Gene therapy offers groundbreaking possibilities for treating genetic disorders, yet its journey to mainstream clinical use is hindered by key obstacles, involving safety, efficacy, delivery, and high manufacturing costs. In this interview with Muhammad Younis, OpenCell Technologies' Executive Chairman Behzad Mahdavi shared deep insights on these pressing challenges and unveils the strategies being implemented to address them.

#LBS: Gene therapy has made significant strides in recent years, yet there remain challenges related to safety, efficacy, and delivery. Could you discuss the current state of research on addressing these challenges, and what innovative strategies are being explored to overcome these hurdles in the field of gene therapy?

Behzad Mahdavi: Gene therapy holds transformative potential for treating genetic diseases, but its widespread clinical adoption is limited by challenges in safety, efficacy, delivery, and high manufacturing costs. A striking example of these obstacles is Bluebird Bio's Skysona, a gene therapy for cerebral adrenoleukodystrophy (CALD), priced at $3 million per patient. Despite its potential, Bluebird Bio was forced to withdraw Skysona from the European market due to challenges in securing reimbursement, highlighting the financial and logistical hurdles gene therapies face (FiercePharma).

The Challenge of High Viral Doses

A major issue is the requirement for high viral doses to achieve therapeutic efficacy. For treatments like hemophilia, up to 1 x 10^12 viral genomes (vg) per kilogram of patient weight may be necessary, resulting in doses of 1 x 10^11 to 1 x 10^14 vg per patient. This escalates the complexity and cost of manufacturing, further driving up the price of these therapies.

Innovative Strategies to Overcome These Challenges

To address these obstacles, researchers are exploring advancements in manufacturing processes and biological optimisation to reduce the required viral doses.

1. Improved Manufacturing Processes: Efficiency improvements in manufacturing are essential to making gene therapies more scalable and cost-effective. Several strategies are under investigation:

  • Higher Yields: Innovations in cell culture systems and bioreactor designs are boosting viral vector production, enabling higher yields per manufacturing run. 
  • Optimised Transfection: At Opencell Technologies, the development of Softporation—a scalable and gentle transfection method—enhances the efficiency of cell transfection, allowing for better cell recycling and maximising viral vector output. 
  • Better Plasmid Design: Optimising the genetic constructs used in plasmid design improves gene expression and stability, contributing to more efficient viral vector production and reducing the overall quantity needed for effective treatment.

2. Biological Optimisation and Targeting: Alongside manufacturing advancements, improving the biological targeting and utilisation of viral vectors is key to reducing dose requirements:

  • Capsid Engineering: Modifying the AAV capsid to target specific tissues, such as the brain or liver, increases delivery efficiency. This reduces the viral dose necessary to achieve therapeutic benefit by ensuring that the vectors reach the intended cells with greater precision. 
  • Immune Evasion: The body's immune response to viral vectors is a significant hurdle. To mitigate this, techniques such as coating viral vectors with exosomes to "camouflage" them from the immune system are being investigated. These strategies aim to prolong the therapy's duration in the body and reduce the need for repeated high doses.

In conclusion, the future of gene therapy is poised for transformation through the reduction of viral dose requirements and a significant increase in manufacturing productivity. Innovations aimed at enhancing manufacturing efficiency and biological optimisation are crucial for overcoming current challenges. By addressing these issues, gene therapies can become not only safer and more effective but also more accessible to a wider patient population. This progress will unlock the full potential of gene therapies, paving the way for more transformative treatments that can significantly improve patient outcomes and broaden the scope of personalised medicine.

#LBS: How are emerging gene editing technologies, particularly CRISPR, shaping the future of gene therapy treatments, and what potential do they hold for more precise and effective therapies?

Behzad Mahdavi: Emerging gene editing technologies, particularly CRISPR-Cas9, are poised to revolutionise gene therapy by enhancing precision, efficacy, and accessibility. Here are key aspects of how CRISPR is shaping the future of gene therapy:

  • Precision Editing and Off-Target Effects: CRISPR technology allows for precise genome edits, targeting specific genes linked to genetic disorders. While CRISPR is generally more accurate than earlier gene editing technologies, off-target effects—where unintended areas of the genome are edited—remain a concern. New techniques such as base editing and prime editing aim to improve accuracy by allowing more controlled modifications without causing double strand breaks in DNA. These advancements enhance safety for therapeutic applications and reduce the risks associated with off-target mutations. 
  • Distinctions Between Ex Vivo and In Vivo Approaches: In gene therapy, ex vivo editing involves modifying cells outside the body before reintroducing them into the patient, which allows for greater control over the editing process and minimise off-target effects. This method has been successfully used in therapies for genetic disorders like sickle cell anaemia. Conversely, in vivo gene editing delivers CRISPR components directly to target cells within the living organism. This approach presents challenges in achieving precise targeting and delivery, often necessitating localised injection methods to improve specificity and minimise off-target effects. 
  • Broader Therapeutic Applications: CRISPR has expanded the range of treatable conditions, showing promise for genetic disorders such as Duchenne muscular dystrophy and cystic fibrosis. A notable application includes a clinical trial where CRISPR-modified T cells were used in the treatment of certain cancers, underscoring its potential in immunotherapy. 
  • Innovations in Delivery Mechanisms: Effective delivery of CRISPR components remains a critical hurdle, especially in vivo. Innovative strategies, such as the use of nanoparticles and viral vectors, are being developed to enhance the specificity and efficiency of delivery, ensuring gene editing occurs exclusively in intended tissues. 
  • Agricultural and Environmental Applications: Beyond human health, CRISPR is being applied in agriculture to develop crops with desirable traits, such as disease resistance and improved nutritional profiles. This not only addresses food security challenges but also promotes sustainable farming practices, thereby contributing to environmental conservation .

In conclusion, CRISPR-Cas9 and emerging gene editing technologies hold immense potential to reshape gene therapy by enabling more precise, effective, and targeted treatments for genetic disorders. As research advances and delivery mechanisms improve, CRISPR is likely to play a central role in the next generation of gene therapies, addressing both inherited diseases and agricultural challenges while continuing to mitigate concerns related to off-target effects.

#LBS: What are the major ethical and regulatory challenges currently facing gene therapy, and what measures are being taken to address these issues to ensure safe and effective treatments? 

Behzad Mahdavi: Gene therapy represents a transformative approach to treating genetic disorders, but it also raises significant ethical and regulatory challenges that require careful navigation to ensure safe and effective applications.

 1. Ethical Concerns:

  • Germline Editing: The potential for germline editing—modifying genes in embryos—poses ethical dilemmas, particularly regarding the risk of creating “designer babies.” This concept raises profound questions about consent, the implications for future generations, and the potential for exacerbating social inequalities in access to genetic enhancements. As the scientific community deliberates on these issues, international guidelines and moratoriums are being considered to prevent premature applications until comprehensive ethical frameworks are established. 
  • Equity and Access: The cost of gene therapies is often prohibitively high, raising concerns about equitable access. There is a risk that only affluent patients or countries can benefit from advanced gene therapies, leading to a widening gap in healthcare equity. This concern is prompting discussions among policymakers and health organisations to explore models that promote fair access to these groundbreaking treatments. 

 2. Regulatory Challenges:

  • Inconsistent Regulations: Gene therapy regulations vary widely across countries, creating a fragmented landscape. For instance, while the FDA in the U.S. mandates extensive testing and safety assessments, other regions may have less stringent oversight. This inconsistency can hinder international collaboration and complicate the approval processes for cross-border clinical trials. 
  • Long-Term Safety Monitoring: Ensuring the safety of gene therapies necessitates rigorous long-term monitoring to track adverse effects. Regulatory bodies are establishing frameworks for post-market surveillance, emphasising the importance of tracking patient outcomes to identify any late-onset complications.

3. Measures Being Taken:

  • Establishment of Guidelines: International organisations, including the WHO and NIH, are developing comprehensive ethical guidelines for gene therapy research. These guidelines emphasise transparency, informed consent, and the necessity of public engagement in ethical discussions surrounding gene editing. 
  • Regulatory Harmonisation Initiatives: Efforts to align regulations globally are underway, with collaborations between agencies like the FDA and EMA. By establishing best practices and harmonised guidelines, stakeholders aim to ensure that gene therapies are subjected to consistent oversight, reducing the risk of unethical applications. 
  • Public Engagement and Dialogue: Fostering public dialogue on gene therapy is critical for understanding societal values and addressing ethical concerns. Engaging diverse stakeholders, including ethicists, healthcare providers, and patient advocates, can help shape policies that ensure the responsible use of gene editing technologies.

In conclusion, as gene therapy continues to evolve, addressing the ethical and regulatory challenges it poses is essential for ensuring its safe and equitable application. Ongoing efforts to establish guidelines, enhance monitoring, and promote public engagement will be crucial in navigating these complexities and maximising the potential benefits of gene therapy for all.

#LBS: Could you outline the critical milestones involved in translating gene therapy from experimental research to practical clinical applications, and how are collaborations between academic institutions and biotech companies influencing this process?

Behzad Mahdavi: Translating gene therapy from experimental research to clinical applications is a complex process that involves critical milestones ranging from preclinical studies to regulatory approval and post-market surveillance. Collaborations between academic institutions and biotech companies are instrumental in facilitating this journey, enhancing the development and accessibility of gene therapies for patients in need.