The Genetics Podcast

This week on The Genetics Podcast, Patrick is joined by Dr. Nicky Whiffin, Associate Professor and Wellcome Career Development Fellow at the Big Data Institute, University of Oxford. They discuss the discovery of a new neurodevelopmental syndrome caused by mutations in the small nuclear RNA gene RNU4-2, what this reveals about the non-coding genome and the spliceosome, and how large-scale genome sequencing is reshaping diagnosis, variant interpretation, and the future of genetic medicine.
Show Notes: 
0:00 Intro to The Genetics Podcast
00:59 Welcome to Nicky
02:09 Overview of the non-coding genome and its functional elements
03:59 How small nuclear RNAs drive splicing and exon recognition
04:54 Overview of the major and minor spliceosomes and the role of small nuclear RNAs in intron removal
06:34 Discovery of recurrent de novo RNU4-2 mutations in developmental disorders through large-scale genomics data
12:18 Growth of patient advocacy groups and global networks following the discovery of ReNU syndrome
14:43 Potential for antisense oligonucleotide therapies for ReNU syndrome
16:06 Clinical endpoints, treatment timing, and biomarker development for ReNU
18:32 Impact of RNU4-2 discovery on exome design, genome sequencing adoption, and targeted testing strategies
19:52 Distinct dominant, recessive, and retinal phenotypes arising from variants within RNU4-2
22:15 Open questions on mutation rates and selection in spliceosomal small nuclear RNAs
25:25  Limits of non-coding variant discovery and the unresolved genetic burden in developmental disorders
29:52 Therapeutic upregulation strategies targeting untranslated regions in haploinsufficiency 
33:40 The MRC Centre of Research Excellence in Therapeutic Genomics’ approach to scalable genetic medicines
35:54 Long-term prospects and delivery challenges for gene editing approaches 
36:56 Newborn genome screening, actionability debates, and implications for rare disease diagnosis
40:25 Population genomics insights from unascertained newborn genome sequencing cohorts
42:04 Closing remarks
Find out more: ReNU discovery paper

This week on The Genetics Podcast, Patrick is joined by Dr. David Dismuke, Chief Technical Officer at Forge Biologics, and Dr. Steven Gray, Professor at UT Southwestern Medical Center. They discuss the evolution of AAV gene therapy from academic labs to industrial-scale manufacturing, how vector design and capsid engineering are improving CNS delivery, and what manufacturing innovation and next-generation delivery technologies mean for safety, cost, and the future of gene therapy.
Show Notes: 
0:00 Intro to The Genetics Podcast
00:59 Welcome to David and Steven
01:47 David and Steven’s overlapping academic paths and long-term collaboration
03:39 Steven’s research on AAV engineering for central nervous system (CNS) gene therapy
04:50 Forge Biologics’ platform approach to scalable AAV manufacturing
06:28 How AAV vectors are manufactured
08:24 How CNS AAV vectors are designed, tested, and refined across programs
10:58 How manufacturing quality and trial outcomes can shape AAV development decisions
15:13 Factors that impact the ratio of full versus empty AAV capsids
17:21 Manufacturing scale, capsid efficiency, and the future cost curve of AAV gene therapy
24:19 Scaling AAV manufacturing for common diseases and the shift toward industrialized production models
27:07 Engineered AAV capsids for CNS delivery and the tradeoffs between innovation and platform stability
30:31 Next-generation AAV delivery and gene editing technologies
34:41 Lessons from Jude Samulski on translating AAV science into real-world therapies
37:21 Closing remarks
Find out more: Forge Biologics

This week on The Genetics Podcast, Patrick is joined by Daniel Chung, Chief Medical Officer of Beacon Therapeutics. They discuss lessons from developing the first ocular gene therapy (Luxturna), the complexities of designing and executing pivotal trials in inherited retinal disease, and how endpoint selection, delivery, and immunogenicity shape clinical and commercial success.
Show Notes: 
0:00 Intro to The Genetics Podcast
00:59 Welcome to Daniel
01:57 Daniel’s firsthand experience with the development and approval of Luxturna for inherited retinal dystrophy
06:13 Factors contributing to delays in approval for gene therapies in recent years 
08:13 Overview of ocular diseases and their suitability for gene therapy
11:40 Why Daniel joined Beacon Therapeutics and current priorities for the lead program
13:22 Key challenges in designing and executing a pivotal gene therapy trial for X-linked retinitis pigmentosa (XLRP)
15:49 Lessons from prior inherited retinal disease trials and selecting the right clinical endpoints
21:03 Expanding beyond the lead program into earlier patients and additional ocular indications
23:43 AAV packaging constraints and managing immunogenicity in ocular gene therapy
26:29 Lessons from academia–industry collaboration in developing gene therapies
28:23 Access to genetic testing in inherited retinal diseases and remaining gaps
32:10 Key scientific, regulatory, and commercial challenges facing gene therapy today
35:39 Closing remarks
Find out more:
Beacon Therapeutics

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This week on The Genetics Podcast, Patrick is joined by Zornitza Stark, Professor at the University of Melbourne and Co-Group Leader at the Murdoch Children’s Research Institute. Using early findings from the BabyScreen+ genomic newborn screening study, they examine feasibility, clinical impact, and family-wide implications beyond standard screening, and consider what these insights mean for infrastructure, policy, and equitable implementation at scale.
Show Notes: 
0:00 Intro to The Genetics Podcast
01:00 Welcome to Zornitza
01:55 Methods and findings of the BabyScreen+ study 
04:35 Scaling the BabyScreen+ study from pilot to population screening
07:46 Balancing benefits, risks, and downstream implications in genomic newborn screening
15:55 How the genes tested in BabyScreen+ were selected
19:00 Cascade testing and the family-wide implications of genomic newborn screening
22:05 What large-scale genomic newborn screening could reveal about penetrance 
23:57 Expanding genomic newborn screening over time and addressing equity, scale, and long-term value
27:47 Rapid genomic sequencing in critically ill newborns from pilot studies to national implementation
34:32 Building evidence infrastructure to interpret variants and support reimbursement decisions
37:25 Why global data sharing in genomics requires policy alignment and sustained infrastructure investment
39:55 Current priorities and the future direction of genomics in Australia
42:14 Closing remarks
Find out more:
BabyScreen+ study

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This week on The Genetics Podcast, Patrick is joined for a special recording at the Flagship Pioneering studio during JPM 2026 by Michelle Werner, CEO of Alltrna, and Mike Severino, CEO of Tessera Therapeutics. They discuss the molecular mechanisms behind Alltrna’s engineered tRNA and Tessera’s gene-writing platforms, why 2026 marks a major inflection point as both programs enter the clinic, and considerations around trial design, patient needs, and delivering therapies at scale.
Show Notes: 
0:00 Intro to The Genetics Podcast
00:59 Welcome to Michelle and Mike
01:26 Overview of Alltrna’s therapeutic approach to rare genetic diseases using engineered tRNAs
03:19 Overview of Tessera Therapeutics’ gene writing approach
04:51 Preclinical evidence supporting first-in-human testing of Alltrna’s lead candidate
07:50 Why Tessera’s preclinical models are predictive of clinical success
10:40 Key features that differentiate Tessera’s RNA-based gene writing
14:02 Advantages of using basket trials for engineered tRNAs
18:00 Clinical trial design and early efficacy signals for gene writing in alpha-1 antitrypsin deficiency
21:59 Genetic testing, patient identification, and patient advocacy in Alltrna trials
24:18 Differentiating Tessera’s gene writing approach for patients and investigators
26:35 Site readiness and expertise required for genetic medicine trials
28:32 Scaling Alltrna’s platform across mutations, tissues, and diseases
32:34 Expanding Tessera’s gene writing platform beyond alpha-1 antitrypsin deficiency
35:57 Perspectives on biotech funding, pharma partnerships, and rare disease investment
39:08 The data pharma looks for when partnering on novel genetic therapies
42:49 Emerging technologies Michelle and Mike are watching beyond their own platforms 
47:19 Closing remarks
Find out more:
Alltrna (https://www.alltrna.com/)

Tessera Therapeutics (https://www.tesseratherapeutics.com/)

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