Genetic medicines have been advancing at an extraordinary pace. Following the first wave of adeno-associated virus (AAV)–based gene therapies, the toolbox for gene therapy has expanded considerably. New therapeutic modalities like RNA medicines and CRISPR are unlocking even more doors. Together, these next-generation tools hold promise for a future where treatments can be tailored not only to rare disease populations but also to individual patients.Each modality is associated with a unique set of advantages, best use cases, and limitations, which makes it possible to match therapies more precisely to the biology of each condition. To see how this next wave is unfolding, we delve into these three approaches and the distinct roles each plays in the evolving precision medicine landscape.
AAV: Durable delivery with broad validation
AAV continues to dominate the field of gene therapy and is the most established for in vivo applications. Unlike retroviruses, they do not integrate into the host genome but persist as episomes, allowing for durable expression in non-dividing cells. A major advantage of AAV is the wide range of natural and engineered serotypes, each with different tissue tropisms, which makes it possible to target therapies to specific organs with greater precision and lower doses.
According to the American Society of Gene and Cell Therapy’s (ASGCT) Q2 report, of the 36 gene therapies that are currently approved globally, seven rely on AAV for in vivo delivery (approximately 28%). Most therapies use lentiviral or retroviral ex vivo approaches (e.g., CAR-T), and a few rely on adenoviral or non-viral delivery. Notably, in April 2025, BBM-H901 became the first AAV gene therapy approved in China, using an AAV8 vector engineered to reduce immune recognition and improve liver targeting. Multiple AAV-based therapies also received FDA designations such as Breakthrough Therapy and Orphan Drug, including several aimed at neurodegenerative diseases that had long been overlooked in gene therapy development. To explore these recent developments, download our whitepaper AAV gene therapy trends: Navigating the boom in viral vectors.
Despite this progress, challenges remain. Pre-existing immunity excludes 40-60% of participants from trials, re-dosing is rarely possible, and safety concerns such as immune reactions and liver toxicity continue to drive regulatory scrutiny. Manufacturing is also complex and expensive, with limited yields and capacity constraints. Even so, AAV remains the most widely validated vector for systemic delivery, and ongoing innovation in capsid engineering and trial design continues to expand its potential.
RNA medicines: Flexible, adaptable, and increasingly diverse
RNA medicines encompass a wide range of therapeutic strategies, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and messenger RNA (mRNA). Unlike DNA-targeting approaches, RNA medicines act at the transcript level, allowing for transient, repeatable interventions that do not permanently alter the genome. According to the ASGCT’s Q2 report, of the 4,469 therapies (gene, cell, and RNA therapies) currently in development, 29% are RNA-based.
ASOs are short synthetic strands of nucleic acids that bind to RNA and modulate splicing, block translation, or degrade transcripts. Approved ASO therapies are already reshaping care. Exon-skipping ASOs for Duchenne muscular dystrophy (e.g., eteplirsen, golodirsen) have shown that ASOs can deliver clinical benefit in neuromuscular conditions where no alternatives existed.
Beyond approved drugs, ASOs have also enabled rapid, individualized therapies. Milasen, designed in under a year for a child with Batten’s disease, proved how quickly a personalized ASO can be administered, although intervention came too late to prevent Mila’s tragic death. More recently, the n-Lorem Foundation provided personalized ASOs for children with KIF1A-associated neurological disorder, stabilizing symptoms in one case and allowing the same therapy to be extended to another child with the same mutation.
Other RNA medicines such as siRNAs and mRNAs are also advancing rapidly into clinical practice. The first siRNA therapy, patisiran, was approved in 2018 for hereditary transthyretin amyloidosis and marked a turning point for the field. More recently, fitusiran was approved in 2025 for the treatment of hemophilia A and B. mRNA medicines take a different approach, supplying genetic instructions for cells to produce therapeutic proteins. Their versatility was first proven at scale with COVID-19 vaccines, and new applications are now emerging in rare diseases and oncology.
Taken together, ASOs, siRNAs, and mRNAs demonstrate the adaptability of RNA as a therapeutic platform. All share the advantages of rapid design and development, but also face common challenges of delivery, durability, and scalability that will shape their long-term impact.
CRISPR: Precise and permanent genome editing
CRISPR gene editing enables direct modification of DNA in the genome, offering the potential for permanent correction of disease-causing mutations. Unlike ASOs, which modulate RNA expression, or AAV vectors, which deliver replacement genes, CRISPR cuts and repairs the genome itself. This precision allows for one-time treatments that can durably restore normal gene function.
Over the past decade, CRISPR has moved from a controversial concept to a clinical reality. The field has evolved rapidly, from early ex vivo trials to in vivo delivery, base editing, and now bespoke therapies for individual patients. Casgevy and Lyfgenia, both approved in 2023, demonstrated that CRISPR can deliver curative outcomes for blood disorders such as sickle cell disease and beta-thalassemia, with patients achieving transfusion independence and long-term remission. Like ASOs, CRISPR is highly suitable for n-of-1 conditions. In May 2025, news broke of a newborn with a life-threatening metabolic condition who was the first to receive a custom-designed in vivo CRISPR therapy, created and administered within six months of diagnosis. Early reports suggest the therapy was safe and effective, as the infant showed an improvement in symptoms and met developmental milestones.
The technology is particularly well suited to monogenic diseases where a single faulty gene can be targeted with precision. Delivery into hard-to-reach tissues is still evolving, off-target effects must be carefully monitored, and the high cost of one-time treatments continues to raise questions about patient access and equity.
Limitations and infrastructure gaps
AAV, RNA medicines, and CRISPR each demonstrate immense therapeutic promise, but they all face common challenges around long-term safety, scalability, and cost. Accessibility remains a common barrier, as most approved therapies are priced in the hundreds of thousands to millions of dollars, and trial eligibility is often constrained by strict genetic or immunological requirements.
For n-of-1 therapies (ASOs or CRISPR), while it is possible to design and deliver bespoke treatments, there is no streamlined infrastructure to make these approaches efficient, repeatable, or widely available. The immediate goal is to turn bespoke successes into repeatable pipelines. Manufacturing needs to be streamlined through shared processes, and safety can increasingly rely on platform-based data rather than starting new studies from scratch. Clinical testing should then use flexible designs adapted to ultra-rare populations.
Progress will require not only scientific innovation but also more consistent regulatory frameworks and coordinated collaboration between regulators and payers. Approvals and post-market requirements must be adapted to the realities of advanced therapies, and payment models must evolve to ensure that once therapies are approved, they are accessible to patients.
How Sano can help
Sano Genetics supports sponsors by tackling some of the most persistent barriers in advanced therapy trials. One of the biggest challenges in AAV development is pre-existing immunity, which can derail recruitment and delay timelines. To address this, Sano has introduced at-home antibody testing. This approach allows eligibility to be determined early, without requiring site appointments, and makes it possible to screen larger and more diverse populations at lower cost. For participants, providing a sample from home reduces burden and makes participation faster, easier, and more inclusive.
Genetic prescreening is another core component of our approach. By confirming that patients meet complex eligibility criteria before they reach a site, we lower screening costs, reduce site burden, and improve the likelihood that referrals will lead to successful enrollment. This is particularly important in rare disease settings where every participant matters.
Finally, patient recruitment is tailored through customized protocols that draw on genetic databases, patient advocacy groups, healthcare providers, and digital outreach. This blended strategy improves both speed and diversity, helping sponsors build cohorts that are more representative and more likely to deliver results.
Conclusion
The next generation of genetic medicines is already reshaping healthcare, but their full impact depends on more than scientific progress alone. Addressing cost, accessibility, and operational complexity will be essential to bring these therapies to the patients who need them. Regulators and payers must also work together to streamline approval, post-market oversight, and reimbursement pathways so that innovation is matched by access.
By building flexible, scalable trial infrastructure, Sano Genetics enables sponsors to deliver advanced therapies more efficiently and inclusively, ensuring that breakthroughs at the bench translate into real-world impact.