One-liner: BE Corp is a spinout company out of Jean Hebert’s lab at Einstein College of Medicine, working on brain tissue replacement.

Shepherds/Squad: Tuan Dinh, Maria Marinova, Tim Peterson, Tyler Golato Scientific & IP Evaluation: Sebastian Brunemeier, Tim Peterson, Nina Patrick, Diane Seimetz, David Wilson

Sourced by: Laurence Ion

Project PI: Jean Hebert

Simple Summary Apollo Health Ventures has finished negotiations to spin out Jean Hebert's work on engineering replacement brain tissue.

They will provide $1.5M and are offering the VitaDAO community the opportunity to participate in the formation and operation of BE Therapeutics Inc, with an allocation of $100,000.

Jean Hebert is a leading expert on the subject of brain aging and he is creating methods for brain tissue replacement for use in stroke with his laboratory at the Albert Einstein College of Medicine.

Comparison with the initial VDP-10, dated Oct 4, 2021

The prior iteration of VDP-10 (10/4/21) advised VitaDAO to “either A) own a small piece of Jean’s work via an IP-NFT and a sponsored research agreement, B) participate alongside Apollo Health Ventures in the company that is being created around Jean’s work or C) some combination of both”. Since then, we have made significant progress with Option #B, including:

1. A company (BE Therapeutics Inc) was formed, with a CEO (Davide Zanchi, PhD) and a clear commercialization plan
2. Apollo and Einstein College agreed on deal terms
3. A full-fledged research plan with achievable milestones/timeline is in place The current VDP-10 ready for snapshot voting reflects those changes.

Problem A big challenge facing tissue and organ replacement as a strategy to defeat aging relates to the brain. The brain, especially the neocortex - the part that underlies our highest cognitive functions and self-identity - cannot obviously be replaced as a whole organ.

Opportunity The neocortex can be replaced by progressively replacing tissue areas over time without significant disruption in function or self-identity (reviewed by Hébert and Vijg, 2018; and see for example Duffau, 2014, who documents the relocation over time of language without a disruption in speech in older adults in which the original language center was slowly destroyed due to disease). In addition, immature neocortical cells transplanted in mature neocortices develop normal synaptic connections and can respond normally to sensory input or elicit motor output (Falkner et al., 2016; Michelsen et al., 2015; Espuny-Camacho et al., 2013; and our data at Krzyspiak et al., 2022, Stem Cell Res 59:102642; and Quezada et al., 2023 https://doi.org/10.1101/2022.12.09.519776). These studies support the feasibility of age reversal for the neocortex via progressive tissue replacement.

Company Mission. The purpose of the company is to ● develop the technology to engineer functional tissue to replace brain tissue that is becoming impaired by age-related damage, and ● commercialize this tissue and the methodology for its pre-clinical and clinical applications.

Here, age-related brain damage refers to the normal accumulation over time of all forms of heterogeneous, covalent, non-enzymatic macromolecular changes associated with aging. Although such age-related damage occurs in the absence of disease, it also predisposes the brain to tissue loss as a result of strokes, tumors, and neurodegenerative conditions. The primary mission of the company will be to apply its technology to reverse age-related damage to prevent age-associated cognitive decline and disease, and secondarily or as steps toward the primary mission, to repair tissue loss when already caused by disease or trauma.

Scientific Background. Evidence from across mammalian species, including humans into their 90s, has established the plastic nature of the brain, particularly of the neocortex (seat of our highest cognitive functions). This plasticity refers to the ability of brain functions to seamlessly change their neural substrates over time without an interruption in the use of said functions. Preclinical studies have provided ample proof-of-concept for the integration of transplant-derived neurons into existing adult brain circuits, including in cases of brain tissue loss or degeneration. The new neurons can exhibit appropriate electrophysiological responses to natural input, and when activated can elicit appropriate behavioral outputs. Although sparser, data from human studies using transplants to treat Parkinson’s support the notion that neuron precursors transplanted in the aged human brain can also functionally integrate. The plastic nature of brain function and tissue, together with the ability of young neurons to integrate into existing networks, underscore the need to develop replacement technology for repairing the loss of functional brain tissue.

Product Concept. The engineered human brain tissue is a reassembly of the precursor cell types that comprise normal developing tissue, in such a way that their differentiation results in normal cell type ratios, cytoarchitecture, connectivity, and function. As a first step in the reassembly process, the Hébert lab has demonstrated the feasibility of using the adult mouse neocortex as a platform for rebuilding layered vascularized neocortical tissue in situ, with the integration of both neuronal and vascular components with the host (Quezada et al., 2023 https://doi.org/10.1101/2022.12.09.519776). Engineered tissue can be used to model human brain disease and perform drug screening, treat localized tissue loss, such as that due to trauma or stroke, and treat diffuse progressive loss of tissue function, such as that due to aging or neurodegeneration. For localized loss, the afflicted brain area is cleared of electrophysiologically silent tissue or scar tissue prior to tissue rebuilding. For diffuse loss of tissue integrity, tissue areas are sequentially rebuilt over time with concurrent progressive silencing of neighboring areas to allow memory and function to relocate.

Strategy in Brief. The initial focus is on repairing damage to the neocortex (the largest and arguably most important part of the human brain), followed -with an overlap in time- by a focus on other brain areas. For the sole purpose of demonstrating proof of concept, the technology can be applied to non-age-related forms of damage in pre-clinical and clinical studies prior to its application to treating age-related brain diseases and aging itself.

Team Jean Hebert is a professor of genetics and neuroscience at the Albert Einstein College of Medicine. He is an expert in the field of cell and tissue replacement for the adult neocortex to repair damage or age-related degeneration. Ole Mensching is a Co-founder of Apollo Health Ventures and HR expert focusing on team building. He founded CareerTeam, a headhunting agency with over 200 employees, and has built up several companies with TruVenturo as a partner and board member. Ole obtained his PhD with distinction at the Universities of Cologne and California, Berkeley, as the youngest and fastest-finishing postgraduate in his faculty. Alexandra Quezada earned her PhD in Neuroscience from the Albert Einstein College of Medicine, during which she developed novel methods for cortical transplantations and reconstruction using cells and scaffolds. Currently, she is applying her skills and knowledge towards engineering brain tissue as the Lead Scientist at BE Therapeutics. Davide Zanchi is the CEO of BE Therapeutics and an entrepreneur in the life sciences. Before joining BE Therapeutics, Davide led drug development programs at Roche and spun off biotech companies from leading research institutions (Stanford, UCSF). Davide got his MBA from Stanford University and his PhD in Neuroscience from the University of Basel.

Company Timeline

• Year 1-2: Human Prototype Development
  • Identification of cell types and ECM components
  • Cell type generation/ ECM production
  • Graft assembly - MVP
• Year 3-4:In vivo prototype efficacy studies
• Year 5+: Engage with FDA for clinical trials

Senior Reviewer digest

This proposal has been evaluated by three scientists and business experts, obtaining an average score of 4.3/5. The common consensus from senior reviewers and business/scientific advisors is that the project falls into the high-risk/high-reward category, with the very high risk being well recognized.

Based on the feedback from the senior reviews, we summarized the strengths/weaknesses of the project below.

Strengths

• Robust experimental data: (i) demonstrating vascularization of neuronal precursor cells & promising results of graft construction and layer of grafts, (ii) a mouse model has been established to assess in vivo performance of several product types and to identify the most promising tissue composition and cytoarchitecture (cell types, ratio of cell types, different scaffolds and layering), (iii) Initial studies support that from human iPSCs relevant precursor cell types found in the neocortex can be generated.
• Many breakthrough opportunities to address a variety of diseases, Alzheimer’s, Parkinson’s, stroke, age reversal, regeneration for spinal cord, and regeneration of nerves (reverse neuropathy). The technology could be used as for brain disease modelling and drug discovery with human brain tissue.
• The scientific approach to replace all relevant brain cell types incl. neurons, glia, and vascular cells embedded in an ECM scaffold is strong. The approach builds on successes seen with cell- and tissue-engineered products composed of a single cell type while the key differentiator is the mimicking the variety of different cell types and cell type distribution in brain tissue.
• Strong founding team: strong and longstanding scientific track record of the scientific founder *Apollo Health Ventures as co-investor into the NewCo is a good external validation of the project
• Reasonable timeline: the proposed plan of 4 years for human prototype development and in vivo prototype efficacy studies seems reasonable given the complexity of this first in class tissue engineered product. With stroke a meaningful entry indication is proposed, followed by several age-related degeneration conditions.

Risks

• May have challenges procuring and using fetal tissue due to ethical issues and regulatory burden.
  • Response from BE Corp: A few fetal samples will be needed to guide the reverse engineering of fetal-like tissue. After a long search, BE Corp has approval and can receive the few necessary samples of live human and primate fetal tissue from multiple sources.
• High risk & long-term project. Requires continued funding for 5-10 years just for research, unknown timeline on when transplantation in humans would be possible. The company likely needs $10-50 Million for 5 years. The initial funding likely only supports BE Therapeutics for 12-18 months. Future dilution of equity is expected.
• Responses may differ between mouse and primate models and different source cells for the production of the brain tissue, thus conclusions from one model to the other are limited.

Other Feedback

• In some parts of the application it is proposed that lenti- or retroviruses will be used to transduce excitatory neuron precursors with hM4Di prior to tissue construction. This will need careful consideration as this has a high chance of negatively influencing the overall results. The team is encouraged to consider different approaches.
• Due to the complexity and novelty of product development incl. questions on the best animal model, earlier regulatory interactions are strongly recommended, e.g. INTERACT (if granted) or in the EU at the national agency level. The advantage of EU regulatory bodies is that sponsors can come at a very early stage and discuss results in an iterative fashion.
• No detailed plans for exploring the best immunosuppression regimen (as little as needed) are proposed. This should be considered. While a circumvention of immune rejection in brain cell transplants is not excluded, it is unlikely that the first clinical trial would proceed without a well-justified and explored immune suppression regime.
• No plans on the surgical procedure and device for application into humans are presented. This should be considered and well-planned early on.
• No information on plans for cGMP-compliant manufacturing and the development of methods to characterize critical quality attributes are provided. Due to the novelty of the approach early identification of an appropriate contract manufacturing organization is important.