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Gene Therapy for Common Diseases

March 21, 2025 •  Martin Borch Jensen Chris Towne

The following content was posted by Gordian chief technology officer Martin Borch Jensen on the Norn Group website. The Norn Group is a nonprofit research organization focused on helping people live better and longer lives.

The first therapies developed using AAV gene therapy targeted monogenic disorders where the therapeutic target was unambiguously known but not well treated with traditional modalities. This strategy made sense to avoid adding risk when testing a new delivery modality. But because of this history, some features of ‘gene therapy for rare disease’ are often assumed to be integral to AAV gene therapy. Now that gene therapies for Parkinson’s, macular degeneration, heart failure, osteoarthritis, and other common diseases have entered clinical trials, it is useful to highlight ways that AAV gene therapy for common disease would have different dynamics and the challenges/opportunities this creates.

Cost

Approved gene therapies have had prices high enough to grab headlines, and which would not be feasible for treating large populations. This comes from a combination of three major factors: 1) real cost of production, where complex manufacturing requires optimization for abundant yields, 2) gene therapies for rare diseases with very few patients need to cover development costs based on low number of treatments provided, 3) in comparison to pills and injections administered over and over, the cost of gene therapies are compressed into a single administration.

For the first factor, we expect from other manufacturing in and out of drug development that costs of production will fall as processes are optimized. A relevant comparison is manufacturing costs for antibody drugs, similarly produced in living cells. The cost per antibody dose has dropped two orders of magnitude since this modality began in the late 1980s, from a combination of finding producer cells with higher yields, standardizing and optimizing handling, and setting up larger and larger bioreactors to gain economies of scale [1-4]. AAV gene therapy manufacturing costs have dropped ~ a single order of magnitude since the 2000s, now at tens of thousands of dollars per dose for many applications (though higher for some)[5]. Therapies for common diseases will demand much larger production batches to treat patient populations. Larger batches also mean that less material is lost to quality control assays (currently double digit percent). Overall, similar optimization as for antibodies is relevant and ongoing and the cost curve has so far been similar [5-8].

Figure 1. Decreasing costs of antibody and AAV therapies over time [1, 2, 5, 8-15]

The second factor is dramatically different outside of rare disease. Conditions like diabetes and arthritis affect tens of millions of patients just in America, instead of thousands for the rare diseases that were initially targeted with gene therapy. So R&D costs can be diluted by a factor of more than a thousand.

The third factor, one-time dosing, still applies in common disease. But if cost of manufacturing stays on the order of $10K, and margin for each dose can remain low because tens of thousands to millions of doses are administered, overall costs for gene therapies against common diseases could be comparable to a single year of treatment with other modalities.

Safety

Safety is an important consideration for new modalities, especially for expanding into larger patient populations. There is a growing body of real-world data across multiple genetic conditions supporting AAV gene therapy’s safety and feasibility: AAV therapies have so far been administered to over 7,000 patients worldwide, spanning both clinical trials (~3000 patients) and approved therapies for rare diseases (~4000 patients across FDA-approved AAV gene therapies dominated by Zolgensma, but also Luxturna, Hemgenix, and Roctavian).

The two major takeaways from this data are 1) overall safety is favorable, with rare adverse events (<1%) that are generally manageable with immunosuppression, 2) under certain conditions AAV gene therapy has significant risks and can lead to serious adverse events and mortality [16-20].

A total of thirteen deaths have been linked to AAV gene therapy (~0.2%), all between 2021 and 2024. Every event happened at AAV doses at or above 1E14 vg/kg, and involved immune activation and/or thrombotic microangiopathy. Based on this, more recent therapies aim for lower dosing and have updated patient monitoring plans.

Life saving gene therapies like Zolgensma might be compared to cancer immunotherapies that are regularly approved with single to double digit % mortality risks [21]. For common diseases, acceptable thresholds are much lower. For example, the drug rosiglitazone was pulled from European markets for increasing risk of heart attacks and deaths by >0.05% [22], though it remains approved in the US. It should be noted that since almost half the AAV data comes from clinical trials that involve finding safe dosing, and the vast majority of approved doses being above the 10^14 threshold, the overall rates of adverse events are exaggerated compared to individual approved drugs.

Nevertheless, extending AAV gene therapy to common diseases requires a very clear safety profile. We now know that this will depend on doses (well) below 1E14 vg/kg, at which point most side effects can be addressed with short-term immunosuppression. Fortunately, this requirement dovetails with the need to reduce cost per dose, so the challenge is finding targets that are effective at these doses.

Figure 2. Relationship between AAV gene therapy dose and safety (data as of March 2025) [23-49]

Eligibility

An important factor for targetable patient population is the prevalence of neutralizing antibodies (NAbs). Since AAV is derived from naturally occurring viruses, many people – depending on the specific AAV serotype – have been exposed to similar viruses and have pre-existing antibodies that can block vector delivery before it reaches target cells. For some AAV serotypes, as many as 30–70% of adults have detectable neutralizing antibodies [49]. For common diseases, cutting targetable population in half may still leave millions of eligible patients, but in rare disease this majorly impacts target populations and consequently strategies to avoid nAbs have already been explored for more than a decade. Local injections, already being used for diseases like Parkinson’s, macular degeneration, heart failure, and osteoarthritis, limits the influence of nAbs on delivery. More elegantly, groups have found ways to temporarily deplete the antibodies while administering AAV, either by blood exchange or using antibody-cleaving enzymes like IdeS. This strategy has already been pursued clinically for organ transplantation [50] which combined with proof of concept studies with AAV suggest that it would mostly eliminate nAbs as a blocker to AAV administration [51].

Durability

“One and done” treatment is a hope for AAV gene therapy, at least for cells without constant turnover. As a new type of therapy, we don’t yet have decades of data to test this. In early studies, expression was lost over time, likely by triggering immune responses and epigenetic silencing. These effects were then designed around in later efforts. In 2017, expression from AAV gene therapy was observed in ~90% of neurons of primates 15 years after administration to the brain (which notably has low cellular turnover and immune activity). In humans, patients in early trials of hemophilia and smooth muscle atrophy still show efficacy eight years after administration. Durability data is summarized in Tables 1 and 2.

Table 1 – AAV gene therapy durability in non-rodent models [52-55]

Table 2 – AAV gene therapy durability in humans [56-62]

Long-term human studies focus on clinical outcomes rather than expression, because biopsies would be needed to evaluate expression unless the target is a secreted protein.

More time will be needed to say whether durability extends to multiple decades, and whether this is true only for some tissues. This has been a significant cause of hesitation for AAV gene therapy, under the early assumption that redosing would be impossible due to nAbs. But today we can already see multiple paths around redosing: In vivo gene editing [63] and correction [64] has been achieved in clinical trials, which would preserve effects in dividing cells. But simply redosing AAV after depleting antibodies may suffice in tissues that are not highly proliferative, and dosing every five or ten years would be a boon for patients.

On this note,

Conclusions

From the above, we can draw the following conclusions on the prospects of gene therapies for common diseases, which are increasingly entering clinical trials.

  1. Market/pricing dynamics of AAV gene therapies for common disease are extremely different than currently approved therapies, and intuitions should be reset in this context. Cost per dose could be $tens of thousand or less.

  2. Safety is an important consideration, and we’ve learned a lot about AAV side effects. Finding targets effective without massive doses is critical.

  3. Re-dosing will be possible very soon, so durability is important but does not need to be lifelong.

At the relevant doses, current AAV manufacturing capacity is plentiful even for common diseases: Ten 2000L bioreactors would be sufficient to treat 2 million osteoarthritis patients per year at doses being tested in the clinic. Total CDMO capacity is hundreds of thousands to over a million liters, not including dedicated manufacturing at gene therapy companies. So production will not be a bottleneck for the first generation(s) of common disease gene therapies.

But even at parity of price and safety, the convenience of single or rare dosing is not an overwhelming reason to engage a new modality. So are there additional advantages to using AAV gene therapy?

One is the possibility of improved safety profiles. About half of clinical trials fail due to drug toxicity, and even approved drugs commonly have side effects that hurt patients, interact with other drugs, and sometimes lead to withdrawal from the market. Most of these toxicities come from effects of the drug in organs other than what is targeted for treatment, most often in liver and heart [65]. In contrast, AAV gene therapy can be targeted and active only in specific organs or even cells of that organ, by selecting the right serotype and promoters. This could both limit side effects, enable more combination treatments, and open up targets that are effective but untenable due to side effects in other organs.

More importantly, current estimates are that ~20% of potential drug targets are ‘druggable’ with small molecule and protein drugs [66]. With AAV gene therapy, all but the largest genes could be expressed and any gene could be inhibited. How many cures and therapies will be found in this expanded druggable space is speculative, but seems very unlikely to be zero. With the right approaches to finding good targets for complex diseases, gene therapy could remove barriers to effective treatments. One example of a large population not currently being served by drug development is color blindness.

One remaining challenge is our ability to deliver gene therapies to every cell in the body. Some diseases, especially preventative treatments, would need to reach many tissues at high saturation, which is at odds with low dosing titers. And some organs can not be effectively transduced yet. So early therapies will be in organs where AAV has been derisked, while multiple companies and labs are working on delivery to other organs (a more extensive report on this is forthcoming from Norn Group).

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