The Genetics Podcast

Summary: This week on The Genetics Podcast, Patrick Short takes a solo deep dive into the current state of gene therapy ahead of next week’s live recording at ASHG. He explores the promise and limitations of adeno-associated virus (AAV) delivery, examples of gene therapies for neuromuscular diseases, and the challenges of balancing safety, cost, and commercial viability in rare diseases. Show Notes: 0:00 Intro to The Genetics Podcast00:59 Episode overview02:50 Definition and scope of gene therapy 04:50 Gene therapy delivery via adeno-associated virus (AAV) and associated challenges and advantages06:40 AAV-based gene therapy and other advanced therapies in spinal muscular atrophy (SMA)10:29 Recent safety concerns around Sarepta Therapeutics’ AAV-based gene therapy for Duchenne muscular dystrophy (DMD)19:30 Commercial viability challenges for rare disease gene therapy24:26 Risk-benefit analysis of gene therapy for rare diseases 28:33 Considerations for optimizing AAV design and delivery routes31:26 Alternative approaches for delivery using viral and non-viral methods36:09 The future of AAV gene therapy41:42 Closing remarksFind out moreUpdate on Sarepta Therapeutics’ gene therapy for DMD (https://www.fiercepharma.com/pharma/sarepta-shares-more-elevidys-safety-data-response-patient-group-fda-petition)Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

Summary: This week on The Genetics Podcast, Patrick is joined by Andy Singleton, Program Lead of the Global Parkinson’s Genetics Program (GP2), and Sonya Dumanis, COO of the Coalition for Aligning Science. They discuss the creation of GP2, how the initiative is closing representation gaps in genetics, and building global infrastructure and capacity for research.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Sonya and Andy01:50 Aims and overview of the Global Parkinson’s Genetics Program (GP2)03:15 The Aligning Science Across Parkinson’s (ASAP) initiative and how it led to the creation of GP204:37 Gaps in Parkinson’s genetics that inspired the creation of GP207:21 Closing the global representation gap in Parkinson’s genetics08:37 ASAP’s model for long-term resources and adaptive funding11:18 How GP2 overcame pandemic disruptions and data-sharing challenges to grow global capacity15:01 Using harmonized data to compare Parkinson’s with other neurological diseases17:02 Expanding GP2’s scope while keeping Parkinson’s at the core18:42 Using genetics to guide targeted Parkinson’s therapeutics 21:37 Early biomarkers beyond genetics including proteomics and alpha-synuclein seed amplification assay (SAA) to guide therapy timing23:01 Adapting GP2 to incorporate new discoveries and build capacity for functional and longitudinal studies26:54 Insights from GBA variants into gene expression and Parkinson’s risk biology28:24 How GP2’s open access data can be used to power clinical trials and advance drug development31:37 Lessons from GP2 on building sustainable global collaboration and capacity that can be applied across disease areas36:10 Navigating global differences in genetic testing access, regulation, and return of results across the GP2 network38:29 Building coalitions between philanthropy, nonprofits, and industry to sustain large-scale initiatives41:09 The story behind the GP2 tattoos and the team spirit that fuels the program42:23 Closing remarksFind out moreASAP (https://parkinsonsroadmap.org/#)GP2 (https://gp2.org/)Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

This week on The Genetics Podcast, Patrick is joined by Wanda Smith, founder of CureGRN. They discuss Wanda’s journey from caring for her mother to driving FTD research, the discovery of progranulin and development of new therapies, the diagnostic odyssey and need for earlier genetic testing, and how the CureGRN community is expanding support and awareness worldwide.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Wanda02:18 Wanda’s journey into frontotemporal dementia (FTD) research from being a caregiver to establishing a brain bank06:31 Shifting focus after the discovery of progranulin (GRN) and accelerating FTD research through collaboration08:23 How GRN haploinsufficiency drives FTD and what it means for therapy11:57 Implication of progranulin in neurodegenerative diseases and therapies now in clinical trials13:33 Why earlier genetic testing and diagnosis are critical for families with GRN mutations15:31 Barriers behind the diagnostic odyssey and limited access to genetic testing17:03 Moving from symptom-based diagnosis to early diagnosis with biomarkers19:50 Expanding CureGRN’s reach through global collaboration21:14 Raising awareness to drive FTD research 22:44 Overcoming stigma and shame to encourage trial participation in FTD24:41 Navigating family conversations about FTD with compassion and meeting people where they are26:39 Providing multiple pathways for families to access support, education, and community28:35 Insights into the future of FTD and addressing the gaps preventing progress in care and diagnosis30:58 The importance of genetic testing and community resources in FTD33:23 The role of younger gene carriers in shaping early detection, prevention, and long-term care in FTD37:00 Closing remarksFind out moreCureGRN (https://www.curegrn.org/)Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

This week on The Genetics Podcast, Patrick is joined by Terry Pirovolakis, CEO and Founder of Elpida Therapeutics. They discuss Terry’s journey to create a life-saving gene therapy for his son, the founding of Elpida Therapeutics to bring hope to families with ultra-rare diseases, and the challenges of scaling therapies that aren’t commercially viable.Show Notes: 0:00 Intro to The Genetics Podcast00:58 Welcome to Terry01:24 The beginning of Terry’s gene therapy journey after his son Michael was diagnosed with SPG5003:24 Learning the biotech industry and building a gene therapy team05:17 Terry’s experience with learning about gene therapy without a scientific background06:42 The process of building a gene therapy in under three years during the COVID-19 pandemic09:30 Fundraising through community support and major donors11:06 Expanding access of Michael’s gene therapy to children all over the world12:32 The creation of Elpida Therapeutics to develop non-commercially viable therapies and adapting to a challenging funding landscape15:24 Insight into cost, accessibility, and the role of endpoints and manufacturing20:06 Learning from safety events as gene therapy scales and the importance of considering the risk/reward ratio in rare disease23:24 Landscape of precision therapeutics available today beyond AAV vectors27:09 Designing trials at Elpida to demonstrate efficacy in ultra-rare disease29:24 Adapting meaningful endpoints to disease progression and FDA flexibility 34:02 Background of Priority Review Vouchers and the negative impact of its non-renewal on rare disease funding37:48 Finding optimism in rare disease family initiatives and gene therapy successes, and the future of advanced therapeutics 41:07 How to support the rare disease community and families 44:16 Closing remarksFind out moreElpida Therapeutics (https://www.elpidatx.com/)Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

This week on The Genetics Podcast, Patrick is joined by Samuli Ripatti, Director of the Institute for Molecular Medicine Finland (FIMM), Vice Director at HiLIFE, and Professor of Biometry at the University of Helsinki. They discuss Samuli’s research on lipid and cardiovascular genetics, how polygenic risk scores are moving into clinical care, and the power of the FinnGen biobank. Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Samuli01:48 Samuli’s path from statistics to genetics at the beginning of a new era03:09 Remembering Leena Peltonen and the Human Genetics Summer School05:46 Samuli’s research in lipid and cardiovascular genetics and the power of collaboration09:14 Integrating polygenic risk scores into cardiovascular and breast cancer care14:52 Using medication history in FinnGen to uncover cardiometabolic genetics and predict treatment patterns18:50 The future of polygenic risk scores in predicting prognosis and guiding treatment21:21 The confounding effect of treatment in genetic studies23:14 Overview of FinnGen and its impact on genetics and drug discovery27:04 The next 5 years in proteomics and molecular profiling to move beyond associations29:56 Using polygenic risk scores in clinical trials31:41 Future directions, from refining phenotypes in large biobanks to piloting clinical applications of polygenic risk scores34:04 Scaling population biobanks versus deep phenotyping and why the future requires both35:29 Closing remarksFind out moreGenetic predictors of lifelong medication-use patterns in cardiometabolic diseases (https://www.nature.com/articles/s41591-022-02122-5)Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

This week on The Genetics Podcast, Patrick is joined by Jonathan Marchini, Head of Statistical Genetics and Machine Learning at the Regeneron Genetics Center. They discuss Jonathan’s pioneering role in developing computational methods from the HapMap era through to today, how those innovations underpin large-scale imputation and analysis, and why exomes with imputation remain more powerful than whole genomes for discovery at Regeneron.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Jonathan01:47 Jonathan’s career path from teaching in rural Tanzania to genomics research at Oxford04:43 Lessons from the HapMap era and the birth of imputation08:30 Ongoing challenges with data sharing and usable tools 10:30 Handling massive genetic datasets at Regeneron and developing new computational methods to scale15:26 Key discoveries from the million-exome paper18:04 Pushing computational limits in meta-analysis 19:50 Polygenic risk scores in the clinic and their role in trial design23:38 Why Regeneron prioritizes exomes with imputation over whole genomes and what that means for discovery27:58 Where AI truly adds value in genomics and where simpler models still win32:27 Interpreting rare variants, the promise of protein models, and why better phenotyping is key35:31 Closing remarks and opportunities at RegeneronFind out moreRegeneron Genetics Center (https://www.regeneron.com/science/genetics-center)Million exome paper (https://www.nature.com/articles/s41586-024-07556-0)Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

This week on The Genetics Podcast, Patrick is joined by Max Bronstein, CEO of Aviva Strategies. They discuss the shifting regulatory and political landscape shaping biotech, the realities of today’s drug development process, and why new incentives and flexible trial pathways are critical to advancing rare and ultra-rare disease therapies.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Max01:51 Regulatory shifts and FDA challenges under the new administration05:40 Overview of the regulatory process for therapeutic development and the push for patient-centered trials11:26 Challenges in drug development from regulatory gaps to shifting FDA priorities15:45 Unprecedented government turnover and its impact on biotech industry stability18:32 Status and significance of the pediatric priority review voucher program for rare and ultra-rare disease development22:02 How Congress uses “must-pass bills” to advance or block health policies25:17 Max’s role in creating Advanced Research Projects Agency for Health (ARPA-H) to drive high-risk innovation 30:02 How ARPA-H is funded 31:21 Adapting science policy to politics33:35 Breakthroughs in rare disease therapies and the policy frameworks needed to ensure access37:15 Lessons from the Orphan Drug Act and why new incentives are needed to make ultra-rare disease drug development viable39:23 The push for flexible rare disease trial pathways and the disconnect between FDA rhetoric and practice43:26 Closing remarks and a call to connect for patient organizations and rare disease parentsFind out moreAviva Strategies (https://www.avivastrategies.com/)Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

This week on The Genetics Podcast, Patrick is joined by Richard Wilson, Senior Vice President, Primary Focus Lead of Genetic Regulation at Astellas. They discuss where the gene therapy field stands today, diving into successes, persistent barriers, regulatory considerations, manufacturing strategies, and other reflections on important approaches to precision medicine drug development.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Richard01:33 Current wins and challenges in gene therapy 07:13 The need for more open non-competitive data sharing and a clearer pathway towards reimbursement and incentivization11:15 Building post-approval systems into the genomic medicine lifecycle14:47 Rethinking evidence standards in rare disease trials, and the global push for regulatory and reimbursement alignment20:28 Genetic medicine breakthroughs in central nervous system diseases22:25 The challenges of starting clinical development with an end in mind24:34 The need for careful analysis around endpoints, vector design, and delivery approaches29:33 Navigating regulatory hurdles when making mid-program changes to vectors or payloads31:16 Strategies for enhancing scalability and quality of gene therapy manufacturing 36:05 Exploring other delivery methods beyond AAV39:32 Getting ready for the Timmerman Traverse and raising nearly $1M for Life Science Cares43:48 A call to refocus on patients, partnership, and purpose in uncertain times45:55 Closing remarks Find out moreAstellas (https://www.astellas.com/)Timmerman Traverse fundraising for Life Science Cares (https://timmermantraverse.blackbaud-sites.com/)Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

This week on The Genetics Podcast, we celebrate our 200th episode with a look back at some of the earliest episodes, particularly ones that foresaw major trends or went on to spark real-world impact. These include Eric Topol’s early predictions about AI in healthcare, Laurence Reid’s vision for gene therapy in hearing loss, Sir Rory Collins on the potential impact of the UK Biobank, Daphne Koller on uniting biology and machine learning, and Vineeta Agarwala on harnessing large datasets for drug discovery. Patrick adds updates and reflections on how these bold ideas have shaped the genomics and biotech landscape.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Overview of episode content and guests featured01:47 Eric Topol predicts the role of AI in healthcare in 201905:58 Patrick’s reflections on AI’s progress today and future potential06:57 Laurence Reid outlines Decibel Therapeutics’ gene therapy plans for otoferlin-related hearing loss 10:58 Patrick’s updates on Decibel’s success and acquisition by Regeneron 11:44 Sir Rory Collins on the creation and vision of the UK Biobank18:20 Patrick on the lasting impact of open science and the UK Biobank19:10 Daphne Koller on building insitro to fuse biology and machine learning 24:30 Patrick on the future of large-language models in biology25:55 Vineeta Agarwala on investing in large datasets for drug discovery32:24 Patrick on applying multi-omic data to rare disease research32:52 Closing remarksFind out moreThe Genetics Podcast is now on Instagram! Follow us for clips from recent episodes and release announcements (https://www.instagram.com/thegeneticspodcast/).Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

This week on The Genetics Podcast, Patrick is joined by Xin Jin, Associate Professor in the Department of Neuroscience at The Scripps Research Institute. They discuss how in vivo Perturb-seq enables scalable and high-resolution modeling of neurogenetic disorders like autism, how introducing mutations directly into living mouse brains reveals cell-type vulnerabilities and convergent pathways, and why this approach could transform therapeutic development by identifying shared mechanisms across diverse genetic mutations.Show Notes: 0:00 Intro to The Genetics Podcast00:58 Welcome to Xin 01:52 Overview of in vivo Perturb-seq05:10 Identifying de novo variants in autism spectrum disorder09:00 Using perturbations to map how autism-linked mutations affect specific brain cell types13:04 Applying Perturb-seq to other brain diseases14:30 In vivo versus in vitro models and extending genetic screening approaches beyond the brain18:44 Using in vivo models to trace variant effects, rank gene drivers, and uncover therapeutic pathways22:35 Conservation of genes between mouse and human in the context of neurodevelopmental disease modeling 24:21 Impact of genetic discoveries on drug development by convergence onto common pathways 27:22 Xin’s early interest in science through her grandfather’s work in plant taxonomy and botany29:48 Xin’s path from China to MIT and how early research shaped her scientific mindset31:58 Reflections on AI’s rapid progress and limits in biology, and the need for new models 37:21 Closing remarksFind out moreJin lab (https://www.jin.scripps.edu/)In vivo Perturb-seq explainer video (https://vimeo.com/549737357)Please consider rating and reviewing us on your chosen podcast listening platform! https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link