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MSCRF Annual ReportMission FocusedWe are staying focused and on course with our mission to develop new medical strategies for the prevention, diagnosis,treatment and cure of human diseases, injuries and conditionsthrough human stem cells.We hold the charge of ensuring thatthese programs under the Accelerating Cures initiative remainrelevant for the next 20 years and that we increase our impactand reach. We are surrounded by research institutes that are second to no other region and it is our mission to create an environment that accelerates these assets and discoveries to deliveron the promise of cures. We continue to operate our five keyprograms. Additionally, we expanded our support through keymarket research data and also organize meetings, conferencesand seminars for our researchers.2018new medical“Developstrategies for theprevention, diagnosis,treatment and cure ofhuman diseases, injuriesand conditions throughhuman stem cells.”Enhance Research and InnovationAccelerating Cures starts with support for research andinnovation at a very basic level of understanding the cellprocesses that are enabling the stem cells to differentiate,proliferate and regenerate human tissue. We continue tosupport the research through our Validation Program andwork with our researchers side by side, leading and guiding them as they develop a commercialization plan, validatetheir technologies and are ready for the next step.2

We Are the ConnectiveTissue to the Industry& Academia inMarylandDuring the last year we have partnered with many groups and provided several meetings, seminars, conferences and eventsto our community. We also partnered with global organizations and promoted Maryland to companies considering relocationfrom other parts of the world.Some of our events in the past year include: Maryland Stem Cell Symposium – held inconjunction with TEDCO’s EntrepreneurEXPO. This event attracted 1,000 peopleto participate in 12 hours of science andtechnology discussions. First Cardiac Regenerative Symposium forCongenital Heart Disease - a daylong sessionby world leaders on advances and challengesin cardiovascular research and surgery. We also supported a few of the Universityof Maryland Stem Cell Center seminars aswell as the grand opening of the new CellTherapy Center. In late May we hosted a panel discussion onRegenerative Medicine: Opportunities andChallenges in partnership with AmericanGene Technologies in Rockville. We continue to partner with Biotrac to offercrucial hands on training and other relevantcourses to scientists in the stem cell field.3

This is a great time to be a Marylander and an amazing time to be a stem cell researcher in Maryland. We continue to supportour community on many levels and through great partnerships with leading universities, companies and organizations. Togetherwe can accelerate our research into products and treatments that will revolutionize medicine.New Look Same Great ProgramsAfter 10 years our website is finally getting a new look withupdated information about the research that we support aswell as current news and innovation in the stem cell /celltherapy field from around the world. This new user-friendlywebsite is up and running and will be a great tool to educate,grow and support our community. The new home page willserve as a news for stem cell, cell therapy and regenerativemedicine news and our partners and researchers would beable to both read and contribute information.4Building Great CompaniesOver the past year we actively worked with our portfoliocompanies helping them grow and succeed in this rapidlyprogressing field. We awarded some new companies and welcomed several others to our community in MD. We remaincommitted to supporting the growth of our portfolio companies and facilitate their progress into the clinic and help themestablish themselves with additional funds and employees.We have dedicated section on our website to these companiesin our portfolio. We also provide our companies an opportunity for enhanced media coverage through our strategic partnerships. Some examples of such media can be seen on themedia section of our website as well as on our social mediachannels.

Annual ReportClinical ResearchGrant Awards

Clinical Grant AwardsLuis Garza, M.D., Ph.D.Johns Hopkins UniversityAward Amount: 650,000Disease Target: AmputationsStem Cell Therapy to Convert Stump Skin toPalmo-Plantar Skin in AmputeesCellular therapy holds great promise in medicine. This grant will employ autologous fibroblasts stem cells in an attempt to help more than 1.7 million (1 out ofevery 200) people in the US who have had amputations. While improvements inprosthetics exist, their use is still dramatically limited by pain and skin-breakdownat the stump. Our long-term goal is to convert the skin at the stump permanentlyto volar type (palmo-plantar) skin. Volar epidermis is markedly thicker than allother skin and uniquely expresses Keratin 9 (KRT9) that makes it more frictionand irritant-resistant. If the skin at the stump is thick volar type skin then the useof prosthetics will be enhanced dramatically. The markets for this technology arelikely to be even broader and include preemptive modification of pressure pointsin wheelchair and bed-bound patients to prevent pressure ulcers ( 8.5 billion dollar annual costs). We propose the method to convert skin identity from non-volarto volar will be the injection of volar fibroblast stem cells, and our endpoint willbe KRT9 given that it is pressure responsive, provides structural support, and themost unique volar skin gene. We already have full IRB and FDA IND approval(CBER IND #15658), and registration on ClinicalTrials.gov (NCT01964859) fora human clinical trial to test the ability of fibroblast stem cells to convert the skinidentity from non-volar to volar skin. We have enrolled more than 20 subjectswhere we are testing on buttocks skin for proof of concept. We have tested multiple variables and show-- particularly after mild wounding to prepare the recipient site--statistically significant induction of KRT9 in our human subjects wherewe have injected 10 million volar fibroblasts compared to injections of non-volarfibroblasts or vehicle (n 3, p 0.05). We also induce other genes found in volarskin such as KRT6 and AKR1B10. Finally, we have showed architectural changes(the increase of cytoplasmic area of keratinocytes) as in volar skin. These resultsprove the feasibility and eventual clinical potential of this product. As we planfor phase 2 and 3 trials we are encountering two challenges which this grant willaddress. The *first* is that manufacturing costs are high and although we havediscovered a dose ceiling where the therapy is ineffective (30 million), we havenot discovered the dose floor. What is the minimum dose we can use to minimizeside effects and manufacturing costs? The *second* is our end users (amputeesand their caregivers, prosthetists) resist the idea of using mild wounding at thestump site to improve engraftment/identity conversion. Can we find a replacementfor wounding? We will use Department of Defense grant funding to analyze howwounding enhances engraftment and KRT9 induction to provide matching fundsfor the following work suggested by our animal data: After an initial dose of fewercells, test if 2 follow-up weekly injections of vehicle only (freezing media) will enhance engraftment/KRT9 induction to substitute for mild wounding and allow forlower dosages of cells.66MSCRF 2018:Annual ReportAnthony Oliva, Ph.D.Longeveron, LLC.Award Amount: 750,000Disease Target: Aging FrailtyL ongeveron Mesenchymal Stem Cells (LMSCs)to Improve Vaccine Response in Aging FrailtyAging frailty is characterized by the progressive physiologic decline in multipleorgan systems, leading to increased vulnerability to disease, comorbidity, andmortality. This includes the age-related decline of the immune system, termedimmunosenescence. Immunosenescence results in diminished responsiveness toantigen challenges such as vaccinations, and increases vulnerability to infectionand associated complications such as opportunistic infections, increased hospitalization rate, and death. Aging Frailty and immunosenescence appear driven, atleast in part, by a chronic pro-inflammatory state, called inflammaging. Therefore,decreasing this pro-inflammatory state could potentially improve immune functioning. In this phase 1/2 clinical trial, we are investigating the potential efficacyof Longeveron-produced allogeneic mesenchymal stem cells (LMSCs) improveimmune-response to influenza vaccine in Aging Frailty subjects. LMSCs are aproprietary formulation of mesenchymal stem cells, which are multipotent cellsthat have powerful anti-inflammatory properties, and support intrinsic repair andregenerative mechanisms. LMSCs are also immunoprivileged, and thus offer promise as an “off-the-shelf ” allogeneic therapeutic. This study entails 3 phases. Firstwas a Run-In Phase to demonstrate provisional safety and tolerability. All subjectsof this phase have been treated with LMSCs and vaccinated against influenza. Safety was demonstrated, and the Data Monitoring Committee (DMC) recommended the remainder of the trial proceed without modification. The second phase(Pilot Phase) was designed to evaluate the optimal time-interval between LMSCtreatment and influenza vaccination. All subjects of this Phase have been treatedwith LMSCs and vaccinated against influenza. Safety was again demonstrated.Preliminary efficacy data also support the hypothesis that LMSCs can improveimmune response and immunosenescence in Aging Frailty subjects. The thirdphase of this study is a Placebo-Controlled, Double-Blinded, Randomized Phasedesigned to evaluate efficacy. This phase is currently enrolling. We anticipate thatthe results of this study will demonstrate that LMSC therapy is an efficacious adjuvant therapy that provides significant advantages over influenza vaccine alone.We also anticipate that these results should broadly translate across a spectrum ofdiseases by restoring back towards normal the functioning of the immune system.

MSCRF 2018:Annual Report2015Annual ReportCommercializationGrant Awards

Commercialization Grant AwardsLuis Alvarez, Ph.D.Theradaptive, Inc.2018 Commercialization AwardAward Amount: 299,005Disease Target: CartilageD evelopment of a Biphasic MSC Delivery Systemfor the Repair of Osteochondral DefectsTheradaptive has developed a novel tunable delivery platform, ConForma thatcan control both the dose and timing of release of a protein therapeutic at the siteof injury. ConForma offers endless versatility in that (1) it is mechanically tunabledue to the particle size ranging from nano particles to millimeter granules, (2) itsupports the delivery of a wide variety of small molecules, peptides and proteins,and (3) it has demonstrated an excellent targeted release performance in a caninemodel. With the Maryland Stem Cell Research Fund (MSCRF) Commercialization Grant, we can extend the utility of the current ConForma composite by:(1) optimizing the delivery of MSCs in the biphasic matrix, and (2) validating thekey components and competitive advantages of ConForma‘s MSC delivery matrixcompared to the market benchmark for focal cartilage defects. The incorporationof a subpopulation of MSCCD29 with high chondrogenic potential into ConForma delivery platform offers a breakthrough technology in reconstructive medicine. With Theradaptive‘s new MSCCD29 readily seeded onto ConForma, orthopedic surgeons can for the first time offer patients a potent, viable and regenerativerestoration for focal cartilage defects without the need for marrow isolation.86MSCRF 2018:Annual ReportEmily English, Ph.D.Gemstone Biotherapeutics, LLC2019 Commercialization Award (1st Round)Award Amount: 299,998Disease Target: Severe burnsS tem Cell Loaded Extracellular Matrix ReplacementScaffolds for Skin Regeneration in BurnsSkin wound healing is a complex process involving three overlapping phases: inflammation, proliferation, and remodeling, and stem cell niches in the skin play arole in all phases of healing. Mesenchymal stem cells enhance cutaneous healingby modulating the inflammatory response, promoting cytokine secretion, andstimulating cell differentiation. However, commercialization of stem cell-basedtherapies has been slow because of technical challenges associated with manufacturing, storing, and delivering cell-based therapies for clinical use. GemstoneBiotherapeutics is developing and commercializing its Extracellular Matrix Replacement (EMR) for regenerative medicine applications, with the goal of commercializing products that offers scar-free skin regeneration for acute and chronicwounds. The EMR is a UV-curable synthetic material that promotes skin regeneration in preclinical third-degree burn and excisional wound models. Because itis a synthetic material with tunable manufacturing parameters, the EMR technology can be customized to address specific pathologies by the addition of drugs,biologics, or cells to the material. We propose to optimize the EMR for deliveryof viable and scalable RoosterBio hMSCs to third degree burns, an indication forwhich there are few effective therapeutic approaches. This approach will combinethe regenerative capacities of both hMSCs and the EMR, leveraging establishedmanufacturing and regulatory pathways for the product components. The resultant stem cell-loaded EMR will comprise a new regenerative medicine productoffering in Gemstone Bios portfolio, building on the core EMR technology, whichwas developed at and licensed from the Johns Hopkins University Whiting Schoolof Engineering, and leveraging the unique capability of RoosterBios scalable andcGMP manufacturable xeno-free human MSC technology.

MSCRF 2018:Annual Report2015DiscoveryGrant AwardsAnnual Report

Discovery Grant AwardsPeter Calabresi, M.D.Johns Hopkins University (JHU)Award Amount: 345,000Disease Target: Multiple Sclerosis (MS)T ranscriptional and Functional Profiling ofiPSC Derived A1 Astrocytes fromPeople with Multiple SclerosisMultiple sclerosis (MS) is a disabling neurological disease characterized by demyelination, gliosis, and neurodegeneration in the central nervous system (CNS).There is known genetic susceptibility, with 240 gene variants being associated withrisk of developing the disease, but the course of the disease and severity of disability is highly heterogeneous. Further, it is unclear why certain patients respond wellto therapies targeting peripheral immune cells, while others develop the progressive form of the disease and are refractory to presently available immunotherapies.The absence of approved therapies for progressive MS is partly due to a lack ofknowledge regarding pathogenesis of this form of the disease. The mechanismsunderlying progressive MS likely involve phenotypic changes in subsets of microglia (M1 and M2) and astroglia (A1 and A2) that result in failed endogenousremyelination and neurotoxicity. Our ability to interrogate the biological responses of the glia is markedly hindered by limited access to human tissues, especiallyduring periods of ongoing CNS injury rather than years later, at post mortem examination. We propose to generate MS patient-derived astrocytes from existingiPSC lines. We will determine whether patient-specific gene variants predisposeto neurotoxic A1 astrocyte profiles. We will also examine the transcriptomic profile of astrocytes from different patients and controls before and after exposure todifferent inflammatory cytokines. Taken together, our data may help to elucidatemolecular pathways involved in A1 astrocyte formation and to identify therapeutic targets to develop novel treatments for this untreatable form of MS, as well asperhaps other diseases characterized by A1 astrocytes and neurodegeneration (e.g.ALS, Parkinson’s, and Alzheimer’s Disease).106MSCRF 2018:Annual ReportSamarjit Das, Ph.D.Johns Hopkins University (JHU)Award Amount: 318,615Disease Target: HeartD esign and Use of HumanPluripotent Stem Cell Bioreactors inMyocardial PreservationHuman induced pluripotent stem cells (hiPSCs) hold great promise for myocardial preservation after acute myocardial infarction (AMI), but are susceptible to various concerns. For instance, when iPSCs were injected into mice following myocardial ischaemia (MI), or in the AMI model, the results showed beneficial effectsin terms of cardiac contractility. In contrast, a higher incidence of tumorigenesiswas observed when iPSC injection was performed in rat hearts. Additionally, poorsurvival and engraftment coupled with inadequate cardiac commitment of theadoptively transferred hiPSCs diminishes the improvement in cardiac function.Recently, we and others have demonstrated an important and underappreciatedmechanism of paracrine cell-cell communication involving exosomal transfer, andits subsequent functional impact on recipient cells. Exosomes enriched in proteins, mRNAs, and miRNAs characteristic of parental hiPSCs represent a potentialapproach for myocardial preservation after MI. hiPSCs have the ability to produceextracellular vesicles (EVs), including exosomes; however, their effect in the context of the heart is unknown. We have calculated that hiPSCs release approximately 2000 EVs/cell/hour, including almost 70-75% of the EVs with an avarage122 nm in size. The common tetraspanin markers CD9, CD63 and CD81 by theseEVs, which we termed hiPSC-secreted exosomes (hiPSC-exo). We have developeda novel strategy to isolate hiPSC-exo from the ultracentrifugated (UC) fraction ofcell culture media using Fluorescence-activated Exosome Sorting (FAEs). We thenincubated the CD81 EVs in the culture media of human cardiomyocytes (iPSCdifferentiated cardiomyocytes, hiPSC-CM) (1X106 hiPSC-exo /105 cells). Ourpreliminary data suggests that the uptake of iPSCs-exo protects the hiPSC-CMagainst oxidative stress by reducing apoptotic cell death, and by improving cardiaccontractility. Bioanalyzer data suggests that the majority of the total RNA withinhiPSC-exo are small RNAs, such as miRNAs. Thus, we propose to characterize themiRNA-enriched hiPSC-exo and show its cardioprotective role. We hypothesize that miRNAs found within hiPSC-exo can be internalized by cardiomyocytes,and exert protective effects on the heart against oxidative stress. We will test thishypothesis through two specific aims. Aim 1. To validate the miRNA(s) presentwithin hiPSC-exo and identify the specific miRNA(s) which offer cardioprotection. Using RNA-Seq for small RNAs, we have identified the 13 most abundantmiRNAs inside the hiPSC-exo. Thus, we hypothesize that all or a subset of these13 miRNAs compartmentalized in the hiPSC-exo play a cardioprotective role. Wewill validate these miRNAs in the hiPSC-CM, and subsequently identify whichmiRNA(s) offer cardioprotection. Aim 2. To determine the effect of hiPSC-exoon the repair of ischemic myocardium. We hypothesize that hiPSC-exo contents,including miR-206, are transferred into cardiomyocytes, and can protect the heartfrom I/R injury. We are proposing to study hiPSC-exo cardioprotection in response to I/R injury with an in vitro model, and an in vivo model by ligating the leftanterior descending coronary artery. These studi

Reducing RAB GTPase14 to Drive In-Vitro Human Erythropoiesis Gabsang Lee, Ph.D. . Laying Foundation for Curing Achalasia Hilary Vernon, M.D., Ph.D. Johns Hopkins University . Brain Injury Repair Congratul