Author: logancollins
Logan’s List of Entrepreneurship Funding/Mentorship Resources
After compiling these resources for my personal reference, I realized that others may benefit from them as well. As a person of collaborative spirit, I decided to post them here! Although these are focused on early-stage biotech entrepreneurship, many of the resources should also have broader applicability. I should note that some of the items listed may exist transiently, so parts of this compilation might eventually end up out-of-date. I hope that you find this list helpful for your own adventures!
Accelerators/Incubators
- Part of the 1517 Fund. Offers up to $100K in funding for launching tech companies (including biotech).
- Emphasizes escape from issues with academia and emphasizes sci-fi-like technologies.
- “You want to hit ‘pause’ on the academic rat race and spend 3 months on first-principles exploration of either applied, practical problems that can be commercialized within a VC-funded startup in the near-medium term (5 years) or moonshot fundamental science.”
- Work full-time for 1 summer (presumably some of the $100K may go towards living expenses?)
- Appears to not require a specific location, though there is a weekend retreat at the beginning of the summer and a dinner at the end of the summer.
- “Fellows receive a yearly living stipend of $100K, plus travel allowance, health insurance, and relocation. This enables them to focus on their project full-time. Each project also receives $100K in R&D funds at zero cost and access to at least $75K in additional flexible capital.”
- 2-year program.
- Also offers intensive mentorship, entrepreneurial education, community support, and research facilities.
- Eligibility issue for repeat founders: “Must be leading the commercial development of a hardware-based technology innovation for the first time if awarded the fellowship i.e., not a repeat hard tech founder.”
- Eligibility issue for medical biotech: “Our Fellowship does not currently support innovators developing technologies that only have application in mammalian health. If the underlying technology has the potential to pivot to other, non-healthcare markets and the stage of development is early enough such that market exploration during the fellowship is a key activity, the Activate Fellowship is likely to provide transformative support and it is worth applying. Specifically, if a focus during the fellowship is pursuing FDA approval, Activate is not a good fit. We encourage you to think broadly about the applications and potential impact of your technology and look at other companies we have supported for examples.”
- Communities in Berkeley, Boston, New York, and Houston. But does not appear to require a specific location.
- “For the therapeutics track, because only $250K is upfront and the other $1.75 million is over time, we are looking for truly novel platforms and methodologies that need this time to prove their concept.”
- Requires a co-founder.
- New York or San Francisco location.
- “At the start of the program founders receive an equity free Talent Investment (grant)* to cover living costs.”
- “During FORM, the goal is to test cofounder partnerships and ideas at pace as you build a company from day one. You’ll be supported by a team of Talent Investors and our global network of advisors, who will challenge your ambitions and develop your vision of success. Throughout FORM, we will push you to obsess about customer development, validating your ideas with customer feedback and traction from the outset. Our goal is to help founders build their initial edge and develop their longer term vision. For those with the biggest ambitions, this will involve getting early traction with US customers and building their vision for that market, which we will support with our network of SF advisors and operators.”
- “Towards the end of the program teams pitch to our Investment Committee for up to $250,000 in funding per team. This is made up of a $125,000 investment from EF, and the opportunity to receive a further $125,000 investment from EF’s third party investment partner, Transpose Platform*.” If you do not form a company or we choose not to invest at IC, we don’t take any equity and you don’t have to repay the grant. Instead you gain access to a global community of alumni to leverage for future success.
- It should be noted that the first $125K is “a post-money SAFE* (Simple Agreement for Future Equity) for 8% of your company” and the other potential $125K is an “investment from our partner Transpose Platform via an uncapped MFN (Most Favoured Nation) SAFE.”
- “At EF, we build technology companies. The majority of individuals who join EF will have a technical background, from self-taught developer through to a Computer Science PhD.” Note that they have also backed biotechnology companies.
- Spring, Summer, and Winter programs are available.
- Begins with an 8-week program (FORM) located in San Francisco, New York, London, Paris, or Bangalore. Concludes with a 4-week program where startups settle in San Francisco.
- Part of Soma Capital. Offers a $30K grant (non-dilutive) and an 8-week summer program in San Francisco or New York City where the goal is to “become an expert at something, solve a riddle, write a research paper, prove a math theorem, start a hedge fund, master chess or poker, develop a new drug, launch a space company, design a chip, build a new LLM, or search for aliens!”
- “We’ll give you a 30k grant, a beautiful office space in SF or NY, access to an elite community, catered dinners and events, and aspirational experiences”.
- A student-led organization which identifies, educates, connects, and empowers academic biotechnology entrepreneurs to create and run startups. George Church, Tom Kalil, and Pamela Silver are some of the advisors. “Nucleate is a student-led organization that represents the largest global community of bio-innovators”.
- Website provides the Nucleate Operationalizing Your Therapeutics Spinout Playbook as an educational resource.
- Offers a six-month activator program that equips academic biotechnology founders with the skills and connections for successful business development.
- “Activator is a six-month, equity-free cohort program designed for academic biotech founders. Its curriculum has served more than 100 life sciences ventures that have raised over $190 million in venture funding. Participating teams refine their scientific discoveries into biotech venture theses and train under Nucleate’s unparalleled network, rigorous curriculum, funded fellowships, legal support, and highly subsidized perks. Activator culminates in a final pitch showcase before world-renowned judges”.
- Activator program is free and they do not take equity.
- Activator program requires projects that have not received any equity funding, but which do have early proof-of-concept data.
- “Activator takes place in-person in several regions globally. If there is not a Nucleate Chapter in your region, we also offer a Global Virtual Activator. (Ann Arbor, Atlanta, Baltimore, Bay Area, Boston, Canada, Chicago, DC, Denmark, Florida, France UniCA, Germany, Global Virtual, Israel, Los Angeles, New Haven, New York, Philadelphia, RTP, San Diego, Seattle, Switzerland, Texas, Twin City, United Kingdom)”.
- A program by Boost VC. They emphasize that they are looking for extremely ambitious founders building sci-fi-like technologies. Scientist-founders should have a rebellious spirit and the ability to build businesses in addition to doing science.
- “The residency includes workshops, office hours, and guest speakers—seasoned Bio founders and top Bio VCs to share journeys and insights to help you move faster.”
- “The week wraps with a science fair-style showcase happy hour with Bio VCs and networking. Each startup will receive continued access to our housing and office space for 2 weeks after to continue building alongside fellow deep tech founders.”
- Offers “$500K for 10%” and “Free housing & office space in Silicon Valley” and “Access to a week of hands-on programming designed to help founders craft their business plan and prepare to raise a full pre-seed round”.
- Gathers the “most ambitious innovators in Bio” in Silicon Valley for an intensive learning and networking experience over the course of 2 weeks.
- An accelerator program aimed at startups and student teams. (But one can apply either as a student or as an incorporated startup). It does not require applicants to be students.
- For startups: “$750K uncapped (YC standard safe). Each founder gets $10K profit share of Neo fund carry. We get participation rights in your next equity round to buy up to 5% total ownership”.
- Residency provides “3 months at our beautiful SF space. Maximize your productivity and build lasting relationships with founders and mentors at our intensive 2-week Oregon bootcamp. Access to world-class mentors, tech leaders & VCs. Learn from fabled founders and seasoned operators. Meet industry leaders at intimate events and 1:1 sessions. End the program with a Demo Day and bespoke VC intros. OpenAI & Microsoft perks, community, & more.”
- Neo also offers additional investment opportunities “Pre-seed & seed funding: Contact one of our team members (we prefer warm intros). We lead priced equity rounds or safes with our standard side letter.”
- At least one member of the founding team must be technical.
- One can apply as a solo founder or as a team. The program strongly encourages people looking for a cofounder find one before applying.
- Occurs in person for ~3 months (SF location).
- 1-week program which says they make one into a “Silicon Valley insider”.
- “Get access to a community of experienced alumni and mentors, networking events, and learn first-hand insights from Silicon Valley-based Big Tech professionals, investors, and tech entrepreneurs. A program to get fast-tracked into Silicon Valley through workshops, private community and networking events held in and around the cities of the San Francisco Bay Area. It’s a deep dive into the expertise of heads of Global tech corporations, professors of top world ranked universities, and founders of successful companies.”
- Offers industry-leader talks, visits to companies and universities, networking opportunities, and a Slack community.
- They also invest small $10K checks into companies through a separate application.
General Funding Opportunities
- Boost VC offers a $500K investment (unclear as to if this is a SAFE or something else) for early-stage startups, particularly for technical founders who are good at storytelling and possess exceptional determination.
- “Boost VC is looking for founders with the courage to stand up for what they believe, and the determination to build an enormous company. In order to do this, you must have a unique insight on the universe and have the self confidence to build things that seem impossible to your family/friends/everyone. Only apply if you DARE MIGHTY THINGS! On a GOOD QUEST! We invest $500k to be the first partner in important things!”
- Boost VC offers a $50K investment at a $1.5M valuation cap for early-stage startups, particularly for technical founders who are good at storytelling and possess exceptional determination.
- “Boost VC is proud to introduce the Boost VC Fellowship (an equity based Fellowship), where we will invest $50K at $1.5M Cap into a founder or founders looking to start a new Deep Tech company… If it’s a potential fit, we will schedule one call and give you a quick decision… Are you Technical? Do you have the courage to stand up for what you believe? Are you good at storytelling? Are you a little possessed to build something great?”
- Startup fellowship which offers $10K at a $1B valuation cap (or participation without the money), mentorship and guidance, connections, and a 1-week workshop at the end of the program.
- “Z Fellows are technical builders of all ages working on side projects and startups. We are your first believer. We’ve worked with high school dropouts, college students, and people with full-time jobs across a variety of industries, including consumer, social, enterprise, defense, healthcare, edtech, fintech, gaming, cloud infrastructure, cybersecurity, crypto, AI, ML, climate, biotech, and more. Z Fellows is a one-week startup program. But it really doesn’t end after one week. We continue to help you for the life of your company, and beyond — and so does the ZF alumni community”.
- Does not require fellows to relocate.
- “Impetus Grants is designed to fund ambitious longevity science that would not happen otherwise. We prioritize speed, conviction, and leverage, so researchers can move fast on ideas that could reshape the field. We provide up to $500k within 3 weeks for scientists to start working on the most important problems in aging biology. To date we have deployed $34M in the field.”
- “Impetus focuses on work that is too speculative for government funding and too early for company formation.”
- Offers open field grants (round 4 is targeting total funding of about $5M with up to $500K per awardee) as well as focused grants in areas like “AI-enabled datasets” and “infectious disease and aging”.
- Philanthropic funding opportunity offered to highly motivated entrepreneurs (and others) with scalable project ideas for meaningfully improving society. Most awardees receive around $10K-$20K, but there are rumors that larger awards have been issued as well. Has a simple online application process centering on a 1500-word proposal.
- “Launched in 2018, Emergent Ventures is a low-overhead fellowship and grant program that supports entrepreneurs and brilliant minds with highly scalable, ‘zero to one’ ideas for meaningfully improving society. Mercatus Center faculty director Tyler Cowen administers the program”.
- Part of Soma Capital, Soma Fellows is a program that provides funding, mentorship, and network connections for driven entrepreneurs starting disruptive new tech companies.
- Offers $100K to $1M in uncapped SAFE funding. Might follow on with over $10M for exceptional companies.
- “Teams have the opportunity to receive $100k to 1m in funding from Soma Capital at the most founder-friendly terms possible. Soma Cap has the firepower to keep supporting you across the full path to IPO and the early stages are just the beginning for us… The program spans several weeks, offering sessions that guide you through the early stages of your entrepreneurial journey and help you build a foundation for scaling lasting companies. The Soma team, leveraging years of experience with top companies of our generation, will become your closest allies in establishing your company’s core and creating a product that impacts billions. The program culminates in a demo day, where founders showcase their products to potential customers, investors, and the community”.
- No location requirement.
- Provides $100K to resourceful self-directed people trying to build the future. (No equity taken according to their website).
- Funds not only founders, but also other people working on exciting projects with high potential to make positive change.
- 10 fellowships of $100K (plus networking) are offered per year, along with up to 20 grants of $10K plus access to the O’Shaughnessy Ventures network.
- “The O’Shaughnessy Fellowships is a one year program for researchers, builders and creatives advancing civilization. Twelve Months of pure possibility. No equity. No corporate overlords. No thesis requirements. No committee approvals. Just you, your vision, and the resources to make it real.”
- “You don’t have to quit your job, but we prefer candidates who are willing to go all in for one year, dedicating a minimum of 40 hours a week to their work during the Fellowships period and ideally north of 60 hours a week.”
- Does not have a location requirement, though optional gatherings may be hosted.
- Highly competitive: thousands of people apply for the 10 spots (plus the 20 runner-up grants).
- “Every applicant is automatically considered for both the $100,000 Fellowship and the $10,000 Grants.”
- “The fellowships are aimed primarily at individuals. However, we do encourage you to start a company if you are able to.”
- “If you’ve already started a startup or plan to raise outside investment to build a venture-scale company, please apply to Infinite Adventures – our venture capital arm, using the contact form.” See the O’Shaughnessy Ventures entry in the investor firms section for more.
- “Our mission is to engage skilled researchers and support ambitious ideas in the longevity and neuroscience fields. In the past few years, we have donated and committed over $50M to research spanning neuroAI, brain aging, centenarian genetics, and next-gen neurotechnologies.”
- One can reach out to them to discuss applying for funding through an email on their page.
- Has a list of longevity priorities listed online referred to as Bottlenecks of Aging. One can submit proposals directly to Bottlenecks of Aging through a link on their page.
- Sister organization is Starbloom Capital, which invests in longevity biotech, neuroAI, and emerging industries.
Funding for Nonprofits
- Offers: “salary of $125,000-$250,000, commensurate with experience, to explore an important problem of their choosing, along with an additional budget for a team and other operational expenses, as necessary; a chance to pitch us and others in our network for longer-term, larger-scale support; medical benefits; and access to substantial compute and programmatic resources”.
- Focuses on non-proprietary science for public good, so emphasizes nonprofit research programs, generating large datasets, and open-source products.
- Location in Emeryville California but may offer remote options in the future.
- Does not permit journal publications on research they fund.
- Have not found a specific program that offers funding, but they are a philanthropic firm that is likely to offer funding of some kind for nonprofit research organizations.
Training Programs
- 1-week long series of “live virtual sessions covering the fundamentals of finding a co-founder, validating your idea, developing a business model, and raising capital.”
- Also includes “live virtual and recorded talks from experienced founders.”
- Positions participants in a community of future founders and helps them stay connected.
- One applies to join (likely has some level of competitiveness).
- Hosted by Pillar VC and sometimes others (e.g. MDplus).
- No geographic requirement.
- Fifty Years offers a free program called 5050, which provides education on how to transition from a scientific role into operating as a founder.
- “Over 16 weeks, you’ll work closely with the 50Y team to answer the following questions: Do I have an idea worth pursuing? How do I turn breakthrough research into a startup? Am I addressing a problem with a large enough market? How do I recruit a world-class team? Am I the right person to do it?”
- Sessions are held in Boston, San Francisco, and remotely. Entire cohort is flown to San Francisco for kickoff and camp weekends.
Investor Firms
- “We back strong technical leaders who work on world-changing technologies from pre-seed to series A.”
- “We also run SciFounder Fellowship which comes with up to $1MM to get started and hands-on mentorship from us.”
- “We love scientists, engineers, hackers… Fifty Years is a pre-seed and seed focused VC firm. We back founders using technology to solve the world’s biggest problems. We also help start companies. 50Y founders are building massive businesses while solving the world’s most important problems: the climate crisis, disease, connectivity, malnutrition, and more.”
- Fifty Years sometimes offers Manifest Grants of $25K-$100K for translational research in certain areas. Applications appear to be closed as of the time of this writing.
- Fifty Years sometimes offers a free program called 5050, which provides education on how to transition from a scientific role into operating as a founder.
- They have an academic Spinout Playbook resource on their website.
- “Petri develops pre-seed companies attacking the world’s largest problems at the frontier of biology and engineering.”
- “Every Petri company receives access to comprehensive resources and 1:1 coaching to help develop your idea into a company.”
- “Co-founded and funded by Pillar VC”.
- Petri emphasizes founder-led companies.
- Four key areas: “restorative cultivation, scaling intelligence, the net-zero transition and curative therapeutics”.
- Curative therapeutics area has four key themes: “effectively leveraging computational approaches to address complexity; developing therapeutics that can compute in-vivo and respond dynamically to the changing internal environment; creating better systems, models and analytics to support therapeutic discovery and development; and a focus on the root cause, including fixing and buffering molecular level damage, fixing broken or unhelpful messaging and signalling pathways, correcting errors at every level of gene expression and modifying the state of cells to drive regeneration.”
- “Founders joining us have up to 18 months to form a company, are funded for the full duration and get to work with a dedicated sector specialist team. They join to work on opportunities that have been pre-scoped by us and have the chance to form more than one company over the course of their time with us, de-risking the standard founder proposition.”
- They look for “Ambitious, resilient founders, with a real sense of urgency” and “Deep technical expertise with industry experience” and “Empathetic founders, with a strong ability to persuade through concise storytelling”.
- Has a focus on disruptive technologies and highly driven founders, aims to be more founder friendly than other VC firms.
- “Soma Capital invests in brilliant, fearless teams building Category Kings. We focus on software to automate the world, across any sector and geography that can touch billions of people and push humanity forward”.
- A venture capital group that provides very early-stage funding to highly motivated and rebellious outside-the-box entrepreneurs, particularly young dropouts and sci-fi scientists working at the cutting edge of technology.
- “1517 is a venture capital fund and community supporting college dropouts solving hard problems and deep tech scientists with investment at the earliest stages of their companies. Founded by the cofounders of the Thiel Fellowship, it supports founders across software, hardware, and deep tech verticals and also provides a community to hackers, makers, and scientists from across the world”.
- Boost VC says they are “the most active Deep Tech investor on the planet” since they “average one deal per week.”
- “We invest into emerging and frontier categories on the edges of the map… We lead Pre-Seed rounds with $500k checks, and we write $50k Founder Start checks as well.”
- Emphasizes sci-fi-seeming technologies.
- VC firm which funds early-stage companies.
- Located in Boston.
- An investment firm focusing on bold early stage founders: “We back tomorrow’s companies & creators before the world knows their names. Whether you’re coding, filming, writing or building, we’re here to provide the resources, support and connections you need. The Mission: Bet early on bold founders with radical ideas.”
- Also supports book publishing through Infinite Books as well as films and podcasts.
- Offers the O’Shaughnessy Fellowship of $100,000 (more details in the general funding opportunities section).
- Invests in deep tech: longevity biotech, neuroAI, and emerging industries.
- Sister organization to the Amaranth Foundation.
Notable Recent Events in Gene Therapy Translation January 2023 to January 2026
PDF version: Notable Recent Events in Gene Therapy Translation January 2023 to January 2026
Clinical gene therapy has seen a lot of big wins and a lot of big setbacks over the past few years. To help myself keep track of recent important events in the field, I decided to write up this catalogue of key happenings. Though the landscape is ever-evolving, this resource should nonetheless be useful in the relatively near future and perhaps serve as a historical record later on. It has been fascinating to read up on the industry’s dynamics! I hope any readers out there who encounter this page will find my catalogue similarly interesting and valuable.
BioMarin and Roctavian (AAV)
- June 2023: The FDA approved BioMarin’s Roctavian, an AAV5 gene therapy for hemophilia A. It is the first AAV gene therapy for hemophilia [16].
Sarepta Therapeutics and Elevidys (AAV)
- June 2023: the FDA approved (Accelerated Approval pathway) Sarepta’s AAVrh74 gene therapy for Duchenne’s muscular dystrophy (DMD) in ambulatory of male patients 4-5 years old [1]. This treatment is known as Elevidys. It treats DMD by expressing a microdystrophin to replace the role of the defective endogenous dystrophin. The per patient cost of the one-time Elevidys treatment was listed at $3.2M [2]. It used a high AAV dose of 1.33×1014 vg/kg [3].
- October 2023: Sarepta’s Elevidys failed to reach statistical significance for its primary endpoint (functional mobility) in a phase 3 clinical trial, though substantial evidence of secondary endpoint effects was reported by the company. A p value of 0.24 for the main functional mobility test was reported [4].
- February 2024: Despite its setbacks, the FDA still accepted an efficacy supplement to the Biologics License Application (BLA) of Elevidys, which removed age and ambulation restrictions from the treatment.
- March 2025: Sarepta reported a patient death due to acute liver failure after Elevidys treatment [5]. A recent cytomegalovirus infection was identified by the reporting physician as a possible contributing factor, but the main reason was probably the high AAV dose.
- June 2025: Sarepta reported another patient death due to acute liver failure after Elevidys treatment [6]. Both of the deaths were in non-ambulatory teenage boys.
- June 2025: Sarepta paused shipments of Elevidys to non-ambulatory patients. The FDA began investigating the Elevidys deaths. Sarepta also reported a third death (which had actually occurred in June), this time of a 51-year-old non-ambulatory patient in one of their clinical trials for limb-girdle muscular dystrophy (LGMD) [7]. This patient had been treated with an investigational gene therapy which leveraged the same AAVrh74 capsid as Elevidys [8].
- July 2025: The FDA issued a major action bundle which placed Sarepta’s muscular dystrophy gene therapy clinical trials on hold, revoked AAVrh74’s platform technology designation, and made a voluntary request for Sarepta to immediately cease all Elevidys distribution [9]. Roche then paused shipments of Elevidys for non-ambulatory patients outside of the USA [10].
- July 2025: Sarepta initially resisted the request to stop distributing Elevidys. But after further consideration, Sarepta agreed to the FDA’s request [7]. To mitigate financial losses, Sarepta performed major restructuring, laying off about 36% of their workforce (~500 employees) [11].
- July 2025: The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued an official negative opinion on the conditional marketing authorization (CMA) of Elevidys for ambulatory DMD patients of 3-7 years [12]. Roche noted that over 900 DMD patients (760 ambulatory) had received Elevidys, demonstrating a manageable safety profile.
- July 2025: The FDA began investigating the death of an 8-year-old boy who died in June after receiving Elevidys [13]. However, the treating physician deemed this death unrelated to the Elevidys treatment [14].
- November 2025: The FDA approved a new label for Elevidys which included a Boxed Warning, limited the indication to ambulatory DMD patients 4 years of age and older, and added new recommendations for safety and monitoring [15].
Vertex Pharmaceuticals, CRISPR Therapeutics, and Casgevy (ex vivo electroporation)
- November 2023: The United Kingdom MHRA (Medicines and Healthcare products Regulatory Agency) approved Casgevy (developed by Vertex Pharmaceuticals and CRISPR Therapeutics through a strategic partnership) for the treatment of sickle cell disease and transfusion-dependent beta thalassemia. Casgevy is the first CRISPR-Cas9 gene therapy applied in humans. It performs gene editing ex vivo on blood stem cells derived from the patient (via electroporation of Cas9) to knock out the erythroid-specific enhancer region of the BCL11A gene, disinhibiting production of fetal hemoglobin [17].
- December 2023: The FDA approved Casgevy to treat sickle cell disease [18]. Both the FDA and MHRA approvals represented the first regulatory authorization of a CRISPR therapy in the world.
- January 2024: The FDA approved Casgevy to also treat transfusion-dependent beta thalassemia [19].
Bluebird Bio and Lyfgenia (ex vivo lentivirus)
- December 2023: The FDA approved Bluebird Bio’s Lyfgenia to treat sickle cell disease [18]. Lyfgenia is an ex vivo lentiviral gene therapy which delivers a copy of HbAT87Q into blood stem cells derived from the patient. This hemoglobin behaves similarly to normal hemoglobin and thus treats the sickle cell condition. The one-time Lyfgenia treatment price is $3.1M.
Orchard Therapeutics and Lenmeldy (ex vivo lentivirus)
- March 2024: The FDA approved the Orchard Therapeutics gene therapy Lenmeldy to treat children with metachromatic leukodystrophy (MLD) [20], [21]. Lenmeldy is an ex vivo gene therapy which uses a lentiviral vector to modify a patient’s stem cells to add a functional copy of the ARSA (arylsulfatase A) gene. This gene encodes the ARSA enzyme and degrades harmful sulfatides. MLD patients possess mutations in their endogenous ARSA enzyme gene. Lenmeldy is the most expensive therapy in the world at $4.2M [21].
Krystal Biotech and Vyjuvek (topical HSV-1)
- May 2023: The FDA approved Krystal Biotech’s Vyjuvek to treat dystrophic epidermolysis bullosa (DEB). It uses a herpes simplex virus 1 (HSV-1) vector to deliver normal copies of the COL7A1 (collagen type VII alpha 1 chain) gene into wounds caused by the disease [22]. A healthcare professional applies the vector topically to the patient’s wounds once per week. The treatment costs $630,500 per year [21].
Abeona Therapeutics and Zevaskyn (ex vivo RVV + topical cell sheets)
April 2025: The FDA approved Zevaskyn, a unique autologous cell sheet gene therapy, for treatment of recessive dystrophic epidermolysis bullosa (RDEB) [23]. Cells derived from the patient are collected and transduced with a replication-incompetent retroviral vector (RVV) carrying a copy of the COL7A1 gene [24]. These cells are used to grow sheets of skin which are grafted onto the patient’s wounds. The treatment costs $3.1M and provides up to 12 cell sheets.
Pfizer and Beqvez (AAV)
- April 2024: The FDA approved Pfizer’s Beqvez, an AAVRh74var vector encoding factor IX, for treatment of hemophilia B [25]. It was priced at $3.5M per patient [26].
- May 2025: Pfizer discontinued Beqvez due to lack of patients adopting the therapy (no patients had received the treatment outside of clinical trials) [26]. After discontinuing Beqvez, Pfizer was left with no gene therapies on the market or even in development, a setback for the gene therapy field.
Rocket Pharmaceuticals and RP-A501 (AAV)
- May 2025: During a phase II clinical trial for treatment of Danon disease with an AAV9 vector (6.7×1013 vg/kg), a patient died [27]. This led the FDA to put a clinical hold on the trial.
- August 2025: The FDA lifted its clinical hold on RP-A501 less than 3 months later [28]. They confirmed that Rocket Pharmaceuticals had addressed the issues relating to the clinical hold by changing the dose to 3.8×1013 vg/kg and modifying their immunomodulatory drug regime. Rocket Pharmaceuticals thus resumed the clinical trial.
Intellia Therapeutics and NTLA-2001 (LNP)
- August 2024: In a phase I clinical trial, Intellia Therapeutics demonstrated the first redosing data of an in vivo CRISPR therapy in humans [29]. This therapy treats transthyretin amyloidosis (ATTR) by knocking out the TTR gene in hepatocytes. It uses a lipid nanoparticle (LNP) delivery platform. It should be noted that further redosing was not planned for NTLA-2001 specifically, but the data may be useful for future therapies from Intellia.
- October 2025: During the MAGNITUDE-2 phase III clinical trial for NTLA-2001, a patient experienced a grade 4 liver adverse event and was hospitalized. As a result, the FDA placed the MAGNITUDE and MAGNITUDE-2 trials on clinical hold [30]. (The MAGNITUDE trial is for treating ATTR with cardiomyopathy and the MAGNITUDE-2 trial is for treating ATTR with polyneuropathy).
- January 2026: The FDA lifted its clinical hold on MAGNITUDE-2 [31].
UniQure and AMT-130 (AAV)
- December 2024: UniQure and the FDA reached an agreement for Huntington’s disease gene therapy AMT-130 to enter the accelerated approval pathway [32]. AMT-130 uses an AAV5 vector encoding a miRNA which inhibits expression of the mutant Huntingtin protein [33]. The AAV5 is delivered directly to the brain via a micro-catheter [34].
- September 2025: UniQure showed a statistically significant 75% slowing of Huntington’s disease progression in a phase I/II clinical trial for AMT-130, a major breakthrough [35].
- November 2025: Although UniQure had previously reached an agreement with the FDA for AMT-130 to enter the accelerated approval pathway (and had later presented the breakthrough data on slowing Huntington’s disease progression by 75%), the FDA stated the data were insufficient to support approval due to the use of an external control group [36]. UniQure continues to work with the FDA in an effort to move AMT-130 forward despite this setback.
Capsida Biotherapeutics and CAP-002 (AAV)
- September 2025: In a phase I/II clinical trial (CAP-002 SYNRGY) intended to treat syntaxin-binding protein 1 (STXBP1) encephalopathy, Capsida Biotherapeutics used an AAV capsid which had been engineered to efficiently cross the blood-brain-barrier while exhibiting liver-detargeting. The first patient (a child) dosed with this treatment died [37]. The trial was placed on clinical hold.
- January 2026: After investigating, Capsida found that the patient’s death was triggered by cerebral edema, but the root cause remained undetermined (i.e. no one knows whether the treatment had been directly responsible for the death) [38]. All of this has resulted in increased scrutiny on the field of blood-brain-barrier crossing AAVs.
Replimune and RP1 (HSV-1)
- July 2025: The FDA issued a Complete Response Letter (CRL) to Replimune’s biologics license application (BLA) for treatment of advanced melanoma with RP1 [39], an oncolytic engineered herpes simplex virus 1 (HSV-1) equipped with a fusogenic protein that encodes GM-CSF (granulocyte-macrophage colony-stimulating factor). The CRL voiced concerns about the RP1 IGNYTE trial’s design, interpretability, and inadequate controls, and the heterogeneity of the patient population. This represented a major (and highly publicized) setback for the company.
- October 2025: After presenting a revised trial design during a type A meeting with the FDA, Replimune’s BLA resubmission was accepted [40]. This means that RP1 is cleared for further FDA evaluation towards possible approval for marketing in the U.S.
Beam Therapeutics, BEAM-302 (LNP), and BEAM-101 (ex vivo electroporation)
- March 2025: In a phase I/II clinical trial of its base editor formulation BEAM-302, Beam Therapeutics showed successful human proof-of-principle for treating alpha-1 antitrypsin deficiency (AATD) [41]. The formulation consists of a lipid nanoparticle (LNP) carrying guide RNA and an mRNA (the latter encodes the base editor).
- March 2025: The FDA cleared Beam’s investigational new drug application (IND) for BEAM-302 to treat AATD [42].
- December 2025: Beam announced strong safety and efficacy data from its phase I/II clinical trial BEACON for their BEAM-101 ex vivo base editor therapy sickle cell disease therapy [43]. In BEAM-101, stem cells from a patient are electroporated with base editors which modify the promoter regions of HBG1/2 genes, preventing binding of the transcriptional repressor BCL11A. After reintroduction of the cells into the patient’s bone marrow, this increases expression of fetal hemoglobin, combating the sickle cell disease.
References:
[1] “FDA Approves First Gene Therapy for Treatment of Certain Patients with Duchenne Muscular Dystrophy,” 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy
[2] “After delays, Sarepta’s DMD gene therapy Elevidys finally crosses FDA finish line at $3.2M,” 2023. https://www.fiercepharma.com/pharma/sareptas-dmd-gene-therapy-finally-makes-it-accelerated-approval-finish-line-restricted
[3] “Sarepta Therapeutics Announces Topline Results from EMBARK, a Global Pivotal Study of ELEVIDYS Gene Therapy for Duchenne Muscular Dystrophy,” 2023. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-topline-results-embark-global-0
[4] “Sarepta Fails Confirmatory Trial for DMD Therapy, Still Eyes Label Expansion,” 2023. https://www.biospace.com/sarepta-fails-confirmatory-trial-for-dmd-therapy-still-eyes-label-expansion
[5] “Community Letter: ELEVIDYS Safety Update,” 2025. https://www.sarepta.com/community-letter-elevidys-safety-update
[6] “FDA investigates patient deaths after treatment with Sarepta’s gene therapy,” 2025. https://www.reuters.com/business/healthcare-pharmaceuticals/fda-investigates-patient-deaths-after-treatment-with-sareptas-gene-therapy-2025-06-24/
[7] “Sarepta, bowing to FDA pressure, pauses shipments of Duchenne gene therapy Elevidys,” 2025. https://www.fiercepharma.com/pharma/sarepta-getting-back-fdas-good-side-pauses-shipments-duchenne-gene-therapy-elevidys
[8] “Sarepta Therapeutics Announces Pipeline Progress for Multiple Limb-Girdle Muscular Dystrophy Programs,” 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-pipeline-progress-multiple-limb
[9] “FDA Requests Sarepta Therapeutics Suspend Distribution of Elevidys and Places Clinical Trials on Hold for Multiple Gene Therapy Products Following 3 Deaths,” 2025. https://www.fda.gov/news-events/press-announcements/fda-requests-sarepta-therapeutics-suspend-distribution-elevidys-and-places-clinical-trials-hold
[10] “Roche pauses shipments of Elevidys gene therapy outside US,” 2025. https://www.reuters.com/sustainability/boards-policy-regulation/roche-pauses-shipments-elevidys-gene-therapy-outside-us-2025-07-22/
[11] “Sarepta to lay off about 500 employees after Duchenne gene therapy setbacks,” 2025. https://www.biopharmadive.com/news/sarepta-layoffs-restructuring-elevidys-duchenne-research-cuts/753256/
[12] “Roche provides regulatory update on ElevidysTM gene therapy for Duchenne muscular dystrophy in the EU,” 2025.
[13] “FDA Investigating Death of 8-Year-Old Boy Who Received Elevidys,” 2025. https://www.fda.gov/news-events/press-announcements/fda-investigating-death-8-year-old-boy-who-received-elevidys
[14] “Sarepta Therapeutics Provides Clarifying Statement on ELEVIDYS,” 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-provides-clarifying-statement-elevidys
[15] “FDA Approves New Safety Warning and Revised Indication that Limits Use for Elevidys Following Reports of Fatal Liver Injury,” 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-safety-warning-and-revised-indication-limits-use-elevidys-following-reports-fatal
[16] A. Philippidis, “BioMarin’s ROCTAVIAN Wins Food and Drug Administration Approval As First Gene Therapy for Severe Hemophilia A,” Hum. Gene Ther., vol. 34, no. 15–16, pp. 665–668, Aug. 2023, doi: 10.1089/hum.2023.29251.bfs.
[17] “Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, CASGEVYTM (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia,” 2023. https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-authorization-first
[18] “FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease,” 2023, [Online]. Available: https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
[19] “Vertex Announces US FDA Approval of CASGEVYTM (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia,” 2024. https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene
[20] “FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy,” 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystrophy
[21] A. Mullard, “FDA approves gene therapy for metachromatic leukodystrophy, the tenth for a genetic disease and the priciest yet,” Nature Reviews Drug Discovery, 2024.
[22] “FDA Approves First Topical Gene Therapy for Treatment of Wounds in Patients with Dystrophic Epidermolysis Bullosa,” 2023, [Online]. Available: https://www.fda.gov/news-events/press-announcements/fda-approves-first-topical-gene-therapy-treatment-wounds-patients-dystrophic-epidermolysis-bullosa
[23] “ZEVASKYN,” 2025. https://www.fda.gov/vaccines-blood-biologics/zevaskyn
[24] “FDA approves cell-sheet-based gene therapy for severe skin disease,” 2025. https://www.nature.com/articles/d41573-025-00082-2
[25] “U.S. FDA Approves Pfizer’s BEQVEZTM (fidanacogene elaparvovec-dzkt), a One-Time Gene Therapy for Adults with Hemophilia B,” 2024. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-beqveztm-fidanacogene-elaparvovec
[26] “Pfizer Jettisons FDA-Approved Hemophilia B Gene Therapy Beqvez,” 2025, [Online]. Available: https://www.cgtlive.com/view/pfizer-jettisons-fda-approved-hemophilia-b-gene-therapy-beqvez
[27] “Patient Dies After Treatment With Rocket Pharmaceuticals’ Danon Disease Gene Therapy RP-A501 in Phase 2 Trial,” 2025. https://www.cgtlive.com/view/patient-dies-after-treatment-rocket-pharmaceuticals-danon-disease-gene-therapy-rp-a501-phase-2-trial
[28] “Rocket Pharmaceuticals Announces FDA Has Lifted the Clinical Hold on the Pivotal Phase 2 Trial of RP-A501 for the Treatment of Danon Disease,” 2025. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-announces-fda-has-lifted-clinical-hold
[29] “Intellia Announces Positive Clinical Proof-of-Concept Data for Redosing a CRISPR-Based Therapy with its Proprietary LNP-Based Delivery Platform,” 2024. https://ir.intelliatx.com/news-releases/news-release-details/intellia-announces-positive-clinical-proof-concept-data-redosing
[30] “Intellia Puts Phase 3 Trials for Transthyretin Amyloidosis Gene Editing Therapy Nex-Z on Hold Following Grade 4 Liver AE,” 2025. https://www.cgtlive.com/view/intellia-phase-3-trials-transthyretin-amyloidosis-gene-editing-therapy-nex-z-hold-grade-4-liver-ae
[31] “Intellia Therapeutics Announces FDA Lift of Clinical Hold on MAGNITUDE-2 Phase 3 Clinical Trial in ATTRv-PN,” 2026. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fda-lift-clinical-hold-magnitude
[32] “uniQure Announces Alignment with FDA on Key Elements of Accelerated Approval Pathway for AMT-130 in Huntington’s Disease,” 2024. https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-alignment-fda-key-elements-accelerated
[33] “Silencing the mutant huntingtin gene.” https://www.uniqure.com/programs-pipeline/huntingtons-disease
[34] “Phase I/II Clinical Trial of AMT-130,” 2025. https://www.uniqure.com/programs-pipeline/phase-1-2-clinical-trial-of-amt-130
[35] “uniQure hopes to launch 1st Huntington’s gene therapy next year following phase 1/2 success,” 2025. https://www.fiercebiotech.com/biotech/uniqure-hopes-launch-1st-huntingtons-gene-therapy-next-year-following-phase-12-success
[36] “uniQure’s ballyhooed gene therapy for Huntington’s hits FDA roadblock,” 2025. https://www.fiercebiotech.com/biotech/fierce-biotech-layoff-tracker-2026
[37] “Capsida pauses phase 1 gene therapy trial after child dies,” 2025. https://www.fiercebiotech.com/biotech/capsida-pauses-phase-1-gene-therapy-trial-after-child-dies
[38] “An Important Update Regarding Our CAP-002 Program: A Letter to the STXBP1 Community,” 2026. https://capsida.com/an-important-update-regarding-our-cap-002-program-a-letter-to-the-stxbp1-community/
[39] “Replimune Receives Complete Response Letter from FDA for RP1 Biologics License Application for the Treatment of Advanced Melanoma,” 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics
[40] “Replimune Announces FDA Acceptance of BLA Resubmission of RP1 for the Treatment of Advanced Melanoma,” 2025.
[41] “Beam Therapeutics Announces Positive Initial Data for BEAM-302 in the Phase 1/2 Trial in Alpha-1 Antitrypsin Deficiency (AATD), Demonstrating First Ever Clinical Genetic Correction of a Disease-causing Mutation,” 2025. https://investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-announces-positive-initial-data-beam-302-phase
[42] “Beam Therapeutics Announces Clearance of Investigational New Drug Application for BEAM-302 for the Treatment of Alpha-1 Antitrypsin Deficiency (AATD) by the United States (U.S.) Food and Drug Administration,” 2025. https://investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-announces-clearance-investigational-new-drug
[43] “Beam Therapeutics Reports Updated Data from BEACON Phase 1/2 Trial of ristoglogene autogetemcel (risto-cel) Highlighting Durable, Differentiated Profile in Sickle Cell Disease (SCD) at American Society of Hematology (ASH) Annual Meeting,” 2025. https://investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-reports-updated-data-beacon-phase-12-trial
The Path to Scalable Psychiatric Gene Therapy and a Future of Cures for Widespread Mental Illnesses — Restoring Joy to a Billion Lives
The Promise of Psychiatric Gene Therapy
Current psychiatric interventions remain insufficient to address the highly prevalent mental illnesses which plague more than a billion people (1 in 7) across the world.1 Widespread and debilitating diseases like major depressive disorder (MDD),2 anxiety disorders,3 schizophrenia,4 bipolar disorders,5 post-traumatic stress disorder (PTSD),6 substance abuse disorders,7,8 and personality disorders9,10 pose an enormous global health burden and are one of the most central causes of human suffering. Patients frequently do not respond to pharmacological interventions for these conditions, resulting in vast numbers of people struggling through life without options for proper management. As a result, at least 800K people die by suicide annually.11 Today’s neuropharmacology industry employs small molecule drugs which modulate neurochemical states, utilizing strategies like neurotransmitter reuptake inhibition and receptor agonism. Mechanistic underpinnings of many neuropharmacological treatments are not well understood.2,12 Furthermore, small molecules suffer from extensive off-target binding13 and frequently come with side effects, many of which can be extremely debilitating and/or dangerous. Though it has been cemented into place by partial successes,12 the way we currently treat mental illnesses is woefully inadequate.
Why might gene therapy solutions eventually offer better treatment options for common psychiatric disorders compared to traditional small molecule pharmaceuticals? Gene therapies possess a number of intrinsic advantages like cell-type-specific targetability, direct in situ expression of therapeutic proteins or RNAs, and the capacity to dynamically respond to environmental conditions. They also have potential for spatiotemporal programmability via emerging sonogenetics14–17 and chemogenetics18 approaches. (Sonogenetics has particular promise, which will be discussed in more detail later). In addition, gene therapies may be engineered to downregulate (RNAi or CRISPRi)19 or even ablate (CRISPR knockout)20 expression of almost any gene in the genome, offering an unprecedented array of new therapeutic targets. CRISPRa might also be employed to upregulate target genes without altering the genome.19 Engineering gene therapies which express multiple proteins or RNAs at once may synergistically improve efficacy.21,22 Importantly, gene therapies can be engineered to persist for long periods of time23,24 or to only provide a burst of short term expression. Depending on the genetic payload, one or the other of these durations may represent the most optimal choice. Gene therapies altogether provide a much larger space of possibilities for precision alteration of brain states than has been possible for small molecule treatments. I would argue that this space’s capabilities remain severely underexplored primarily because of a lack of delivery system capabilities.
Better Delivery Systems are Needed
Gene therapy promises to open a new world of precision psychiatric treatments, yet its potential has gone unrealized. This makes sense as there are a number of obstacles which render psychiatric gene therapy a difficult target. Among these, the challenges of brain delivery, safety, and manufacturing scalability represent particularly recalcitrant bottlenecks. Adeno-associated virus (AAV) gene therapies have progressed furthest in the brain delivery field. Industry players like 4DMT, Dyno Therapeutics, Apertura Therapeutics, and Capsida Biotherapeutics have made efforts via directed evolution, rational design, and machine learning towards optimizing AAV capsids for blood-brain-barrier (BBB) crossing efficiency. However, safety concerns stemming from several patient deaths in systemically administered AAV therapies over the past few years have slowed this progress. Additionally, limitations in AAV manufacturing capacity pose a problem for scaling the vector to populations of 1M+ patients.25 This will be discussed in more detail further on. It should be noted as well that AAVs are limited by their small DNA packaging capacity of 4.7 kb. To unlock the potential of psychiatric gene therapy, we need safer and more scalable delivery systems.
Although there exist multiple obstacles to overcome before gene therapy can realize its potential as a psychiatric modality, I propose a lack of delivery systems represents a foundational missing piece. Without strong delivery vehicles to feasibilize solutions, the field of psychiatric gene therapy will not be credible enough to receive substantial investment. It is a “tools problem”. As mentioned earlier, there is a particular need for vectors which at once possess high safety, scalability, and efficacy. I strongly suspect that the emergence of vectors with these qualities would seed an explosion of efforts towards gene therapies for brain diseases, which would eventually allow us to tackle psychiatric ailments. While psychiatric diseases are unlikely to represent the initial targets of brain gene therapies, opening the door to brain delivery will in my view be necessary to take steps in the direction of modernizing psychiatry through precision genetic medicines.
Examination of the Current Landscape
As mentioned earlier, AAV gene therapies are the current frontrunner for brain delivery yet possess both scalability and safety limitations. I will explain the scalability issue using publicly available information on AAV manufacturing: Final yields (after purification) of AAVs have been reported or modeled in scientific literature with values ranging from around 7.5×1012 vg/L to 7.5×1013 vg/L.26–28 I will thus assume here that 5×1013 vg/L is a typical yield. For this rough calculation, I will also assume that the yield scales linearly with bioreactor volume. As such, a 2,000 L bioreactor would make batches of around 1017 vg and a 200 L bioreactor would make batches of around 1016 vg. According to a 2024 report, a 200 L AAV production run at cGMP quality costs about $2M (including analytics).29A 2022 meta-analysis study of clinical AAV doses states that per patient systemic delivery amounts range from 3.5×1013 vg total to 1.5×1017 vg total.30 Huang et al.’s highly promising AAV BIhTFR1 capsid (the basis for Apertura Therapeutics) was originally administered to mice at a higher dose of 1014 vg/kg and a lower dose of 5×1012 vg/kg.31 Generously (perhaps too generously) assuming that the lower dose is sufficient, this would equate to about 4×1014 vg total in an average 80.7 kg North American adult human.32 Dividing 1016 vg from a $2M (200 L) batch by 4×1014 vg per dose, this means each batch would provide 25 doses for about $80,000 each. Even if substantial improvements in manufacturing yield and in lowering required dosage happen, I am skeptical that systemic AAV approaches will scale to disease indications with 1M+ patients. Despite this, AAVs remain still a central point in the gene therapy industry for a reason and paradigm-shifting approaches to manufacturing25 and/or efficacy might still change the current scalability challenges.
Another existing modality is transient focused ultrasound BBB opening (BBBO). I would argue that BBBO is extremely promising for some applications but not a universal solution. Treatment of many brain diseases necessitates brain-wide delivery. By contrast, BBBO is generally a localized delivery technique.33 Although some common psychiatric diseases fit these parameters, most common ailments with clean clinical endpoints do not. Some work has been done to extend BBBO ultrasound to larger-volume delivery through multiple sonication34,35 or raster scanning,36 but this remains much less well-developed by comparison to localized BBBO approaches and may exhibit greater safety concerns. Indeed, while single-site BBBO possesses a fairly strong safety profile, there is still evidence it can cause problematic inflammatory responses and occasional microhemorrhages.37–39 Also, the level of risk may increase if delivery of vectors with large diameters (e.g. 100 nm) is needed.40,41 As BBBO involves a device, an injection of microbubbles, a procedure, and its own set of safety concerns, it adds complexity which can increase regulatory burden. But I do not think BBBO should be discounted. In some situations, it possesses enormous advantages. These situations may indeed include potential treatments for certain psychiatric disorders. Though BBBO does not universally solve the problem of safe and scalable delivery, I expect it may still play a major role in the field of brain gene therapy.
Intranasal delivery represents a highly promising alternative to intravenous injections which maintains minimal invasiveness. It circumvents the BBB by allowing delivery vectors to migrate through the olfactory (and to a lesser degree trigeminal) nerves into the brain.42,43 This minimizes toxicity by vastly reducing exposure of peripheral organs to the delivery vector. Additionally, much lower doses of delivery vector can be used for intranasal delivery, which might bring AAVs back into the equation as a potentially scalable option. The main drawback of the intranasal route is that the vast majority of delivered DNA accumulates in the olfactory bulb and adjacent brain regions.42,44 Roughly, as the distance from these regions increases, the amount of DNA delivered decreases.44 In a study by Chukwu et al., intranasal delivery of AAV9 was shown to achieve 15% transduction efficiency and 9% gene expression efficiency on average across the brain compared to intravenous delivery.44 Remarkably, this intranasal delivery decreased exposure of peripheral organs by a factor of 13,400 compared to intravenous injection. It should be noted that AAV9 has limited BBB crossing efficiency compared to optimized capsids like AAV BIhTFR1.31 Indeed, intravenous AAV BIhTFR1 transduces brain 40-50 times more efficiently than intravenous AAV9 in humanized TfR1 mice. Yet overall, I would speculate that novel intranasal delivery systems have strong potential for safer and more scalable gene therapies. The intranasal route deserves serious consideration.
Translational Strategies
The path to psychiatric gene therapy may require a detour focusing on “easier” high-prevalence brain disease indications with more clearly defined clinical endpoints. This detour will allow the field to consolidate, cultivating enough successes to justify the financial risk of pursuing psychiatric diseases. Additionally, manufacturing, regulatory, and clinical infrastructure for brain gene therapy in large patient populations may establish itself in this way. That said, I do think it would be beneficial for companies to pursue psychiatric indications in parallel. Even if these initial attempts do not pan out, they may help strengthen the field’s knowledge base and infrastructure. What are some high-prevalence brain indications with clear clinical endpoints which represent strong potential targets for early brain delivery? I will start by nominating stroke, Parkinson’s disease (PD), and epilepsy (open to suggestions here). Though it will by no means be easy to develop efficacious gene therapies for such conditions, I remain optimistic that this foundation of successes in brain treatment is attainable.
In my view, sonogenetic genes have immense potential as payloads for psychiatric gene therapy. Sonogenetics broadly speaking involves delivery of genes encoding mechanosensitive proteins, often ion channels.45 The mechanosensitive proteins change state (e.g. channel opening) in response to ultrasound waves, allowing neuromodulation through transcranial focused ultrasound (tFUS). Sonogenetic gene therapy should thus enable both millimeter-scale spatial resolution and cell-type-specific targeting for neurostimulation, offering unprecedented possibilities for treatment of psychiatric diseases.14–17 This technological convergence could radically transform how mental illness is treated. But delivery nonetheless remains among the most central challenges which must be overcome before sonogenetics reaches clinical feasibility. Neuromedicine cannot explore sonogenetic therapies without a strong foundation of enabling delivery systems.
From a translational perspective, one of the greatest strengths of sonogenetics is that the different effects of stimulating a chosen neuronal cell type across numerous human brain regions may rapidly be tested. While this could have benefits at the preclinical level as well, the most important outcomes will likely occur during clinical stage testing. As an example, consider an anxiety disorder patient who has received a gene therapy which expresses mechanosensitive ion channels in a brain-wide fashion across GABAergic neurons. A clinician might leverage tFUS stimulation in the patient’s lateral amygdala for a few weeks.46,47 If that strategy did not improve the patient’s symptoms, the clinician may easily switch the tFUS stimulation to the central amygdala region46 or the bed nucleus of the stria terminalis (BNST)48 or the lateral septum.49 Many distinct brain regions could be explored without needing to develop a new therapeutic. This would allow fast clinical screening of strategies for modulating neural circuits towards better mental health. Since the challenges of clinical trials represent a massive limiting factor for therapeutics in general, the ability to quickly explore this space of possibilities could dramatically accelerate discovery. Combining the incredible precision of sonogenetic tFUS with such a rapid screening strategy may reveal superior therapeutic targets for combating mental illness.
Conclusion
As I have discussed in this essay, a lack of scalable delivery systems is a central roadblock to the promise of psychiatric gene therapy. Because of this, I have begun developing strategies for overcoming the scalable delivery problem through a number of ideas. I have done early-stage experiments towards a couple of these ideas while others remain in the ideation stage. (I cannot publicly describe the details of my ideas on the internet because public disclosure of IP precludes patentability). I should note that I am currently a graduate student and expect to complete my PhD in around six months. This article represents part of my efforts to lay the groundwork for my upcoming scalable brain delivery plans.
Mental illness represents one of the most profound challenges facing humanity. It affects how we live our lives and interact with the world. It affects people we love. It takes away precious time from people who otherwise could have been experiencing the extraordinary beauty of life and the universe. I believe that positive emotional experiences represent the most fundamental form of value in the cosmos. Mental illness blocks people off from experiencing joy, which is in my view an immeasurable tragedy that needs to be righted. It is time to do the science needed to reset our brains to live life to the fullest.
If you are interested in discussing anything related to this space, please reach out to: logan (dot) phospholipid (at) gmail (dot) com!
If you would like to read more about me and my scientific and entrepreneurial background, please check out my bio at: https://logancollinsblog.com/
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Amygdala Structure, Function, and Clinically Relevant Pathways
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Amygdala Structure, Function, and Clinically Relevant Pathways – by Logan Thrasher Collins
Anatomy
The amygdala consists of nuclei which can be grouped into (i) the basolateral nuclear group (BLA), (ii) the superficial cortex-like laminated region (sCLR) which contains the cortical nuclei (Co), and (iii) the centromedial nuclear group.1 The BLA consists of the lateral nucleus (LA) and basal nucleus (BA). In turn, the BA consists of the basolateral nucleus and the basomedial nucleus. The centromedial nuclear group consists of the central nucleus (Ce), medial nucleus (Me), and intercalate cell mass (IC). In turn, Ce consists of a lateral (CeL) subdivision and a medial (CeM) subdivision. The centromedial nuclear group (Ce, Me, and IC) along with the bed nucleus of the stria terminalis (BNST) and sublenticular substantia innominata together comprise the centromedial extended amygdala.
The cellular composition of the BLA nuclei and the sCLR’s Co nuclei resembles that of the cerebral cortex in that the majority of the neurons are pyramidal-like glutamatergic cells while the rest are local GABAergic inhibitory interneurons.1 The inhibitory interneurons include parvalbumin-containing neurons which mainly synapse on the soma and proximal dendrites of the pyramidal cells and somatostatin-containing neurons which mainly synapse on the distal dendrites of the pyramidal neurons. By contrast, the composition of the Ce and Me nuclei resembles the striatum in that many of the neurons are similar to GABAergic medium spiny neurons.
Overview of Amygdala Connectivity
Signals flow into the amygdala primarily via synapses in the BLA. Inputs from cortical sensory areas and from the thalamus (relaying subcortical signals) synapse on neurons in the LA.1 These inputs in the LA facilitate coincidence detection and associative learning tying together the sensory cortical representations of the world with subcortical information coming in via the thalamus. The LA pyramidal-like neurons send excitatory signals to the BA’s projection neurons and to the BA’s interneurons. (It should be noted that the subnuclei of the BA are also interconnected with the prefrontal cortex, hippocampus, and striatum). Next, the BA projects glutamatergic inputs to the CeM’s GABAergic projection neurons. These BA glutamatergic projections additionally synapse on the inhibitory interneurons of the IC and the CeL, both of which regulate the CeM neurons. (An additional layer of complexity comes from further inhibitory interneuron circuits within the LA, BA, IC, CeL, and CeM). Finally, the CeM’s GABAergic projection neurons send output signals to the hypothalamus and brainstem.
Sensory inputs to the amygdala’s LA come from several sources.1 Sensory association areas of the temporal cortex carry visual and auditory information. These areas are part of the ventral stream of sensory processing, which encodes analyses of complex features to facilitate face recognition and auditory recognition. The insular cortex, which encodes somatosensory and visceral sensations, also sends inputs to the LA. Subcortical sensory inputs to the LA come via the thalamus. In addition to LA inputs, the CeM receives visceral and nociceptive inputs directly from the pons. The sCLR receives olfactory input from the olfactory bulb as well as from higher olfactory areas.
Interestingly, the amygdala sends outputs back to cortical sensory association areas as well as primary sensory areas.1 These modulate the valence of specific sensory stimuli, which can be thought of as a way to assign emotional value to particular stimuli.
The amygdala has strong bidirectional interactions with the orbitofrontal cortex (OFC).1 In particular, the OFC receives strong inputs from the BA and targets the IC’s GABAergic neurons. The amygdala also interacts with the dorsal anterior cingulate cortex (dACC) and ventral anterior cingulate cortex (vAAC). The BA sends outputs to the dACC while the vACC projects back to the BA. The BA projects to the entorhinal cortex and receives inputs from the hippocampus as well, which may help tie emotional significance of particular events undergoing processing to associated memories. Finally, the amygdala receives subcortical inputs from arousal systems, including basal forebrain cholinergic inputs, ventral tegmental area (VTA) dopaminergic inputs, noradrenergic locus coeruleus inputs, and rostral raphe serotonergic inputs. The amygdala also projects back to all of these neuromodulatory regions and can influence the arousal systems.
CeM outputs to the hypothalamus and brainstem facilitate visceral behavioral responses to fear. These projections trigger various endocrine and autonomic peripheral nervous system responses such as secretion of adrenocorticotropic hormone (ACTH) into the blood and increased activation of the sympathetic nervous system.
Fear Learning
As mentioned earlier, the convergence of cortical inputs and subcortical inputs onto LA neurons facilitates associative learning between neutral stimuli and unpleasant stimuli. The neutral stimulus is often referred to as the “conditioned stimulus” (CS) while the unpleasant stimulus is referred to as the “unconditioned stimulus” (UC). In classical animal studies, the CS might take the form of a neutral sound (e.g. a tone) while the UC is often an electrical shock to the feet. It is variable as to which input pathways carry information about the CS and which input pathways carry information about the UC.2
In auditory fear learning, both the subcortical thalamic pathway afferents and the auditory cortex afferents have been shown to carry sensory CS information into the LA.2 When an animal must discriminate between two distinct CS sounds to learn which sound is associated with a foot shock UC, the auditory cortical pathway is thought to be necessary because plasticity in the auditory cortex facilitates the discriminative learning. Interestingly, the primary auditory cortex has been shown to carry information about complex multifrequency sounds into the LA while the more ventral associative areas of the auditory cortex bring information about simpler tone sounds.
Both the cortical and subcortical pathways have also been shown to carry parts of the UC. In particular, the parabrachial nucleus of the brainstem has been shown to encode nociceptive UC information. To transfer this information, the parabrachial nucleus projects to the CeM and CeL nuclei of the amygdala.2–4 However, the parabrachial nucleus does not project to the LA.2 It remains unknown if there is a separate (probably glutamatergic) input to the LA which carries aversive information for associative fear learning.
It should also be noted that evidence implicates neuromodulatory systems as carrying part of the UC signal during fear learning. Locus coeruleus noradrenergic projections have been shown to contribute about half of the strength of the fear learning signal.5 That is, when silenced during fear learning in rats, a 50% decrease in learned fear occurred. Additionally, a subpopulation of dopaminergic neurons from the VTA which projects to the BA has been shown to contribute about 30% of the strength of the fear learning signal.6 That is, when silenced during fear learning in mice, a 30% decrease in learned fear occurred. Acetylcholine inputs from the basal forebrain into the BLA have also been demonstrated to be necessary for efficient fear learning.7 These neuromodulators may also be released, though to a lesser degree, during fear memory recall. Finally, serotoninergic neurons (especially from the raphe nuclei) have been implicated to sometimes act on the 5-HT1A receptors of GABAergic interneurons of the LA to inhibit fear learning in LA pyramidal cells.1 That said, serotonin can have other effects in the BLA and its influence is not fully understood.8
Amygdala, Emotion, and Anxiety
The amygdala represents a central part of circuits relating to fear and anxiety as well as of circuits of general emotional valence. Elevated amygdala activity with decreased top-down regulation from the vmPFC has been shown in people with higher anxiety.1,9 It is important to note that the vmPFC overlaps with the ACC and OFC, which were discussed earlier. The vmPFC can facilitate the process of fear extinction: the decline of a learned fear via repeated exposure of a neutral CS without the associated aversive UC. As such, decreased functional connectivity between the amygdala and vmPFC is common in people with anxiety disorders.
The vmPFC facilitates fear extinction by sending excitatory input from the OFC to GABAergic neurons in the IC, which then inhibit the BA’s inputs to the CeM. The BA itself also sends excitatory projections up to the vmPFC which can induce the vmPFC’s fear extinction circuits. A distinct group of excitatory neurons in the BA target the dACC, which then sends excitatory projections back to the amygdala’s BLA to facilitate fear learning (in contrast to the vmPFC projections).10,11 Indeed, LTP occurring via this circuit within the dACC contributes to the formation and maintenance of fear memory. In this way, the dACC is a direct part of the learning network which creates fear memories.
Inhibitory interneurons within the amygdala act as important regulators of anxiety responses.12 In the BLA, inhibitory interneurons can suppress the magnitude of anxiety by releasing GABA onto the pyramidal projection neurons. Inhibitory interneurons in the CeL can also constrain the activity of amygdala output projection neurons of the CeM, which leads to decreased fear behavior. But it should be noted that the BLA can receive sensory input associated with either threatening or rewarding stimuli. Because of this, its projection neurons trigger different behavioral responses (threat or reward behaviors) depending on the nature of the stimulus.
There exist non-overlapping populations of putative projection neurons in the BLA which are thought to fire in response to threat and reward stimuli separately.12,13 These populations are thought to develop via the Hebbian associative learning described previously, which leads to formation of fear pathways for some stimuli, but can also promote association of rewarding stimuli with neutral stimuli and thus form learned emotional pathways of positive valence.13 Additionally, inhibitory interneurons of the BLA suppress threat-related projection neurons when reward-related projection neurons are active and vice versa. With anxiety disorders, these interneuron circuits are frequently dysregulated in that negative valence is assigned to neutral or reward stimuli, leading to activation of only the threat-related projection pathway.
Extended Networks of the Amygdala and Anxiety
As has been discussed to some degree so far, the amygdala does not function in isolation. It makes numerous reciprocal connections with other brain areas to facilitate its operation. Some of the most important of these include cortical regions like the vmPFC, OFC, and ACC, which were discussed earlier. But extended subcortical structures like the BNST and hippocampus (which have so far only been mentioned briefly) also play major roles.
The BNST is a collection of nuclei nearby to the amygdala which is recruited during sustained fear and anxiety responses.13 It is thought that the BNST specifically activates during prolonged stressful periods of greater than 10 minutes in duration.14 The BLA sends glutamatergic projections into the BNST’s anterodorsal (ad) nucleus. Interestingly, these excitatory inputs to the BNST ad nucleus promote anxiolytic outcomes. Additionally, local inhibition of the ad nucleus from the BNST’s oval (ov) nucleus promotes anxiogenic outcomes. The BNST’s ad nucleus facilitates anxiolytic states by sending its own (predominantly) GABAergic projections to the VTA to increase positive emotional valence, to the lateral hypothalamus (LH) to decrease risk avoidance, and to the parabrachial nucleus of the brainstem to decrease respiration rate.15
BNST ad projections to the VTA are mostly GABAergic neurons synapsing onto VTA inhibitory interneurons.16 It should be noted that there are also ventral BNST (vBNST) GABAergic and glutamatergic projections which synapse onto different populations of VTA inhibitory interneurons, triggering anxiogenic phenotypes and anxiolytic phenotypes respectively.17 A major population of BNST ad projections to the lateral hypothalamus are GABAergic neurons preferentially synapsing onto GABAergic target neurons. Among these is a subpopulation of GABAergic projection neurons targeting GABAergic lateral hypothalamus neurons which also produce orexin (a neuropeptide which stimulates food intake behaviors and promotes wakefulness).16 BNST ad GABAergic projections to the parabrachial nucleus probably inhibit glutamatergic neurons which themselves would otherwise signal for increased respiratory rate.18
The amygdala also interacts with the hippocampus. As mentioned earlier, the BLA sends excitatory inputs to the hippocampal formation by first synapsing at the entorhinal cortex (EC), which then sends its own excitatory inputs to the hippocampus.13 These inputs are necessary for acquisition of contextual fear memories, likely mediated by the BLA amygdala’s fear learning mechanism in combination with hippocampal memory representations.
In addition, the BLA sends glutamatergic synapses directly onto pyramidal cells in the ventral hippocampus (vHPC) CA1 region, increasing anxiety-like behavior when these BLA projections are active. In part, the vHPC mediates its effects on anxiety through glutamatergic projections to the lateral septum, which sends its own projections onwards to the hypothalamus. The vHPC glutamatergic projections stimulate activation of corticotropin releasing factor receptor 2 (CRFR2) expressing GABAergic projection neurons in the lateral septum through a mechanism which is not fully understood.13,19 These GABAergic projection neurons inhibit the anterior hypothalamic area (AHA), which itself inhibits the paraventricular nucleus (PVN) of the hypothalamus as well as the periaqueductal gray (PAG). In this way, the lateral septum disinhibits the paraventricular nucleus and the periaqueductal gray, which leads to neuroendocrine and behavioral outcomes associated with persistent anxiety.
Conclusion
While this writeup serves as an initial primer on the amygdala, there remain a plethora of relevant neural circuits to explore beyond what has been described here. Nonetheless, I hope that the information provided will offer a useful starting point for learning about the amygdala’s structure, function, and effects on mammalian emotions. As further reading, I specifically recommend references #1, #9, #12, and #13.
References
1. Benarroch, E. E. The amygdala: Functional organization and involvement in neurologic disorders. Neurology 84, 313–324 (2015).
2. Palchaudhuri, Shriya, Osypenko, Denys & Schneggenburger, Ralf. Fear Learning: An Evolving Picture for Plasticity at Synaptic Afferents to the Amygdala. Neurosci. 30, 87–104 (2022).
3. Han, S., Soleiman, M. T., Soden, M. E., Zweifel, L. S. & Palmiter, R. D. Elucidating an Affective Pain Circuit that Creates a Threat Memory. Cell 162, 363–374 (2015).
4. Herry, C. & Johansen, J. P. Encoding of fear learning and memory in distributed neuronal circuits. Nat. Neurosci. 17, 1644–1654 (2014).
5. Uematsu, A. et al. Modular organization of the brainstem noradrenaline system coordinates opposing learning states. Nat. Neurosci. 20, 1602–1611 (2017).
6. Tang, W., Kochubey, O., Kintscher, M. & Schneggenburger, R. A VTA to Basal Amygdala Dopamine Projection Contributes to Signal Salient Somatosensory Events during Fear Learning. J. Neurosci. 40, 3969 LP – 3980 (2020).
7. Jiang, L. et al. Cholinergic Signaling Controls Conditioned Fear Behaviors and Enhances Plasticity of Cortical-Amygdala Circuits. Neuron 90, 1057–1070 (2016).
8. Bocchio, M., McHugh, S. B., Bannerman, D. M., Sharp, T. & Capogna, M. Serotonin, Amygdala and Fear: Assembling the Puzzle. Front. Neural Circuits Volume 10–2016, (2016).
9. Zhang, W.-H., Zhang, J.-Y., Holmes, A. & Pan, B.-X. Amygdala Circuit Substrates for Stress Adaptation and Adversity. Biol. Psychiatry 89, 847–856 (2021).
10. Toyoda, H. et al. Interplay of Amygdala and Cingulate Plasticity in Emotional Fear. Neural Plast. 2011, 813749 (2011).
11. Jhang, J. et al. Anterior cingulate cortex and its input to the basolateral amygdala control innate fear response. Nat. Commun. 9, 2744 (2018).
12. Babaev, O., Piletti Chatain, C. & Krueger-Burg, D. Inhibition in the amygdala anxiety circuitry. Exp. Mol. Med. 50, 1–16 (2018).
13. Calhoon, G. G. & Tye, K. M. Resolving the neural circuits of anxiety. Nat. Neurosci. 18, 1394–1404 (2015).
14. Hammack, S. E., Todd, T. P., Kocho-Schellenberg, M. & Bouton, M. E. Role of the bed nucleus of the stria terminalis in the acquisition of contextual fear at long or short context-shock intervals. Behavioral Neuroscience vol. 129 673–678 at https://doi.org/10.1037/bne0000088 (2015).
15. Kim, S.-Y. et al. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature 496, 219–223 (2013).
16. Giardino, W. J. & Pomrenze, M. B. Extended Amygdala Neuropeptide Circuitry of Emotional Arousal: Waking Up on the Wrong Side of the Bed Nuclei of Stria Terminalis. Front. Behav. Neurosci. Volume 15–2021, (2021).
17. Jennings, J. H. et al. Distinct extended amygdala circuits for divergent motivational states. Nature 496, 224–228 (2013).
18. Kaur, S. et al. Glutamatergic Signaling from the Parabrachial Nucleus Plays a Critical Role in Hypercapnic Arousal. J. Neurosci. 33, 7627 LP – 7640 (2013).
19. Anthony, T. E. et al. Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit. Cell 156, 522–536 (2014).
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