene-derived anti...
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Preclinical Studies for AAV Gene Therapy

 Preclinical studies for AAV gene therapy are crucial to assess the safety, efficacy, biodistribution, and immunogenicity of the therapy before progressing to human trials. These studies help in understanding the potential risks and therapeutic effects in animal models, which is essential for regulatory approval to proceed to first-in-human studies. Here’s a breakdown of key preclinical study types and their objectives: 1. Efficacy Studies Objective : Determine whether the gene therapy delivers a therapeutic benefit in relevant disease models, such as improvement in phenotypic markers or functional outcomes. Study Design : Use disease-specific animal models that reflect the condition the therapy intends to treat (e.g., knockout models for genetic disorders). Evaluate therapeutic endpoints, such as protein expression, functional assays, or phenotypic changes. Example : For a neurological condition, measure motor function or cognitive outcomes in treated versus control groups. 2. Bio...
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