As outlined in the previous instalments of this series, the rare disease gene replacement technology [GT] landscape has undergone rapid growth over the last decade fuelled by groundbreaking innovation, with the end of 2023 ushering in the approval of the first CRISPR GT [Vertex/CRISPR Therapeutics’ Casgevy for β thalassemia] by the UK’s MHRA. Rare diseases provide an attractive market opportunity for GTs; out of over 10,000 rare diseases, about 80% are of genetic origin, and 95% lack an approved treatment. 12 rare disease GTs have been FDA-approved since 2017, spanning three GT technologies – adeno-associated virus [AAV] GTs, lentiviral vector [LVV] GTs, and CRISPR-Cas9 gene editing technology – with various degrees of commercial success.

In this piece, we consider how pivotal the chosen gene technology is in guiding the success of a GT in rare diseases. To do this, we examine the three approved technologies, outlining how they work and identifying the factors contributing to their various successes. We then take a deep dive into two success stories in the β thalassemia space – Bluebird Bios’s LVV GT Zynteglo and Vertex/CRISPR’s CRISPR GT, Casgevy – to explore the potential role of the technology in driving their respective commercial triumphs.

AAV GT Pioneers – Triumphs and Tribulations   

AAV GTs make up the majority of rare disease GT approvals worldwide1, owing their popularity to a favorable safety profile [triggering only a mild immune response and rarely integrating into the host genome], robust cell tropism [in part facilitated by the in vivo delivery], and somewhat durable transgene expression.

Nonetheless, this technology comes with challenges. The small cargo capacity [~5 kb] limits the size of transgenes that AAV vectors can carry, requiring the construction of shorter genes [e.g. Sarepta’s Elevydis for Duchenne muscular dystrophy] and/or high doses which impact safety. As most AAV GTs pass through the liver before reaching the target tissues, high doses can trigger severe liver damage and, in rare cases, liver-related death [e.g. Novartis’ Zolgensma for spinal muscular atrophy, or Audentes Therapeutics’ AT132 for X-linked myotubular myopathy]. Furthermore, patient eligibility is dependent on the presence of neutralizing antibodies [NAbs] that can inhibit the efficacy of GTs, naturally harboured by some patients due to exposure throughout their lifetime [pre-existing immunity]. AAV GT administration can also trigger the development of these NAbs, limiting re-dosing potential. The latter limitation is especially concerning if waning transgene expression is observed, for example in the case of BioMarin’s Roctavian for hemophilia A, which has contributed to underwhelming uptake.

These challenges call for expansive pre- and post-dose monitoring requirements for AAV GTs, arguably inhibiting AAV GTs from meeting the ultimate goal of being a “one-and-done” therapy. Companies are making attempts to temper the monitoring burden, via patient services [with BioMarin’s Rare Connections even offering mobile lab testing directly to the patients home or work], using corticosteroids to dampen the immune system and improving safety, and repurposing medicines [e.g. small molecules like rapamycin, biologics like Argenx’s Vyvgart] to enable redosing. Again, these added interventions move AAV GTs further away from the “one-and-done” goal, and fail to fully eliminate the treatment burden. Moreover, the costs imposed by monitoring and added interventions are not absorbed into the already hefty price tag of GTs, amplifying the lifetime cost of treatment [ICER estimated BioMarin Roctavian’s total cost at over $14M, including the $2.5M price tag, yet still deemed Roctavian cost effective]. A gap remains for durable and safe GTs without monitoring burden and added interventions that meet the criteria for a true “one-and-done” GT – and the solution could lie in the technology.


LVVs May Not Be The Solution

Newer entrants to the rare disease space are ex vivo LVV GTs, spearheaded by Bluebird Bio’s Zynteglo for β thalassemia, first approved by the EMA in May 2019 [and followed by FDA approval in Aug 2022]. Bluebird Bio is currently championing the space as the market authorization holder for three out of four approved LVV GTs [Zynteglo; Skysona, approved by the EMA in Jul 2021, and the FDA in Sep 2022 for active cerebral adrenoleukodystrophy; Lyfgenia, approved by the FDA in Dec 2023 for sickle cell disease [SCD]], joined recently by Orchard Therapeutics’ Lenmedly for early-onset metachromatic leukodystrophy, which boasts the highest cost of any FDA-approved treatment at a whopping $4.25M one-time cost.

LVVs address some of the aforementioned challenges posed by AAV vectors. The virus edits the patient’s own cells ex vivo and is removed before the cells are returned to the patient, bypassing AAV’s worst enemy – NAbs. Furthermore, the integrating capabilities of LVVs enable stable transgene expression, which is passed onto the next generation of cells as they divide, facilitating longer-term durability. This also renders LVV GT more suitable for cellular disorders, like β thalassemia, in which cells are constantly dividing [which would dilute the AAV]. However, safety remains an issue; as an integrating technology, LVVs carry oncological risks, with both Skysona and Lyfgenia holding a black box warning for haematological malignancy on their FDA labels. However, KOLs at ASH 20233 were relatively unconcerned with Lyfgenia’s black box warning, given this risk is not unique to Lyfgenia but associated with the technology. This suggests that the benefit of these therapies to patients with severe rare diseases may outweigh the risk; but how will this perception change once a safer GT technology becomes available for the same disease?


CRISPR – A New Horizon

Enter CRISPR-Cas9. In 2020, chemists Jennifer A. Doudna, PhD and Emmanuelle Charpentier, PhD were awarded a Nobel Prize for their groundbreaking new gene-editing tool, CRIPSR-Cas9, which leverages site-specific, targeted nucleases, to directly modify the genome. Just three years later, the first world approval of a CRISPR-based therapy was granted to Vertex/CRISPR Therapeutics’ Casgevy for SCD, which was also approved for transfusion-dependent β thalassemia [TDT] shortly after. Researchers believe CRISPR technology could make GT more efficient and precise, in turn improving efficacy and safety. Furthermore, CRISPR technology may be more affordable than AAV and LVV, both during development [due to the flexibility of the technology addressing multiple genetic disorders without the need for various vectors] and manufacturing [owing to its scalability compared to producing AAV vectors]. Could this signal a revolution in GT products?

The jury’s still out, as our understanding of this technology is incomplete, particularly around its safety. CRISPR GTs hold a risk of off-target genome editing, of which the consequences are unknown. These gaps in our knowledge can be exemplified by the tumultuous development of Graphite Bio’s CRISPR GT nulabeglogene autogedtemcel [nula-cel] for SCD, which the company dropped after the first patient dosed in its Ph1/2 CEDAR trial experienced an unexpected serious adverse event of prolonged pancytopenia. Kamau Therapeutics [co-founded by Graphite’s ex-scientific founder, Matthew Porteus MD, PhD, also responsible for nula-cel’s discovery] has since restarted nula-cel’s development, renaming it KMAU-001 and attributing the adverse event to manufacturing. Most puzzling, however, is the unexpected desirable effect of elevated fetal hemoglobin expression, given the therapy targeted adult hemoglobin; investigation into the unknown reasons behind this is ongoing. Nevertheless, even if Kamau succeeds in bringing KMAU-001 to market, its success may be marred by its tainted history, with HCPs and patients likely opting for a potentially safer, and established, CRISPR GT,  i.e. Vertex/CRISPR Therapeutics’ Casgevy.


β Thalassemia – The Proof Will Be in the [GT] Pudding 

Now we have outlined the three approved gene therapies, lets deep-dive into the two β thalassemia GT success stories. Only five years ago, β thalassemia patients relied on lifelong transfusion or bone marrow transplants [which come with their own challenges, including finding an HLA-matched donor, and a risk of transplant-related mortality] to ensure survival beyond early adolescence years. With the recent arrival of two GTs approved for transfusion-dependent β thalassemia [TDT, the most severe form], Bluebird Bio’s Zynteglo and Vertex/CRISPR-Therapeutics’ Casgevy, this subset of patients may now have a better option. But how important is the actual GT technology in influencing the choice between the two products?

Both products are ex vivo therapies [derived from the patient’s own blood stem cells which are modified and returned to them via a hematopoietic stem cell transplant] and both achieve the same goal of increasing blood hemoglobin levels, albeit by different mechanisms. While LVV GT Zynteglo delivers the functioning HBB gene to the cells, CRISPR GT Casgevy directly edits the patient’s HBB gene. As discussed, these different GT technologies come with distinctive safety profiles, which may prove to be a key competitive factor. Zynteglo holds a risk of insertional oncogenesis and requires additional monitoring for ~15 years post-dose, and as discussed, like with AAV GTs, these extensive monitoring requirements inhibit Zynteglo from meeting the “one-and-done” goal of GTs. In contrast, Casgevy’s off-target genome editing potential is viewed as less risky4, and there are no monitoring requirements – could Casgevy be truly “one-and-done”? These differences in safety will likely act in Casgevy’s favor, with patients, HCPs, and payers, more likely to choose the safer option with less treatment burden. This is reflected in predicted sales of both GTs in 2028, with Casgevy expected to generate double [$315M] for TDT than Zynteglo [$145M]5. In tandem with Casgevy’s lower price tag [in the US $2.2M vs. Zynteglo’s $2.8M], Casgevy will likely see a higher return on investment than Zynteglo, and it appears the technology is a critical influence in this comparative success.


Technology Choice is the First Challenge for GT Players

In conclusion, while much of the current discussion around approved GTs for rare diseases focuses on patient access and how companies can navigate high costs and manufacturing challenges [as highlighted in previous Solici articles], the diverse success stories of marketed GTs remind us that the first pivotal decision is the choice of technology. No single technology suits all cases; instead, companies must consider several factors, including efficient gene delivery, target specificity, and immunogenicity – to combat those monitoring requirements and added interventions preventing GTs to be truly classed as “one-and-done” – as well as market potential, differentiation from existing products, manufacturing feasibility and scalability, and reimbursement precedents. Ultimately, these factors related to the technology will impact the return on investment, particularly in rare diseases where the patient pool is limited and as more products are enter the space. This strategic approach is vital for overcoming the unique challenges of rare disease therapeutics and ultimately providing life-changing treatments to patients in need.


[1]     Barclays, “HemoA KOL call focus on Roctavian US Launch, Barclays”, April 10, 2024

[2]     Data from Evaluate Pharma, April 2024

[3]      Barclays ASH 2023 KOL Commentary, “Barclays Healthcare Weekly Call”, Dec 12, 2023

[4]     JMP “CRISPR Therapeutics AG (CRSP). Thoughts After FDA Approval Dust Settle”, December 10, 2024

[5]     Data from Evaluate Pharma, April 2024


Contact us

Reach out to us if you’d like to partner with us, want to join our team or would like a conversation about how we shape the smartest choices in healthcare.