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PERSPECTIVES
Limitations and Opportunities in Cell and Gene Therapies
Dr. Rabab Nasrallah and Florent Gros, investors at Earlybird Health, discuss how the current limitations in this therapeutic field may affect venture financing in the years to come.
Mar 30, 2023
5 Min Read
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As a fast-progressing space, the development cycles for Cell and Gene Therapies are continually shortening. From the time the concept of immunotherapy was coined in the 1890s, immune checkpoint inhibitors and other immunotherapies took several decades to reach the clinical stage. Today, gene therapies can reach the clinic in less than a decade. For instance, isolated in 2012, CRISPR gene editing tools were FDA approved for clinical trials investigating the treatment of HIV already in 2021.
Key Limitations and Opportunities in C>s
Currently, Cell and Gene Therapies (C>s) have demonstrated astounding results in specific disease domains, such as cancer and genetic disorders, with substantial potential benefits and promises. However, as with many other therapies, they have limited efficacy ascribed to certain patient groups; efforts to address these issues are underway.
With reflection on Vector BioPharma’s announcement in 2022 of their recent financing by Versant Ventures, three shortcomings become apparent. Firstly, the alternative delivery systems are designed such that clinical data show an increased risk of immunogenic reactions. Secondly, the need for larger genome packaging capacity persists. Lastly, the fundamental issue of the lack of tissue-specific targeting, a limitation in many therapeutic contexts, persists. The following sections will examine each of these shortcomings in more detail.
1. Increased Risk of Immunogenic Reactions
Supported by Florent’s experience in the viral delivery modalities space, immunogenicity is associated with the need of administering patients repeated treatment doses to achieve the desired efficacy. In complex and chronic diseases, clinical benefit is rarely observed after single dosing. Even with the promise of C>s to fundamentally alter the intrinsic functioning of cells, the majority of proposed therapies to date require repeat dosing, and we assist in a race in the field to develop single-dose modalities that are both safe and effective. With progress in the field, new technologies are using various novel approaches to manage the side effects of repeat injections. These include IgG-breaking enzymes with cleaner gene therapy products (i.e., containing reduced DNA debris, thereby reducing immunogenicity) and other delivery modalities lacking immunogenic properties.
We believe that emerging solutions mitigate the technology risk posed by immunogenicity, thereby reducing the investment hurdle in this area.
2. Insufficient Genome Packaging Capacity
The capability to replace entire genes and thousands of Kbs has always been very appealing. If a disease is caused by a defective gene, enhancer, or stretch of DNA, replacing it appears to be the logical solution. Gene editing tools started with enabling Single Nucleotide Polymorphisms (SNP) modifications, then progressed with replacing small stretches of DNA, and currently with replacing large chunks of DNA. On the other hand, the progress in delivery systems has not been proportionate to the outstanding advancement in gene editing tools. The delivery of such large genetic constructs into cells is currently unattainable due to limited packaging capabilities. With the desire for larger gene capacity remaining unmet, there is a significant interest in new solutions addressing this limitation.
In this context, many viral delivery modalities have different properties making them attractive for particular use cases. The best benchmark for vector transfection capabilities is AAV-based viruses. With high transfection rates and low immunogenicity, these viruses are the standard in the gene therapy industry. Lentiviruses are used for ex-vivo transfection, such as Chimeric Antigen Receptor (CAR) T-cell therapy. It is noteworthy that, to have any clinically meaningful benefits, any new in vivo transfection capacity of a virus delivering a new vector or cargo must remain very high, similar to that of Adeno-Associated Viruses (AAVs). To date, we are unaware of such large cargo vectors with the same transfection capability as AAVs in official use; various research is undergoing in this field.
Based on this knowledge, R&D efforts appear premature, with technology and clinical development risk still high. On the other hand, a successful solution could yield substantial venture returns. For this reason, we follow companies such as Vector Biopharma.
3. Lack of Tissue-Specific Targeting
Targeted drug delivery is the holy grail of therapeutic interventions. Most side effects observed in patients relate to off-target selectivity and lack of specific targeting. Several approaches have been tested to improve specificity, and although there has been some advancement, off-target effects remain a significant challenge in this field. Most drugs today are administered systemically, with a significant proportion of the drugs being processed and lost in the liver without ever reaching their target tissue. The current doses used for humans are high, typically ranging from 10E13 to E14 particles per milliliter. This dosage is required to ensure a high transfectability and counteract losses, but is associated with the risk of severe inflammation of the liver and other organs. A potential solution is to selectively target viruses to specific cells without impairing transfectability. This strategy could reduce the required viral doses, resulting in decreased manufacturing expenses, and improved safety profiles.
We believe technologies targeting modification delivery with significant impact on clinical outcomes, beyond finding new cargo or vectors, and will be delivering high venture investment returns. Interestingly, this opinion seems shared by other European investors; for instance, Coave Therapeutics recently announced its ability to achieve selective targeting of AAVs to specific cells by conjugating peptides onto the AAV surface.
In summary, despite the several existing limitations of C>s, their potential for disruption presents substantial clinical and commercial opportunities. Certainly, a field deserving close monitoring.
If you are a founder of a C>s company, feel free to connect with Rabab and Florent on LinkedIn or reach out to the Earlybird Health team via our contact form.