NANOMEDICINES - V-Smart® Nanomedicines: Non-Invasive Targeted Brain Therapeutics for CNS Diseases

Most brain diseases, especially neuro-degenerative brain diseases, such as Alzheimer’s disease, Parkinson’s disease, and ALS (Lou Gehrig’s disease), have no treatments or, at best, treatment options that are palliative, ie, they control symptoms for a limited time, but do not affect the underlying disease. Research in the past decade or two has brought far more understanding of the causes or driving forces behind these diseases. As a result, many new therapeutics have been proposed that have great promise in affecting actual disease processes with the possibility of stopping, or even reversing, the diseases themselves. However, most of these therapeutics cannot even be tested safely in humans because they cannot pass through the blood-brain barrier (BBB) and reach the areas of the brain that require the treatment.

What is the BBB? The blood vessels in the brain act differently than those in other parts of the body to protect the brain from substances that happen to be in the blood. The endothelial cells that line the walls of the brain blood vessels (which cells are essentially the walls of the blood vessels) form tight junctions with each other and prevent the uncontrolled transport of water-soluble molecules between the vasculature (capillaries, arteries in the brain) and the brain parenchyma.^1,2Thus, nothing passes from the blood in-between those cells and into the brain; anything that can go into the brain, has to go through those cells. In the rest of the body, most “delivery” from blood to tissue is through the loose junctions between the endothelial cells of the blood vessel walls.

Due to the aforementioned nature of the BBB, most potential therapeutics for brain diseases cannot cross the BBB and enter the brain or central nervous system (CNS). Moreover, many potential therapeutics (eg, neurotrophic factors), even if injected directly into the brain (thus, bypassing the BBB), bind to the extracellular matrix in the brain, and cannot spread to all brain areas that require treatment. Even small molecules (eg, those designed to inhibit a critical brain enzyme to treat a brain disease), cannot cross the BBB, unless they have certain chemical properties. In general, small molecules need to at least have a certain amount of lipophilicity (ie, not be very water soluble), although they might have other limitations that restrict them from crossing the BBB.

Other small molecules, as well as proteins and peptides, cannot cross the BBB without there being an inherent receptor-carrier for the respective molecule in the endothelial cells of the BBB. In such a way, the molecule (eg, protein) binds to its receptor-carrier which, then, carries it through the endothelial cells. An example is the transferrin carrier that “ferries” transferrin into the brain from the blood and, thus, supplies the brain with needed iron.³

Potential therapeutics for brain diseases not only have to survive the bloodstream, cross the BBB, and reach all areas of the brain or CNS, they, frequently, also need to target the specific disease sites, neurons, or brain cells in the brain and, thus, reduce possible adverse effects in other areas of the brain. Lauren Sciences LLC has the unique and novel solution to this greatest challenge in medicine for brain disease treatment, considered the “Holy Grail of Neuroscience,” with its breakthrough innovation – V -Smart^®Nanomedicines: Non-Invasive Targeted Brain Therapeutics.

V-SMART PLATFORM NANOTECHNOLOGY

Lauren Sciences’ V-Smart platform uniquely solves this greatest challenge in medicine for treatment of brain diseases – that most therapeutic agents, including biologicals, with potential to treat or cure brain diseases, do not cross the BBB – with its breakthrough innovation – V-Smart Nanomedicines: Non-Invasive Targeted Brain Therapeutics. The New York biotechnology company, with its labs in Israel, licensed the groundbreaking V-Smart platform nanotechnology from Ben-Gurion University, Israel, where it was invented by Professors Sarina Grinberg, Charles Linder, and Eliahu Heldman, then launched development of the innovative V-Smart targeted drug delivery platform and, now, has in development a pipeline of transformative V-Smart targeted therapeutics – V-Smart Nanomedicines.

Lauren Sciences LLC is the revolutionary neuro biotech that has 10 foundation grant awards, a pipeline of 6 products, 18 published peer-reviewed papers,^4,523 conference presentations, 6 presented posters, and 10 patent families on V-Smart technology. V Smart Nanomedicines are game changers that are designed, engineered, and customized to deliver non-brain penetrant therapeutic agents across the BBB, target and selectively release at specific brain sites or cells and be administered systemically. Lauren Sciences’ innovative pipeline of transformative drugs in successful development for CNS are designed to treat neurodegenerative brain diseases, including rare/orphan indications, such as Parkinson’s disease, ALS (Lou Gehrig’s disease), Alzheimer’s disease, Neuro-HIV, and Glioblastoma Multiforme (GBM).

V-Smart Nanomedicines have been proven to encapsulate therapeutic agents (especially, hydrophilic agents that do not cross the BBB on their own), cross the BBB into the brain (“macro” target), target and deliver to specific brain sites (“micro” target), selectively release its therapeutic agent at target sites, be administered systemically, as well as be safe and effective (in animal model). They solve the problem that most therapeutic agents, including biologicals, with potential to treat or cure brain diseases, do not cross the BBB, and offer unique and total BBB competitive advantages over other brain delivery technologies.

V-SMART DRUG DELIVERY PLATFORM

The innovative V-Smart targeted drug delivery platform is universal, versatile, flexible, and has none of the difficulties or limitations associated with other brain drug delivery systems (DDSs). V-Smart is the only drug delivery platform that has all of the following competitive advantages:

High Encapsulation Capacity

V-Smart can encapsulate a wide variety of therapeutic substances (eg, small molecules, biologics: peptides, proteins [neurotrophic factors, enzymes, antibodies, etc], nucleic acids [siRNA, plasmids, etc]; these types of substances are generally non-brain-penetrant). Other DDSs encapsulate only lipophilic molecules, or only tiny amounts of hydrophilic molecules, and cannot encapsulate large proteins with maintenance of activity.

Requires No Modification of Therapeutic Agent

Many other DDSs require that the therapeutic be modified (eg, attached to some other molecule such as a carrier or stabilizer), which may cause the therapeutic to lose activity and/or become immunogenic. V-Smart can encapsulate therapeutics under a variety of conditions, and is able to maintain activity and stability of therapeutic without modification of the therapeutic. The therapeutic, thus, does not become immunogenic, and V-Smart itself is not immunogenic.

Stable in Storage & Blood Circulation

V-Smart does not leak contents, is stable in storage (days or months) and has a half-life in circulation much longer than the time needed to reach the brain. Because the therapeutic is encapsulated within the V-Smart, the therapeutic is protected from degradation (eg, by proteases in the blood), or interaction with non-target tissues (thus, reducing toxicity) in the circulation and non-target organs.

Efficient Controlled Release Mechanism

V-Smart can be engineered to release the therapeutic rapidly, or more slowly, at target sites. Quick release may be preferred to produce high concentration of the therapeutic at the target site. Slower release may be preferred to produce longer therapeutic effects (ie, extended release can produce delayed action).

Can Be Designed for Selective Release

V-Smart can be engineered to release its encapsulated therapeutic only at target sites. For example, when the V-Smart is designed to be subject to hydrolysis by a specific enzyme at the target site, then, only when at the target site, will the V-Smart be hydrolyzed and release the encapsulated therapeutic agent.

Penetrates Intact Through Biological Barriers

V-Smart penetrates intact through biological barriers (eg, cell membranes, BBB, GI) without barrier disruption. Thus, V-Smart has been called, “a disruptive technology that does not disrupt the BBB.” V-Smart passes through the BBB, and through cell membranes, without disruption of V-Smart, and without disruption of the BBB or cell membrane, followed by release of the therapeutic there.

Can Be Designed for Specific Targeting Within the Brain and/or Elsewhere

V-Smart can be designed to target specific sites/cells within the brain (“micro” targeting), independent of its ability to cross the BBB (“macro” targeting).

Administration Options Are Both Oral & Parenteral

V-Smart has demonstrated successful encapsulation, delivery, and brain targeting, with model compounds and therapeutic agents, after both intravenous and oral administration.

Has Wide Therapeutic Window Potential

V-Smart itself is non-toxic at doses to be used for delivery of therapeutics. This advantage, combined with the V-Smart high-encapsulation capacity for therapeutics, selective release of the therapeutic in the brain (or other target site) and “micro” targeting ability, will limit concentration of the therapeutic at non-target sites, thus, limiting off-target toxicity.

V-SMART COMPARED TO OTHER BRAIN DRUG DELIVERY SYSTEMS

There are other drug delivery systems (DDSs), other than V-Smart, that contend to deliver non-brain penetrant therapeutic agents into the brain. Examples of these other DDSs are: carrier-conjugated-to-drug technologies, intracranial (IC) pumps/convection enhanced delivery (CED), intrathecal (IT) pumps, viral gene delivery, nasal inhalation, and others. Some of these have met with some modicum of success, in limited cases, but all suffer from a few or many difficulties/limitations (none of which V-Smart has), such as: (1) highly invasive, require brain surgery to place catheter in brain, (2) therapeutic will not diffuse throughout the brain, nor reach all areas that require treatment, (3) no selective release at target cells, (4) no potential for oral administration, or even intravenous administration, (5) cannot deliver/encapsulate large hydrophilic molecules, such as proteins or, possibly, even small hydrophilic molecules, in doses needed, (6) cannot protect therapeutic in the blood stream (circulation) from degradation, or from causing toxicity in other organs, (7) require modification of the therapeutic, thus, possibly, affecting activity and/or immunogenicity of the therapeutic, (8) no micro-targeting within the brain to areas or cells that require treatment, (9) high amounts of therapeutic need to be administered, with potential toxicity, in order to attain therapeutic amounts at target sites, (10) inability to control amount of therapeutic in the brain, (11) inconsistent dose delivery due to overwhelming of receptor systems or to changes to barrier, (12) intracellular delivery, if needed, may not be possible, (13) inflammation or other reactions, at site of repeated administration.

V-SMART NON-INVASIVE TARGETED NANOMEDICINES

V-Smart Nanomedicines consist of novel, unique, V-Smart nanovesicles. The V-Smart nanovesicle has high encapsulation capacity for hydrophilic agents (the V-Smart nanovesicle has a hydrophilic core that is large), high stability and ability for controlled release of the therapeutic agents (by utilizing V-Smart building blocks engineered to be hydrolyzed at the target site). V-Smart Nanomedicines are independently designed for a distinct medical indication, engineered for delivery to the brain, or other target site, specific targeting within the brain and selective release, customized for encapsulation of a chosen therapeutic agent and optimized for mode of systemic administration and other respective variables.

THE V-SMART NANOMEDICINESPIPELINE

The V-Smart Nanomedicine pipeline is extensive and demonstrates the versatility of the V-Smart technology. The pipeline includes both micro-targeted V-Smart Nanomedicines (eg, LAUR-101 targeted to dopaminergic neurons) and macro-targeted V-Smart Nanomedicines (eg, LAUR-201 targeted to the entire brain). The active therapeutic agents (APIs) in V-Smart Nanomedicines include both small molecules and large proteins, all of which are non-brain penetrant.

LAUR-101: V-Smart-GDNF for Parkinson’s Disease

Glial cell-derived growth factor (GDNF) has shown potential efficacy as a therapeutic treatment for Parkinson’s disease, based on numerous animal and clinical studies. GDNF protects degenerating dopaminergic neurons (brain cells affected in Parkinson’s disease) and induces regeneration of new neurons, in preclinical Parkinson’s disease animal models. V-Smart solves the problem that GDNF is non-brain penetrant and, even after direct brain injection, has limited diffusion such that it cannot reach all the dopaminergic neurons to obtain therapeutic effect.

Lauren Sciences designed LAUR-101 for Parkinson’s disease, engineered it to target, and selectively release at, dopaminergic neurons (the brain cells affected in Parkinson’s disease) in the striatum and substantia nigra (those parts of the brain rich in dopaminergic neurons), which was demonstratedin vitro. Lauren Sciences, then, customized LAUR-101 to encapsulate active GDNF at high efficiency, demonstrated its retention of GDNF activity and successful delivery of its GDNF to the targeted brain regionsin vivo(mice), without toxicity, following intravenous administration (Figure 1).

LAUR-101 demonstrated efficacy in a Parkinson’s disease mouse model (6-OHDA/Hemi-Parkinsonian). LAUR-101 treatment (dosed every other day) reduced rotation behavior (Figure 2), protected TH positive cells and decreased reduction in dopamine levels. LAUR-101 is to be tested in a second mouse model of Parkinson’s disease, to determine minimal effective dosage and safety, to be followed by preclinical IND enabling studies and, then, clinical trials in patients.

LAUR-301: V-Smart-GDNF for ALS

GDNF has also shown potential efficacy to treat ALS. GDNF has been shown to protect degenerating motoneurons (those brain and CNS cells affected in ALS), and induce regeneration of new neurons, in ALS animal studies and in patient clinical studies.

Lauren Sciences designed a V-Smart Nanomedicine for ALS: LAUR-301 (V-Smart-GDNF for ALS), engineered it to target ALS deteriorating CNS motor neurons, customized it to encapsulate active GDNF at high efficiency and selective release of GDNF in these CNS regions. Lauren Sciences has proven LAUR-301 encapsulation of GDNF, maintenance of GDNF activity, cell targeting and dose-dependent delivery and selective release in CNS (both brain and spinal cord) of normal mice, without toxicity, after intravenous administration (Figure 3).

LAUR-301 is to be tested for targeted deliveryin vivoto ALS deteriorating motor neurons in brain and spinal cord of ALS (SOD) mice, following intravenous admin istration, and for therapeutic efficacy in an ALS mouse model (SOD) for: improvement in motor behavior, protection against motor neuron degeneration and increased lifespan, followed by pre-clinical IND enabling studies and clinical trials.

LAUR-201: V-Smart-Tenofovir for Neuro-HIV

Tenofovir, a hydrophilic small mole-cule, is one of the leading anti-retroviral drugs for AIDS; however, it does not cross the BBB. Failure to eradicate HIV effectively in the brain is thought to be responsible for development of neurological symptoms in AIDS patients (Neuro-HIV).

Lauren Sciences designed LAUR-201 for Neuro-HIV, engineered it for delivery to, and selective release in, the brain, and customized it for tenofovir encapsulation. Lauren Sciences maximized tenofovir encapsulated in LAUR-201 and demonstrated successful delivery of therapeutic concentrations of tenofovir into the brainin vivo(mice), after a single intravenous administration, without toxicity (Figure 4). LAUR-201 efficacy studies will be conducted in a Neuro-HIV mouse model for: viral growth inhibition, and alleviation of cognitive deterioration, in brain. These will be followed by IND enabling studies and clinical studies.

LAUR-401: V-Smart-Irinotecan for GBM

Irinotecan (CPT-11) is a small molecule that does not cross the BBB, but has shown potential as a therapeutic for Glioblastoma Multiforme (GBM). Studies have shown that CPT-11 is the most effective chemotherapeutic as a single agent on patient-derived GBM tumors grown in mice.⁶There is also evidence that it will synergize with temozolomide (TMZ), the standard of care (SOC) chemotherapeutic in GBM treatment.^7,8

Lauren Sciences designed LAUR-401 for GBM, engineered it to target to, and to selectively release at, GBM brain tumor cells. Lauren Sciences customized LAUR-401 for encapsulation of CPT-11 and demonstrated its targeting to GBM cells and selective release,in vitro. This work has been supported by Voices Against Brain Cancer.

LAUR-401 has multiple types of selectivity for GBM tumors, resulting in high potency and low toxicity. The active metabolite of CPT-11 (SN-38) is only generated in the liver and in tumor cells. Because LAUR-401 does not release its payload (the CPT-11) in the liver, but primarily in the brain, little systemic toxicity is expected. Because LAUR-401 is targeted to GBM cells, there will be accumulation at GBM cells, in comparison to other areas of the brain or outside the brain (similarly to how LAUR-101 demonstrates accumulation at dopaminergic neurons). At these sites, LAUR-401 is designed to release the CPT-11 rapidly (compared to other areas of the brain), where the GBM cells can absorb the drug and then metabolize (thus, activating) it into SN-38. Because normal neurons cannot metabolize the CPT-11, there will be little SN-38 in other areas of the brain. In addition, LAUR-401 has potential synergy with TMZ, which may allow for an even lower dosage of CPT-11 to be effective.

LAUR-401 is to be studiedin vivo(mice), to determine that, following intravenousadministration, therapeutic concentrationsof CPT-11 are attained in thebrain. LAUR-401 efficacy will be studied inthese mice for: reduction of tumor burden(in patient-derived tumor xenografts (PTX)in subcutaneous and orthotopic models),increased survival as single agent and incombination with SOC. These studies willbe followed with preclinical IND enablingstudies and clinical trials.

LAUR-601: V-Smart-BDNF forAlzheimer’s Disease

BDNF, a protein that does not penetrate the BBB, has shown efficacy for the treatment of Alzheimer’s disease in Alzheimer’s disease animal models and in clinic. Lauren Sciences designed LAUR-601 for Alzheimer’s disease, engineered it to target to, and selectively release at, Alzheimer’s disease deteriorating brain neurons, and demonstrated targeting and selective release,in vitro.

LAUR-601 is be customized to encapsulate and deliver this neurotrophin to brain regions affected in an Alzheimer’s disease mouse model (in vivo), following intravenous administration. LAUR-601 efficacy is to be studied in an Alzheimer’s disease mouse model for: improvement in cognitive function/behavior, neuroprotection, and neurogenesis.

PARTNERSHIP OPPORTUNITIES

Lauren Sciences created its novel V-Smart platform nanotechnology, from which it designed its innovative V-Smart drug delivery platform, which it has validated by, and used in development of, its transformative V-Smart Nanomedicines pipeline. V-Smart Nanomedicines have been shown to encapsulate therapeutic agents (a variety of small molecules, peptides, and proteins), deliver them and other agents across the BBB safely with targeting within the brain and with therapeutic efficacy in animals.

Pharmaceutical companies continuously develop new drugs to address brain diseases that cannot reach the brain safely and can benefit from V-Smart, which can enable their therapeutics by development of a V-Smart Nanomedicine that can deliver the therapeutic into the brain safely and even target selective brain areas.

Lauren Sciences welcomes the opportunity to discuss partnership development of: (1) V-Smart Nanomedicines in its pipeline, (2) V-Smart Nanomedicines in its pipeline for use as a sub-platform for proprietary therapeutics to the same target (eg, LAUR-101 has been used as a subplatform to develop LAUR-102 to deliver other therapeutic agents for Parkinson’s disease to the dopaminergic neurons in the substantia nigra and striatum), and (3) new V-Smart Nanomedicines to be designed for additional indications, engineered to target other sites, with proprietary therapeutic agents, all as a means for therapeutics to reach their targets safely and effectively.

Additionally, V-Smart can extend exclusivity of proprietary products, particularly in connection with drugs that are approaching patent expiration. The V-Smart technology has extensive intellectual property coverage.

Lauren Sciences is a dynamic and sustainable drug development company with a differentiated and versatile superior platform technology, V-Smart. Lauren Sciences is poised for continued success with the valuable potential, and vast opportunities, it offers with V-Smart.

SUMMARY

Lauren Sciences’ V-Smart technology is the breakthrough innovation that solves the greatest challenge in medicine for the treatment of brain diseases. Lauren Sciences unique and novel V-Smart Nanomedicines have been proven to encapsulate therapeutic agents, cross the BBB (“macro” target the brain), target and deliver to specific sites in the brain (“micro” target brain sites/neurons/cells), selectively release at target sites, be administered systemically, as well as be safe and effective (in animal model). V-Smart Nanomedicines, thus, solve the challenge that most therapeutic agents, including biologics, with potential to treat or cure brain diseases, do not cross the BBB.

V-Smart Nanomedicines, developed with the universal, versatile, flexible V-Smart enabling technology, are independently designed for a distinct medical indication, engineered for specific targeting and selective release, customized for a chosen therapeutic agent, optimized for mode of systemic administration (intravenous or oral) and other respective variables.

V-Smart Nanomedicines will significantly improve the lives of patients who will benefit from therapeutic agents whose use is currently unavailable due to inability to cross the BBB, poor pharmacokinetics (PK), bioavailability or toxicity issues, required long-term and non-invasive treatment, or even where oral administration is preferable.

REFERENCES

1. Fenstermacher JD, Rappoport SI. (1984). The blood-brain barrier. In Handbook of Physiology: The Microcirculation (ed by E.M. Renkin and C.C. Michel.), pp. 969-1000. Washington D.C., American Physiological Society.

2. Risau W, Engelhardt B, Wekerle H. Immune function of the blood brain barrier: incomplete presentation of protein (auto-)antigens by rat brain microvascular endothelium in vitro. J Cell Biol. 1990;110,1757-1766.

3. Roberts RL, Fine RE, Sandra A. Receptor-mediated endocytosis of transferrin at the blood-brain barrier. J Cell Sci. 1993;104, 521-532.

4. Dakwar G, Abu Hammad I, Popov M, Linder C, Grinberg S, Heldman E, Stepensky D. Delivery of proteins to the brain by bolaamphiphilic nano-sized vesicles. J. Controlled Release. 2012;10;160(2):315-321.

5. Popov M, Abu Hammad I, Bachar T, Grinberg S, Linder C, Stepensky D, Heldman E. Delivery of analgesic peptides to the brain by nano-sized bolaamphiphilic vesicles madeof monolayer membranes. Eur J Pharm Biopharm. 2013;85(3 Pt A):381-389.

6. Hare CB, Elion GB, Colvin OM, Ali-Osman F, Griffith OW, Petros WP, et al. Characterization of the mechanisms of busulfan resistance in a human glioblastoma multiforme xenograft. Cancer Chemother Pharmacol. 1997;40(5):409-414.

7. Reardon DA, Friedman HS, Powell JB Jr, Gilbert M, Yung WK. (2003) Irinotecan: promising activity in the treatment of malignant glioma. Oncology (Williston Park). 2003;17(5 Suppl 5):9-14.

8. Patel VJ, Elion GB, Houghton PJ, Keir S, Pegg AE, Johnson SP, Dolan ME, Bigner DD, Friedman HS. Schedule-dependent activity of temozolomide plus CPT-11 against a human central nervous system tumor-derived xenograft. Clin Cancer Res. 2000;6(10):4154-4157.2014;5(21):10650-10664.

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Susan Rosenbaum, JD,is a successful visionary entrepreneur and strategic executive for the past 10 years in the field of biotechnology. She is Founder, Chairman, and CEO of Lauren Sciences LLC, a New York biotechnology company committed to development of its novel V-Smart® platform to create a robust pipeline of transformative V-Smart Nanomedicines, consisting of central nervous system-active drugs that normally do not cross the blood brain barrier. Ms. Rosenbaum also is Founder, Chairman, and CEO of Maya Sciences LLC, a New York biotechnology company that developed the novel pan-Akt inhibitor, MY-101, which is now ready for clinical trials in cancer. She has 20 years of prior experience in corporate finance, law, development & management; was founder of (past): an investment banking firm (Rosenbaum & Co.),and law firm (Rosenbaum, P.C.); has served on private and public company boards of directors; and is a national/international author and speaker. Ms. Rosenbaum can be reached atinfo@laurensciences.com.

Dr. Irwin Hollanderis Vice President of Research and Development of Lauren Sciences LLC. He earned his PhD in Biological Sciences at MIT, Cambridge, MA. He completed his post-doctoral work at Boston Univ. Medical School in atherosclerosis, plasminogen activator research at St. Elizabeth Hospital Boston, MA, and antibiotic research at MIT, where he was the first to purify penicillin cyclase. After research as a Research Biochemist at Monsanto/Searle in St. Louis, MO, in immunology and allergy, he was a Principal Research Scientist at Lederle/Wyeth/Pfizer in Pearl River, NY. While there, he helped develop Mylotarg, the first antibody-drug conjugate (ADC) approved by the FDA, in addition to irreversible kinase inhibitors and a PI3K inhibitor, PKI-587, now in clinical trials. Dr. Hollander is an author on 8 patents, and over 30 publications. He is also the Vice President of Research and Development of Maya Sciences LLC. He can be reached atinfo@laurensciences.com.