The Genetics Podcast

Summary: This week on The Genetics Podcast, Patrick is joined by Dr. Rachel Salzman, CEO of Armatus Bio. They discuss the promise of vectorized RNAi for autosomal dominant diseases, the key scientific and clinical hurdles in gene therapy, and Rachel’s lessons from two decades in the field.Show Notes: 0:00 Intro to The Genetics Podcast01:00 Welcome to Rachel01:35 Background of Armatus Bio and the mechanism behind its vectorized RNAi platform05:31 Advantages of vectorized RNAi over conventional RNAi approaches08:07 How microRNAs work and how engineered versions enable highly specific gene silencing10:28 Current preclinical progress at Armatus and next steps toward first-in-human trials14:06 Lessons on making smart risk decisions in rare disease drug development17:26 Reflections on two decades of progress, setbacks, and realities in gene therapy22:07 Hemophilia as a case study in gene therapy missteps and overlooked patient and market realities25:21 Challenges around product purity and the need for financial innovation29:23 Why AAV purity is so difficult to achieve and where pre-competitive collaboration could drive improvement33:32 Rachel’s path from veterinary medicine to gene therapy through a family genetic diagnosis35:58 Founding the Stop ALD Foundation and advancing lentiviral gene therapy into first-in-human use39:58 The future potential of vectorized RNAi 42:00 Closing remarksPlease 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 Slavé Petrovski, Vice President of the Center for Genomics Research at AstraZeneca. They discuss how AstraZeneca is scaling population genomics through massive biobank collaborations, developing AI models for early disease prediction, and pioneering sustainable “green” algorithms to reduce the environmental footprint of large-scale genomic research.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Slavé02:09 Slavé’s career path from business information systems to genomics04:33 How Slavé decided to move from academia to industry07:52 Scaling and diversifying biobank partnerships to unlock new genetic insights12:29 Translating biobank data into predictive and preventive medicine15:14 Discovering protective genetic variants through global biobank studies19:13 Leveraging population genetics to identify and validate protective drug targets23:52 Developing an AI tool (MILTON) for integrating multi-omic and clinical data for early disease prediction28:12 Redefining clinical trials in a presymptomatic and predictive medicine era30:49 AstraZeneca’s efforts to make large-scale genomics computing sustainable through green algorithm innovation39:05 AstraZeneca’s open science strategy and global impact of its shared genomics tools42:10 Fostering critical thinking and avoiding groupthink in large-scale genomics research45:30 Looking ahead to the next decade of genomics and precision healthcare50:01 Closing remarksFind out moreMILTON (https://www.astrazeneca.com/r-d/our-technologies/machine-learning-drug-discovery.html)PheWAS Portal (https://azphewas.com/)Upcoming webcast with deep dive into MILTON & PheWAS (https://www.nature.com/articles/d44224-025-00033-7)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 Dr. Ellen Reisinger, Professor and group leader at the University of Tübingen. They discuss her journey into hearing loss research, why otoferlin has become a leading target for gene therapy, and the emerging science shaping the next generation of treatments.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Ellen01:52 Ellen’s career path that coincidentally led to her work on otoferlin-related hearing loss03:22 Mechanism and advantages of the dual adenoassociated virus (AAV) system 05:35 The genetic landscape of early-onset hearing loss and why otoferlin stands out07:42 Why otoferlin-related deafness is an ideal target for postnatal gene therapy development09:53 Potential next gene therapy targets beyond otoferlin and associated challenges13:13 Carrier and newborn screening as approaches to preventing hereditary hearing loss14:37 How far the field is from prenatal gene therapy and why it remains unlikely in the near term16:07 Exploring gene-agnostic and protective approaches to prevent or slow hearing loss18:22 How genetics and environment interact in age-related hearing loss20:00 Current research focus of Ellen’s group on degenerative hearing loss genes and uncovering cell death mechanisms22:05 Using mouse models and human organoids to study hearing loss mechanisms23:42 Emerging gene editing approaches 25:20 Ellen’s research journey from biochemistry to leading gene therapy research in hearing loss 27:54 Unanswered questions about how inner hair cells release neurotransmitters29:21 Comparing outcomes of gene therapy and cochlear implants for hearing restoration and differences across languages34:20 Closing remarksPlease 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 BridgeBio’s Ananth Sridhar, Chief Operating Officer of Cardiorenal Programs, and Sun-Gou Ji, Vice President of Computational Genomics. They discuss the hub-and-spoke model for de-risking and accelerating rare disease drug development, the role of human genetics in target discovery, lessons from their autosomal dominant hypocalcemia type 1 (ADH1) program, and how portfolio design and predictive genomics are shaping the future of precision medicine.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Ananth & Sun-Gou01:57 How BridgeBio’s hub-and-spoke model de-risks and accelerates rare disease drug development06:45 How programs move from the hub to the spokes in target discovery and development09:10 Translating a target into a therapy for autosomal dominant hypocalcemia type 1 (ADH1)12:28 Challenges in ADH1 drug development and using population genetics to identify patients with gain-of-function variants18:08 Under-diagnosis and incomplete penetrance in rare disease and quantifying genetic versus phenotypic prevalence20:52 Balancing first-in-class innovation with risk management in rare disease drug development24:24 Evaluating rare disease programs using risk-adjusted net present value (NPV) instead of peak sales27:20 Key factors that can make rare disease programs faster and cheaper to develop, and why modality agnosticism is important32:00 Sun-Gou’s experience in computational genetics and building data-driven infrastructure for discovery36:44 Ananth’s lessons from Regeneron and applying patient-centered principles to rare disease drug development39:00 Sun-Gou on the power of newborn sequencing and personal lessons from early diagnosis43:36 Ananth’s views on making predictive medicine more personal and human-centered44:51 Closing remarksFind out moreBridgeBio (https://bridgebio.com/unlocking-rare-diseases-medicine)Hub-and-spoke model (https://www.youtube.com/watch?v=gRURL49QsX4)ADH1 publication (https://www.cell.com/ajhg/fulltext/S0002-9297(25)00244-7)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 Justin Porcano, co-founder and Executive Director of Save Sight Now. They discuss how his daughter’s diagnosis with Usher syndrome type 1B (USH1B) inspired the founding of Save Sight Now, the organization’s efforts to accelerate research and overcome barriers in gene therapy, and the innovative gene delivery methods and therapeutic approaches currently in development.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Justin01:39 How Justin’s daughter’s Usher syndrome diagnosis (USH1B) led to the founding of Safe Sight Now and a mission to accelerate research05:23 Biggest hurdles to therapeutic development for USH1B08:36 Progress in the research with new animal models and advances in clinical endpoint development10:25 How Justin applied design thinking and AI to rapidly learn rare disease science12:38 Advances in gene delivery approaches for USH1B15:45 Therapeutic intervention windows in USH1B with early treatment for hearing loss and later options for addressing vestibular and visual impairments18:32 Save Sight Now’s plans for the next phase of clinical translation and sustainable growth20:50 Why Justin decided to establish Save Sight Now as an independent nonprofit22:27 The need for stronger collaboration between patient organizations and biotech companies25:50 Building global collaborations to expand Save Sight Now’s reach28:00 How the community can support Save Sight Now’s mission and upcoming fundraising gala28:59 Closing remarksFind out moreSave Sight Now (https://www.savesightnow.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

Summary: This week on The Genetics Podcast, recorded live at ASHG 2025, Patrick is joined by Heidi Rehm, Chief Genomics Officer at MGH’s Center for Genomic Medicine and Co-director at the Broad Institute, and Slavé Petrovski, Vice President of AstraZeneca's Centre for Genomics Research. They discuss the rapid progress of large-scale genomics, the barriers to integrating genetic data into healthcare and drug development, and how open collaboration, global data sharing, and a focus on equity are driving more inclusive and impactful genomic discovery.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Heidi and Slavé02:01 Slavé’s role at AstraZeneca and work in genomics-driven R&D 03:24 Heidi’s work at the Broad Institute bridging clinical genomics, rare disease research, and global data-sharing initiatives04:12 Heidi on breaking a Guinness world record for rapid neonatal ICU (NICU) genomics and the shift to open data sharing06:32 Slavé on how large-scale, multimodal human data is transforming genomics research08:10 Heidi’s initiatives to integrate genomics into routine care at hospitals and with primary care physicians11:47 Integrating genomics into clinical trials and healthcare, and enabling global discovery through AstraZeneca’s open data portal15:34 Breaking down legal and logistical barriers to genomic data sharing and centering the patient voice18:40 AstraZeneca’s large-scale plasma proteome study and machine learning models predicting disease onset years before diagnosis21:44 Emerging omics tools advancing rare disease diagnosis24:19 The value and pitfalls of AI in genomics today28:54 Advancing health equity in genomics through data sharing, diverse recruitment, and global collaboration33:40 Progress and challenges in next-generation genetic therapies37:15 Reflections and advice for the next generation entering genomics and data-driven medicine40:44 Audience Q&A51:44 Closing remarksPlease 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 Chris Hopkins, CEO of Glafabra Therapeutics. They discuss how Glafabra is advancing a next-generation cell therapy for Fabry disease, the differences between gene therapy modalities, and the future of cell and gene therapy innovation.Show Notes: 0:00 Intro to The Genetics Podcast00:59 Welcome to Chris01:28 Overview of Fabry disease and reviving a promising shelved gene therapy03:12 Limitations of current Fabry disease treatments versus Glafabra Therapeutics’ approach05:19 How autologous cell therapy avoids an immune response06:43 Comparing this cell therapy approach to that of Casgevy for sickle cell disease11:28 Expanding Glafabra’s platform to other lysosomal storage disorders through enzyme cross-correction13:47 Comparing autologous cell therapy and AAV in Fabry17:02 Path to clinical development and funding strategy for Glafabra’s lead program19:33 Cost efficiency and trial design advantages of an orphan drug approach21:19 Considerations around comparator groups for Glafabra’s therapy24:11 Underdiagnosis and hidden prevalence of rare diseases 25:53 Other innovations Chris is excited about and expectations for the future of cell and gene therapy31:56 How Chris invented a technique to safely “milk” venomous cone snails37:00 Closing remarks and advice for scientists taking the leap from academia to entrepreneurshipFind out moreGlafabra Therapeutics (https://www.glafabra.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

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