We invested in Domina Therapeutics!

We want to share our excitement with all our friends and colleagues in the neuroscience, longevity vertical!

For the past few decades scientists have ascribed to the theory that misfolded or aggregated proteins in the brain are the major drivers of neurodegenerative diseases like Alzheimer’s and Parkinson’s. While the majority of approved drugs to treat these diseases have focused on symptom management, pharmaceuticals and biotech companies have actively pursued strategies to combat these diseases. These drug pipelines have mainly revolved around ways to slow down the accumulation of these misfolded proteins or break them down entirely, either via modulation of proteinases present in the brain, modulating the rate of autophagy and degradation in microglia, or more recently by designing antibodies to recognize and clear them away. Along the way, we have found that this prevailing theory of protein misfolding, while still potentially causal, may not necessarily be the only prevailing or precipitating factor leading to cognitive decline in the elderly.

For example, Alzheimer's patients recently treated with antibodies against beta-amyloid (the misfolded proteins thought to be responsible for Alzheimer’s) do not exhibit marked enhancements in cognitive function, yet their plaque burden is clearly decreased. Likewise, other strategies, like modulating brainwaves, or synchronised electrical pulses, via ocular or auditory means, have shown promise in enhancing cognitive functions of Alzheimer's patients without directly interacting with plaques. One clear example of this disconnect between theory and patient presentation revolves around the finding that some elderly individuals with large burdens of beta-amyloid plaques in their brains do not develop any kind of cognitive impairment. Importantly, recent evidence suggests that these outliers may have large burdens of plaque formation, but what matters is where the plaques accumulate. In these individuals, the plaques do not form at neural synapses and, thus, their neural connectivity and their cognitive function is spared.

These insights imply that the burden of misfolded proteins is not as important as the effect that this burden has on neural connectivity, especially since neural interconnectivity appears to be the underlying propagator of cognition. Neurodegenerative diseases, therefore, may be thought of as a series of maladaptive responses, such as neural degeneration and deficient plasticity, that take place as misfolded proteins continue to accumulate in specific regions of the brain. If we can begin to understand and address these maladaptive responses and re-coordinate them to a prior state, then the burden of misfolded proteins may no longer be the predominant target for drug design.

This is exactly the path that Domina Therapeutics has chosen to follow in their quest to end neurodegeneration and cognitive decline. 

As a science focused fund, we actively study, participate in discussions and help develop technologies that fill the gaps that exist like the ones described above. Given both the market size and human impact value, we are highly interested in the field of neurodegeneration.  

In this pursuit, we came across Domina, a company that has a completely different take on the problem definition. This is an early stage company that has just broken ground that brings in the scientific might of Evan Snyder. We are proud to be the first investors in Domina and provided below is the excerpt from our discussion with the Management team of Domina (Evan Snyder and Ravi Jain)

‍

LTF: "Could you provide us an overall picture of the technology Domina is developing?"

Domina: "Prior approaches to restoring cognition have primarily relied on device-assisted cognitive rehabilitation therapies, including neurofeedback, attention processing training, computer assisted learning and assistive devices. In other words, executive planning, language and certain types of memory - all affected by various cognitive diseases - have lacked restoration by medications. Moreover, the drugs that are on the market for neuropsychiatric diseases primarily address symptomology.

Our approach rebalances the cellular structures that allow for the making of the finely-tuned connections that different parts of the brain need to make in order to work together so that we can function normally. There have been many companies that sought to restore Alzheimer’s neurodegeneration by degrading A-beta. None of those companies succeeded. We have taken an unbiased approach and found molecules capable of restoring neural network communication using, as a model for drug discovery, hiPSC-derived neural networks that come from actual patients. These compounds restored behavior in animal models as well. Given the recent controversy around A-beta*, novel approaches such as ours are well warranted and desired."

‍

‍

LTF: "Why is this approach particularly suited to age-related cognitive decline as opposed to other neurologic disorders where neural circuitry dysfunction may also be playing a large role?"

Domina: "Dr. Evan Snyder’s work in neurological disorders uncovered the aberrant neural network phenomenon underlying those disorders. His research elucidated a mechanistic understanding underlying dysregulated network communication and that mechanism, as far as our current knowledge goes, is particular to cognitive disorders and presents as increasingly skewed as we age.

‍The (mis)fortunate aspect of cognitive diseases is their immensely large unmet medical need. Nonetheless, Dr. Snyder’s work has shown aberrant neural network communication in other neurological disorders as well. Our focus on restoring the neural network, thus, lends itself to finding compounds that address these other disorders (that have a cognitive misregulation component). Domina Therapeutics, at its roots, is a platform company that targets a number of indications, enabling the rapid generation of a deep pipeline of development programs."

‍

LTF: "How do traditional drug modalities fit into this network scheme and how do you modulate a network without a specific target in mind?"

Domina: "Recently, a failed cancer drug was shown to rescue epileptiform-like activity in brain organoids from individuals with Rett syndrome, a rare neurological genetic disorder that causes severe muscle movement disability. The drug’s molecular mechanism of action remains unclear, but there are two important points to note:

- (1)   the drug was able to rehabilitate the epileptic neural firing pattern;

- (2)   small molecules developed for other indications – whether successfully or not – have the potential to affect neural network communication and be effective therapies in the indications Domina Therapeutics is interested in.

Dr. Evan Snyder’s laboratory developed the assays and AI/ML algorithms to be able to assess neural network communication.  Leveraging these technologies, he and his collaborators have been able to find molecules that restore such communication when it is dysregulated.  Domina is utilizing and building on these technologies to find compounds that specifically repair network communication. We then use existing knowledge and molecular can openers to identify the compound’s target. We renormalize cognition (neural network communication) and subsequently uncover the target, as opposed to believing that a target is causative to the disease (A-beta) and hoping that molecules that modulate the target will restore cognition. There is a track record of failure for the latter approach. We have sown success with our approach, at least in animal models."

‍

LTF: "Could you elaborate a bit more on how you anticipate this funding round will be used and why the public should be excited about upcoming developments?"

Domina: "What we will accomplish in the near-term at Domina will pave the way to restoring cognition in patients whose suffering is nearly impossible to imagine. Over the next two years, we will find potential therapeutics that target the underlying causes of diseases such as Alzheimer’s, Bipolar Disorder, and Schizophrenia. This funding round will accelerate the discovery of such compounds, delineate a clear understanding of their biology and test the efficacy of the most promising candidates in animal models. We expect to share our progress starting in six months and quarterly thereafter. 

Testing in animals is a stepping-stone to human clinical trials, a path we aim to traverse as quickly as possible. Our in-vitro modelling system should help to accelerate the preclinical discovery phase significantly. Domina aims to speed-up the path to human trials by following the established drug repurposing route. Specifically, there are compounds that have failed in other indications in FDA Phase II and Phase III trials. Their safety is well established, allowing us to skip the Phase I trial, a time saving of ~2-4 years. An accelerated entry into the clinic provides Domina the ability to leapfrog valuation milestones, accelerate liquidity events and the go-to-market/partnership timeline. In parallel, we will also follow a more traditional drug discovery route by utilizing blood-brain barrier permeable compound libraries. The latter approach will provide us a mechanism for finding new drugs that repair neural network communication. At Domina, our mission and drive are to alleviate the pain and anguish that neurological disorders impose on patients. Never experiencing cognitive decline is our ultimate goal."

‍

“The appealing aspect of our work is that these abnormalities in neural network function, while exacerbated in aging, may also explain some aspects of the cognitive impairment seen in a range of neurological disorders, including psychiatric, neurodegenerative, oncological, developmental, drug-induced, traumatic, ischemic. As someone who has spent his entire career in Regenerative Medicine, indeed, was there at the field’s birth, I am starting to realize, through this work, that we may have been getting some goals wrong when approaching the nervous system: we sought to do cell replacement, cell protection, induce neurogenesis. What we really should have been focusing on was preserving or reconstructing neural networks, not individual cells. So this work has changed my entire focus also in the field of Regenerative Medicine.” - Dr. Evan Snyder

‍

Summary and the Domina Team 

‍

To summarize, Domina’s systematic approach holds great promise as it aims to address complex, polygenic, multifactorial diseases - which actually is how most diseases should be characterized - they are not the result of a single gene or protein or cell type defect; indeed over-focused targeting has been one of the reasons for the failure of so many therapies against prevalent diseases. Instead, Domina aims to develop therapeutics that modulate and restore neuronal communication that directly impacts cognitive function, something that current approaches usually fall short of doing. That being said, recent acquisitions and partnerships between established pharma/biotech and startups focusing on neuropsychiatric/neurodegenerative disorders have garnered multi millions of dollars with the potential for billions of dollars in subsequent milestone payments, and we anticipate Domina should match these achievements in the coming years.

Alongside their technology, Domina has assembled an excellent leadership team. Ravi Jain, their CEO has over 20 years of experience in biotech companies like cBio and Hemostemix, as well as a role as managing director of UCSC’s Genomics Institute. Likewise, Evan Snyder, their CSO is a world-renowned stem cell biologist and expert in neurodegenerative and neuropsychiatric conditions at the Sanford Burnham Prebys Medical Discovery Institute. Ultimately, we chose to invest and support Domina because, while there are many firms engaged in bringing next-generation therapeutics to market for cognitive disorders, none are utilizing network communication as a primary indicator for whether their approach is renormalizing cognition and we think this is the most promising avenue for addressing the highly unmet need of neurodegeneration and cognitive decline in the elderly. 

‍

Who are we?

Longevity Tech Fund is a VC that invests in early seed and pre seed stage companies. We began in 2019 and have so far invested in more than 40 companies out of our fund 1. Our investment thesis revolves around two important aspects of Longevity- Therapeutics and diagnostics including biomarker discovery.

We are currently raising our second fund which is actively seeking investors. While our investment thesis would remain the same, we plan to increase the cheque sizes and also include series A companies along with early seed stage companies.

‍