This month, I have decided to review recent advances in genetic medicine. I thought this would be fun because the last time I spent time studying this was back in the heyday of CRISPR drug companies ~5 years ago. Today, I’m much more interested in the targets and indications genetic medicine can be used for.
The modality is relatively risky and as a result the biology must be clear and straightfoward. Additionally, because of the high upfront costs and complicated trial and regulatory pathway, there is limited competition within each indication/target.
For well understood diseases like Duchenne, its an engineering problem. Efficacy should be proportional to exposure and all the bells and whistles related to sequence engineering, delivery vector design, and chemistry are important. Preclinical in vitro assays can have meaningful readthrough to the drug profile in patients.
Finally, the allure of gene therapy is that you could eventually get a curative therapy. They are science experiments prosecuting human genetics evidence. Sometimes they can make money. But they will always teach something meaningful.
These essentially all involve knocking down expression of the misfolded protein and/or correction of toxic variants.
Alpha-1 Antitrypsin Deficiency (AATD)
Fazirsiran (Takeda / Arrowhead)
WVE-006
Transthyretin amyloidosis
Patisiran (TTR silencer)
Vutrisiran (next generation TTR silencer)
Nucresiran (next next generation TTR silencer)
Wainua (eplontersen; TTR silencer ASO)
Infectious Diseases
The idea here is to silence expression of the viral genome. Of course this is only feasible if you can deliver the silencing technology to infected cells. However, hepatitis by name, is a liver inflammation and commonly caused by A, B, C, D, and E viruses. Some hepatitis viruses including B have this cccDNA (covalently closed circular) that persist and enable chronic infection. Targeting these transcripts with siRNA has been an effective strategy.
Hepatitis B
Xalnesiran: old Dice program, targets conserved regiong of HBV genome
Historically these have been very controversial and high visibility given how devastating these diseases are. Restoring muscle function and development or preventing worsening in young children is difficult but it seems like recently there has been a lot of progress.
Duchenne Muscular Dystrophy (DMD)
Sarepta’s Elevidys and exon skipping medicines are approved
There are proteins with known role in major neurological disease. The question has always been whether therapeutic modulation has failed because the degree of modulation was not strong enough or whether these disease associated proteins have already ‘done the damage’ by the time a therapy is received.
Multiple System Atrophy / Parkinson’s Disease
ION464 (SNCA)
Alzheimer’s Disease
Lexeo has three approaches to both suppress APOE4 and deliver APOE2 and other protective AD variant genes
Frontotemporal Dementia / ALS
Passage Bio (PBFT02): AAV1 modified DNA encoding the granulin gene (GRN)
SOD1 ALS
Tofersen (QALSODY) – FDA approved SOD1 ASO. Peak sales estimate of $300mn
Hematologic Diseases
Commonly modulation of HSCs given feasibility of stem cell transplant.
HSC Indications
β-thalassemia (exa-cel (Casgevy) and beti-cel (Zynteglo))