Exclusive interview: A new generation of senolytic

When is a drug not a drug? When it’s a NaNot. Interesting new technology that’s already on its way through FDA and targeting $40m Series B after current bridge.

Yesterday we covered NaNotics’ breakthrough in nanotech – clever NaNots that use geometry, rather than biochemistry, to distinguish between soluble and membrane forms of T Cell inhibitors – an approach that will work on nearly every pathogenic target.

To get a better understanding of just how the NaNots work – and why they are so important – we sat down with NaNotics‘ CEO, Lou Hawthorne.

Longevity.Technology: You’ve said that the problem for most diseases is not bad cells or tissues, nor a weak immune system, but rather incorrect molecular signals between cells and that correcting aberrant signal flow is the solution. Could you explain this in more detail?
Lou Hawthorne: Cells are like small computers. They have an initial set of programming – analogous to firmware or their operating system – but they’re also designed to receive and respond to inputs, not unlike the way a computer’s output changes in response to data entered with keyboard, mouse or by sensors.

Cells of all types have multiple types of “receptors” on their surfaces. These are biochemical locks that are activated by a specific protein “key” or signal molecule (aka “ligand”), which then causes a series of biochemical events that cross the cell membrane and induce changes within the cell. The precise changes that occur depend on the type of ligand and receptor involved. The response by the target cell to activation (aka “ligation”) of a specific receptor can be anything from secreting a new protein to going dormant or even dying.

Many cell signals are normally delivered in an intelligent cell-mediated way, meaning that one cell actually moves through the body until it’s quite close to a target cell, before releasing the appropriate signal molecules. This greatly increases the likelihood that only the target cell – and not an “off-target” cell – will receive the signal.

However, in various diseases, the delivery of the signal molecule is dysregulated in some way, sometimes because a cell is secreting a signal molecule systemically rather than focally to a target cell. The cell that receives this signal molecule – which it would not have received under normal circumstances – may do something it shouldn’t do, which can manifest at the tissue level as disease. But the target cell may in fact be responding in a perfectly appropriate way to an incorrect signal. Most medicine – even nanomedicine – still focuses on tissues and organs, rather than the underlying cells and signal molecules.

In cancer, the main problem is not the existence of cancer cells – which the immune system routinely clears out – but rather that cancer cells sometimes persist long enough to erect an inhibitory shield. The secreted molecules inhibit either the immune system’s killer cells or the “death signals” those cells produce. There are times when this type of inhibitory signaling is completely appropriate. For instance, the fetus must inhibit the mother’s immune system in order to survive, given that’s genetically only half the mother and thus looks like an invader. Cancer not only mimics the process used by the fetus/placenta but employs many of the same molecules to do it.

For anti-aging, one would deplete the various known pathogenic molecules that increase with age. Many of these are inflammatory and are responsible for what’s termed “inflamm-aging”. We are also designing NaNots to deplete immune inhibitors secreted by senescent cells for their defense, as a new generation of “senolytic”.

For the vast majority of non-genetic diseases, the drivers or enablers of the disease are signal molecules or molecular signal inhibitors. All of these targets can be depleted by NaNot, without drugs and thus without the side effects of drugs.

Longevity.Technology: We understand that the NaNots rely on geometry to enable them to distinguish between soluble and membrane forms, but is their introduction to the patient localised in any way or are they released around the body via injection into the vascular system? And how exactly does the targeting system work?
Lou Hawthorne: The reason most medical nanoparticles – generally designed for drug delivery – have failed – in some cases spectacularly, consuming hundreds of millions of dollars of capital – is that their targeting “moieties” (functional molecules) have failed. The reason they fail is that the nanoparticles get “opsonized” (coated with immune recognition/clearance molecules) before they can reach their targets. Opsonization leads to the nanoparticles being engulfed and digested by macrophages. For drug delivery nano-medicine in cancer, this means that the nanoparticles deliver their toxic payloads inside macrophages inside the patients liver, rather than in the tumor microenvironment.

The problem from a conventional nanoparticle design standpoint is that the targeting moieties need to be on the outside of the nanoparticle in order to bind to target cells when they encounter them, but that just makes those targeting moieties more obvious to the immune system and speeds opsonization.

In comparison, NaNot targets exist not in tissue but in circulation, even when the ultimate goal of the therapeutic is to treat localized disease. NaNots deplete specific targets from circulation which creates a “diffusion sink” (low level of concentration) which induces migration of the target molecule out of whichever microenvironment it’s elevated within.

The process is very similar to the diffusion of drugs except the process is running in the other direction (drug injection creates an excess of the injected molecule in circulation after which those molecules diffuse throughout the body).

For treating cancer, one would first measure which tumor-generated immune inhibitors are elevated in patient blood, then inject NaNots against those inhibitors, leading to deep depletion of these targets from circulation and their migration out of the tumor microenvironment. Once that happens, the tumor is defenseless and the patient’s normal immune system – more powerful than any drug – destroys the tumor.

NaNot capture agents are inside the NaNots, underneath a porous shield. The absence of targeting moieties – and the fact that NaNot capture agents are shielded – both slow opsonization and clearance of NaNots. However, we don’t need for NaNots to circulate very long because our targets are in circulation, i.e. the NaNots don’t have to locate target tissue. NaNots can deplete the targets they are programmed to deplete by >90% in <5 minutes, after which they are cleared and broken down by macrophages.

”The dosing of NaNots can be achieved with much greater precision than is possible with drugs … NaNots can deplete the targets they are programmed to deplete by >90% in <5 minutes, after which they are cleared and broken down by macrophages.”

Longevity.Technology: How do the NaNots affect the body’s signaling pathways?
Lou Hawthorne: NaNots deplete signal molecules or signal inhibitors by binding them and sequestering them beneath a porous shield. You can think of them as the world’s smallest, most specific, sponges. Note that this gives us the ability to increase OR decrease a biological signal in the body by selectively depleting either the signal or the inhibitor of that signal (many signals in the body have a matching inhibitor).

Once a NaNot is “full” – i.e. has captured its maximum load of target – it is inert from that point on and simply circulates without doing anything until it’s cleared by macrophages. There is no need to “turn them off” or filter them mechanically from the body.

The dosing of NaNots can be achieved with much greater precision than is possible with drugs. We know the precise capture capacity of a given quantity of NaNots. Before dosing, we measure target concentration in patient serum and then infuse the specific quantity of NaNots needed to deplete the target by the desired amount.

Longevity.Technology: What can you tell us about the manufacturing process?
Lou Hawthorne: It’s scalable, vat-based chemistry. There is a capture agent inside the NaNot. Our prototypes used antibodies but we’re transitioning now to more advanced capture agents.

Longevity.Technology: Has the FDA struggled to categorise NaNots – nanotech or drug?
Lou Hawthorne: We have received an initial judgment that NaNots are a drug. That’s not actually what NaNots are but it’s OK with us to be categorized that way given the many acceleration levers open to us on the drug pathway.

Longevity.Technology: What sort of funding have you raised?
Lou Hawthorne: We’ve raised $8.75m since our company was founded in early 2016. We are now raising a $5m bridge round in 2 tranches of $2.5m. The first tranche will be sold out this week. We expect the second tranche to close before the end of Q1. That funding can last us until the end of 2020, but well before then we expect to close a $40m Series B with one of the pharma venture funds with which we’re in diligence.