This was a great read! I really enjoyed it! Personally I hope this is a pause as well because these therapies are amazing to read about and huge breakthroughs are coming through the field not only about delivery but new therapeutics like Azalea with in vivo car T cell therapy.
Thanks for reading. Yes, new modalities like the one you mention for in vivo CAR T cell therapy (and potentially in other cell types) is definitely something I will be paying attention to over the next years - although I am curious to know if they will have applications in neurodegenerative disorders.
As someone who has manufactured hundreds of liters of LV vectors for cell/gene therapy, I can confirm that bottleneck in the manufacturing process are significant.
Thanks for reading. Yes, indeed a small batch of an AAV therapy on a bioreactor has a significant cost which contributes to, at least in part, the huge cost of AAV therapies in the market. It will be interesting to see if more efficient manufacturing methods can be developed.
Appreciate this thoughtful exploration of where gene therapy is headed and the care taken to acknowledge both promise and responsibility.
What resonates most is the implicit shift from can we deliver the therapy to can patients live with the therapy over time. For many families, this is not a one time intervention. It becomes a lifelong relationship with uncertainty, follow up, monitoring, and unanswered what ifs that extend well beyond the trial window.
It is also important that any pause in momentum does not diminish what has already been achieved. In rare diseases, gene therapy has delivered meaningful breakthroughs after decades of little to no hope. Those successes matter deeply to patients and families and should remain a source of confidence as the field evolves.
As the field matures, durability, long term safety, re treatment options, and the real world burden placed on patients and caregivers feel just as critical as the initial efficacy story. Those questions do not slow innovation. They make it sustainable.
From a Medical Affairs perspective, this is where support really matters. Helping clinicians and patients navigate expectations honestly without diminishing hope or overstating certainty builds trust. That trust is reinforced when we stay present long after the infusion is complete.
The opportunity ahead is not just advancing gene therapy science. It is designing programs that truly stand alongside patients for the long haul.
Thanks for reading! You’ve captured the shift from delivering a payload to helping people live with a therapy over years; durability, monitoring, caregiver burden, retreatment planning and consent as an ongoing conversation determine whether breakthroughs become durable. I think we should celebrate rare‑disease wins while building long‑term registries, integrated care pathways, psychosocial supports, and Medical Affairs that stay present after infusion. I’ll keep writing about both the science and the systems that make these advances sustainable.
I agree, whilst on paper the mass exodus looks ominous it’s more of a pause/reset than the end. The current CGT business model just does not fit nor is lucrative for big pharma
Thank you so much! This is a really sharp, reality-based synthesis.
What you’re describing reads less like “loss of faith in the science” and more like a rational response to three hard constraints we all feel downstream in patient care:
1. Operational fragility: autologous chains, cold logistics, batch variability, and narrow treatment windows are a mismatch for real-world healthcare systems.
2. Risk tolerance: when the intervention is irreversible, even low-frequency safety signals carry outsized clinical and regulatory weight.
3. Economic mismatch: multi-million-dollar, upfront pricing collides with payer time horizons and uncertainty about durability, especially when outcomes are heterogeneous.
I also appreciate the nuance that this is likely a pause/reset, not an end. The “next wave” seems most plausible where we reduce friction: safer systemic delivery beyond first-gen vectors, more automated/closed manufacturing, clearer endpoints, and reimbursement models that can actually support long-term value. In that sense, the retreat may be a sign the field is maturing, forcing prioritization of indications where benefit is unmistakable and execution is feasible.
P.S. Curious how you see the near-term winners: platform shifts (non-viral/LNP, capsid engineering, in vivo approaches) or indication shifts (rare diseases vs. higher-prevalence conditions once delivery and safety improve)?
Thanks, this is a sharp read. You’ve nailed the 3 major constraints: operational fragility, the outsized impact of irreversible risks, and the payer/durability mismatch; those explain the current pause. Near‑term winners will reduce friction — safer, simpler delivery, more automated manufacturing, and clearer endpoints — but I think the target indications should remain in those with unmistakable benefit (mostly rare diseases) while reimbursement models evolve. The non-viral/lipid delivery methods are certainly promising but getting them to the clinic will be a bumpy road.
Very sober perspective. On my side of this issue, making AAVs and delivery systems is still too low throughout and quality varies. I have always liked the idea of non-viral, genetically encoded vectors that can be produced for cheap, but this requires a lot of bootstrapping and a lot of basic research on viral biology. That’s the space for academic research and startups. It’s our turn now :)
Thanks for reading! Totally — AAV throughput and batch quality are real bottlenecks. Non‑viral, genetically encoded vectors could deliver cheaper, scalable supply, but they need heavy lifting in basic virology, expression systems, and standardized QC — exactly the work academia and startups should lead.
Thanks for reading! Yes, the "new" FDA did not confirm that using externally-matched controls would support accelerated approval. While I did not edit this post (I don't like to extensively edit posts post-publication), I did comment on this decision on a later post on the use of natural history controls - https://open.substack.com/pub/braintrials/p/natural-history-controls-in-neurodegeneration - this is a critical development that will reshape clinical development programs of rare disorders.
This was a great read! I really enjoyed it! Personally I hope this is a pause as well because these therapies are amazing to read about and huge breakthroughs are coming through the field not only about delivery but new therapeutics like Azalea with in vivo car T cell therapy.
Thanks for reading. Yes, new modalities like the one you mention for in vivo CAR T cell therapy (and potentially in other cell types) is definitely something I will be paying attention to over the next years - although I am curious to know if they will have applications in neurodegenerative disorders.
As someone who has manufactured hundreds of liters of LV vectors for cell/gene therapy, I can confirm that bottleneck in the manufacturing process are significant.
Thanks for sharing!
Thanks for reading. Yes, indeed a small batch of an AAV therapy on a bioreactor has a significant cost which contributes to, at least in part, the huge cost of AAV therapies in the market. It will be interesting to see if more efficient manufacturing methods can be developed.
Appreciate this thoughtful exploration of where gene therapy is headed and the care taken to acknowledge both promise and responsibility.
What resonates most is the implicit shift from can we deliver the therapy to can patients live with the therapy over time. For many families, this is not a one time intervention. It becomes a lifelong relationship with uncertainty, follow up, monitoring, and unanswered what ifs that extend well beyond the trial window.
It is also important that any pause in momentum does not diminish what has already been achieved. In rare diseases, gene therapy has delivered meaningful breakthroughs after decades of little to no hope. Those successes matter deeply to patients and families and should remain a source of confidence as the field evolves.
As the field matures, durability, long term safety, re treatment options, and the real world burden placed on patients and caregivers feel just as critical as the initial efficacy story. Those questions do not slow innovation. They make it sustainable.
From a Medical Affairs perspective, this is where support really matters. Helping clinicians and patients navigate expectations honestly without diminishing hope or overstating certainty builds trust. That trust is reinforced when we stay present long after the infusion is complete.
The opportunity ahead is not just advancing gene therapy science. It is designing programs that truly stand alongside patients for the long haul.
Thanks for reading! You’ve captured the shift from delivering a payload to helping people live with a therapy over years; durability, monitoring, caregiver burden, retreatment planning and consent as an ongoing conversation determine whether breakthroughs become durable. I think we should celebrate rare‑disease wins while building long‑term registries, integrated care pathways, psychosocial supports, and Medical Affairs that stay present after infusion. I’ll keep writing about both the science and the systems that make these advances sustainable.
I agree, whilst on paper the mass exodus looks ominous it’s more of a pause/reset than the end. The current CGT business model just does not fit nor is lucrative for big pharma
Thanks for reading. It’ll be interesting to see how this evolves and how the business model adapts.
I love it. This is indeed the phase that comes after hype but before real value.
Delivery technologies will mature, and localized, high-precision bioagent manufacture techniques will appear.
And then we'll enter the value phase of cell and gene therapy.
Thank you so much! This is a really sharp, reality-based synthesis.
What you’re describing reads less like “loss of faith in the science” and more like a rational response to three hard constraints we all feel downstream in patient care:
1. Operational fragility: autologous chains, cold logistics, batch variability, and narrow treatment windows are a mismatch for real-world healthcare systems.
2. Risk tolerance: when the intervention is irreversible, even low-frequency safety signals carry outsized clinical and regulatory weight.
3. Economic mismatch: multi-million-dollar, upfront pricing collides with payer time horizons and uncertainty about durability, especially when outcomes are heterogeneous.
I also appreciate the nuance that this is likely a pause/reset, not an end. The “next wave” seems most plausible where we reduce friction: safer systemic delivery beyond first-gen vectors, more automated/closed manufacturing, clearer endpoints, and reimbursement models that can actually support long-term value. In that sense, the retreat may be a sign the field is maturing, forcing prioritization of indications where benefit is unmistakable and execution is feasible.
P.S. Curious how you see the near-term winners: platform shifts (non-viral/LNP, capsid engineering, in vivo approaches) or indication shifts (rare diseases vs. higher-prevalence conditions once delivery and safety improve)?
Thanks, this is a sharp read. You’ve nailed the 3 major constraints: operational fragility, the outsized impact of irreversible risks, and the payer/durability mismatch; those explain the current pause. Near‑term winners will reduce friction — safer, simpler delivery, more automated manufacturing, and clearer endpoints — but I think the target indications should remain in those with unmistakable benefit (mostly rare diseases) while reimbursement models evolve. The non-viral/lipid delivery methods are certainly promising but getting them to the clinic will be a bumpy road.
Very sober perspective. On my side of this issue, making AAVs and delivery systems is still too low throughout and quality varies. I have always liked the idea of non-viral, genetically encoded vectors that can be produced for cheap, but this requires a lot of bootstrapping and a lot of basic research on viral biology. That’s the space for academic research and startups. It’s our turn now :)
Thanks for reading! Totally — AAV throughput and batch quality are real bottlenecks. Non‑viral, genetically encoded vectors could deliver cheaper, scalable supply, but they need heavy lifting in basic virology, expression systems, and standardized QC — exactly the work academia and startups should lead.
Great information and perspective. Thank you!
Thanks for reading!
Fantastic summary of tech trends on this topic. Thank you for sharing!
Thanks for reading!
Great article, doesnt surprise me this is happening honestly
Thank you for this great article! Just look at uniQure’s AMT-130…
https://open.substack.com/pub/chaotropy/p/the-fdas-reversal-on-uniqures-gene?utm_campaign=post-expanded-share&utm_medium=post%20viewer
Thanks for reading! Yes, the "new" FDA did not confirm that using externally-matched controls would support accelerated approval. While I did not edit this post (I don't like to extensively edit posts post-publication), I did comment on this decision on a later post on the use of natural history controls - https://open.substack.com/pub/braintrials/p/natural-history-controls-in-neurodegeneration - this is a critical development that will reshape clinical development programs of rare disorders.