Realizing New Miracles: Gene Therapy Trends in 2024 and Beyond

Clinical Researcher—December 2023 (Volume 37, Issue 6)


Dr. Jörg Schneider




Cell and gene therapies have been life-changing for many patients. As U.S. Food and Drug Administration (FDA) Center for Biologics Evaluation and Research Director Peter Marks, MD, PhD, said at a Cell & Gene Meeting on the Mesa last year: “We may not believe in miracles. But there are things that are miraculous, and this is one. We want to ensure that we get it right with smaller populations, but then hopefully see this grow to bring the benefits of cell and gene therapy to larger populations. We’ll use all the tools in our toolbox to help make that happen.”{1}

There are many reasons to be excited about the field of advanced medicinal therapeutic products or cell and gene therapies. There are, however, also issues with these products. A recent paper highlighted the disproportionate rise in FDA clinical holds for cell and gene products as compared to small molecules, most commonly due to an adverse event or patient death.{2}

Trends in the near-term will focus on ways to address current limitations, be those due to safety, immunogenicity issues, targeting challenges, dosing issues, or regulatory and payer barriers. The article explores four areas of focus for the year ahead.

Adeno-Associated Virus (AAV) Gene Therapy

As one of the most mature gene therapy technologies, AAV remains the dominant gene delivery vehicle. In recent years, several gene therapies using an AAV vector have received regulatory approval for a variety of rare diseases with unmet medical needs (see below).

The Challenges

There are many challenges to overcome with regards to safety, efficacy, payload size, sustainability, and scalability when leveraging AAV for diseases linked to mutations in genes. From both a safety and efficacy perspective, the human immune system recognizes and responds to AAV vectors, potentially reducing the efficacy of the therapy or causing adverse reactions. Furthermore, patients with pre-existing immunity to AAVs from natural infections may have limited therapeutic benefit and may face safety risks.{3}

The manufacturing scalability of AAV vectors also poses a challenge to the growing demand for these viral vectors in various clinical applications.{4}

Tackling the Limitations

Researchers are assessing different strategies to address these challenges. In one example, a study found that co-administering synthetic vaccine particles encapsulating rapamycin (SVP[Rapa]) with AAV vectors had the potential to modulate vector immunogenicity and allow re-administration.{5} Another study into the use of tolerogenic nanoparticles with hepatotropic AAV vectors suggests the potential for vector re-dosing by suppressing adaptive immune responses.{6}

More efforts will focus on modifying the AAV capsid through molecular engineering to reduce immunogenicity, implementing short-term immunosuppression during the administration of AAV-based therapies to reduce immune responses against the vector and developing new AAV serotypes with lower immunogenicity or that can evade pre-existing immunity.{7}

Lipid Nanoparticle (LNP) Delivery for mRNA and RNA

LNP has proven to be a reliable drug delivery system for mRNA, particularly mRNA SARS-CoV-2 vaccines. In light of the success of these vaccines, there is growing momentum to develop LNP-based RNA therapeutics for various genetic diseases and cancers.{8}

The Challenges

Toxicity and unwanted immunogenicity remain concerns with LNP delivery at the higher amounts and systemic delivery that would be required for therapeutics. Even with vaccines which were administered in relatively low amounts intramuscularly, a minority of recipients experienced significant side effects.{9} In one example, researchers point to a pro-inflammatory role for ionizable cationic lipids, with intranasal administration of LNPs into mice leading to massive lung inflammation and high mortality.{10}

Tackling the Limitations

One approach that seeks to address toxicity concerns is targeted in vivo synthetic particle technology based on ionizable LNPs. Combined with transient gene editing, this technology promises to be potentially safer due to increased biodegradability and lower immunogenicity. It is also more scalable in terms of dose regimen and could potentially address a broader range of disorders.{11}

CAR-T Cell Therapies

CAR-T cell therapies have been used to successfully treat hematological cancer.{12} There is widespread research into the use of CAR-T cells to treat solid tumors as well as to treat various other conditions such as autoimmunity, chronic infections, cardiac fibrosis, and senescence-associated disease.{13}

The Challenges

Hopes for CAR-T to tackle solid cancers have been set back by a number of challenges, including severe toxicities, target heterogeneity, and limited tumor infiltration. Further, there are functional barriers, since CAR-T cells require expertise to create and administer, and engineering issues to scale out manufacturing so that the therapies are accessible to more patients.{14}

Tackling the Limitations

Different pathways and approaches are being investigated to improve CAR-T therapies. One approach that aims to tackle loss of the antigen is to combine CAR-T cell therapy with specific vaccines to boost and maintain an effective CAR-T cell population.{15} Another exciting development is the use of in vivo induced CAR-T cells loaded with CAR-genes and gene-editing tools to tackle toxicity issues.{16} There is also growing interest in other T cell therapies, including gamma-delta T cells, invariant natural killer T cells, natural killer, and dendritic cells.{17}

Gene Editing

One of the most exciting and rapidly developing fields is gene editing. In November 2023, the United Kingdom became the first country to approve Vertex’s revolutionary gene editing, CRISPR-based treatment for sickle-cell disease and transfusion-dependent beta thalassaemia.{18} An FDA advisory committee meeting was held in October to discuss the product, known as exa-cel. Remarkably, the meeting did not question efficacy, but sought insight on off-target genome edits and potential additional studies to assess the risk of off-target editing.

The Challenges

The greatest challenges facing gene editing are identifying the most suitable delivery systems and specificity. With ex vivo gene editing, while there have been important breakthroughs, such as exa-cel, in vivo approaches are required for targeting internal organs, such as the lung or heart.

Tackling the Limitations

Current gene editing successes build on hematopoietic stem cell therapy, which is now standard treatment for leukemia. The clinics, quality standards, and understanding of how to treat patients are in place. While questions remain about gene editing, experts and regulators recognize the importance of the field. Already there are guidelines from FDA to support gene editing products and experts are excited about the potential of these products. As Dr. Scot Wolfe, a member of the FDA advisory committee panel assessing exa-cel noted: “We don’t want to let perfect be the enemy of the good. At some point we have to try things out in patients.”

Realizing the Promise of Gene Therapy

Cell and gene therapy is proving to be transformative for patients with high unmet needs. While there are many challenges to overcome across all platforms, researchers are gaining a greater understanding of the obstacles faced—whether in development or treatment—and with that knowledge, new potential solutions are emerging.

The contents of this article are solely the opinion of the author and do not represent the opinions of PharmaLex GmbH or its parent Cencora Inc. PharmaLex and Cencora strongly encourage readers to review the references provided with this article and all available information related to the topics mentioned herein and to rely on their own experience and expertise in making decisions related thereto.


  1. Peter Marks Outlines FDA’s Commitment to Advancing Gene Therapies. 2022. Genetic Engineering & Biotechnology News.
  2. Clinical Holds for Cell and Gene Therapy 1 Trials: Risks, Impact, and Lessons Learned. 2023. Molecular Therapy: Methods & Clinical Development.
  3. Toxicity Risks of Adeno-associated Virus (AAV) Vectors for Gene Therapy (GT). 2021. FDA Briefing Document.
  4. Challenges in scaling up AAV-based gene therapy manufacturing. 2023. Trends in Biotechnology.
  5. Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration. 2018. Nature Communications.
  6. ImmTOR nanoparticles enhance AAV transgene expression after initial and repeat dosing in a mouse model of methylmalonic acidemia. 2021. Mol Ther Methods Clin Dev.,even%20after%20the%20first%20dose
  7. Immune Responses to Viral Gene Therapy Vectors. 2020. Molecular Therapy.
  8. Lipid nanoparticles for delivery of RNA therapeutics: Current status and the role of in vivo imaging. 2022. Theranostics.
  9. The role of lipid components in lipid nanoparticles for vaccines and gene therapy. 2022. Adv Drug Deliv Rev.
  10. Pro-inflammatory concerns with lipid nanoparticles. 2022. Mol Ther.
  11. Expanding the potential of in vivo cell therapy with tLNP-RNAs (targeted lipid nanoparticle-RNA). 2023. The BioInsights Podcast.
  12. Long-term outcomes following CAR T cell therapy: what we know so far. 2023. Nature Reviews Clinical Oncology.
  13. CAR T therapy beyond cancer: the evolution of a living drug. 2023. Nature.
  14. CAR-T cell therapy: current limitations and potential strategies. 2021. Blood Cancer Journal.
  15. Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity. 2023. Cell.
  16. in-Vivo Induced CAR-T Cell for the Potential Breakthrough to Overcome the Barriers of Current CAR-T Cell Therapy. 2022. Front Oncol.
  17. Beyond CAR T Cells: Other Cell-Based Immunotherapeutic Strategies Against Cancer. 2019. Front Oncol.
  18. UK approves world-first gene-editing treatment for blood disorders. 2023. Imperial College London.

Jorg Schneider

Dr. Jörg Schneider is a Principal Consultant at Biopharma Excellence, a PharmaLex company, where he focuses on ATMPs/CGT products and is involved in regulatory interactions, nonclinical development, and strategic support for multiple clients. A translational biopharmaceutical expert, he has broad knowledge of different technologies and product classes such as recombinant viral vectors, cell therapies, oncolytic viruses, glycoconjugate vaccines, monoclonal antibodies, and non-antibody scaffold drugs.