Axial - Observations #13
Life sciences reflections
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Observations #13
A set of ideas and observations from a week’s worth of work analyzing businesses and technologies.
Lupus and the power of the human immune system
Lupus in particular systemic lupus erythematosus (SLE) is a pretty bad autoimmune disease. I have a personal connection to it - SLE’s complexity and heterogeneity make developing new medicines for it really hard. Promising drugs often fail in phase 2/3 because endpoints aren’t properly set, patient recruitment isn’t done properly, and targets aren’t well chosen.
In SLE, B-cells drive pathogenesis by activating autoreactive T-cells and secreting auto-antibodies that recognize nuclear targets (also known as antinuclear antibodies - ANA). These ANAs form complexes to activate Toll-like receptors (TLR) and other immune pathways to lead to inflammation and organ deterioration.
Genomic tools to read the immune systems has increased our ability to identify new targets for a wide set of diseases:
Influenza - http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=21798894
Nacrolepsy - https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)05582-8/fulltext
For SLE, as well as other autoimmune diseases, their etiologies are not well characterized. Simply, what companies/labs are using genomic tools to dissent the immune systems of SLE patients to map out more autoantibodies for the disease? The thesis here is to then use a cell therapy or maybe a biologic to selectively deplete autoreactive B-cells in SLE. This could be done across most autoimmune diseases.
Cryo-EM and mass spec
Cryo-electron microscopy (cryo-EM) and mass spectrometry (mass spec) are complementary tools to characterize macromolecules - they are almost like Gale Sayers and Brian Piccolo; they both feed each other.
Cryo-EM focuses on large complexes while mass spec is good at measuring smaller macromolecules or fragments. Over the last ~5 years, better electron detectors have improved cryo-EM’s capabilities and better ion mobility spectrometers have improved the overall capacity of mass spec. Cryo-EM is really good at characterizing the structure of a diverse set of proteins but runs into trouble in determining the various conformations and interactions. This is where mass spec steps up to measure certain fragments or parts of a protein to determine their conformational states and so. These two tools are rapidly developing and feeding one another - great companies are and will be built upon them.
HSC transplant therapies
Hematopoietic stem cell (HSC) transplants are an incredible way to reset a patient’s immune system. Finding a patient match or sourcing safe HSCs is really hard along with battling GvHD after transplant are barriers to use. I am pretty sure this problem has been solved already and will reveal itself over time.
As a result, it’s really useful to think through what diseases can be treated with an HSC transplant and why:
Everything from ALL/AML to SCID to neurometabolic diseases (HSCs can cross the blood-brain barrier) can be treated with an HSC
An increasing ability to use lentiviruses to engineer cells ex vivo - this toolkit can be brought to HSCs
Use HSCs to reset a patient's immune system to lead to definitive and curative drugs - HSCs have the ability to self-renew; most cell therapies can’t do this
HSCs can form into several cell types from macrophages to microglia
Because HSCs can cross the blood-brain barrier and differentiate into neuronal cells, they may have a great shot at curing several neurodegenerative diseases
TGF-beta
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates cell growth and has a large role in cancer. In the early development of a cancer, TGF-β acts as a tumor suppressor and later on during development, the cytokine begins to promote cancer proliferation. The opportunity to drug TGF-β has served as the basis to build several very large businesses.
Therapeutics for TGF-β comes in three large classes:
Inhibition of TGF-β ligand-receptor interaction with a ligand trap: a monoclonal antibodies fused with a TGF-β receptor or an anti-receptor antibody
Antisense medicines to prevent TGF-β production
TGF-β receptor kinase inhibitors and aptamers
Full-stack AAV manufacturing
What are the key levers to build a great gene therapy manufacturing business?:
Develop cell lines (HEK293) to increase titers of AAVs
Design better promoters to increase expression levels of gene therapies
Improve transfection of cell lines and find new types of plasmids to use to deliver the essential components (Rep/Cap) of a gene therapy
Improve storage of gene therapies to increase the ability of the modality to address larger indications (~7 days of a gene therapy not being stored in a minus 80 leads to a 50% reduction in efficacy)
Design gene therapies that can be dosed multiple times and not initiate neutralizing antibodies against the gene therapy
The actual fermentors and machinery
