The development of vaccines and therapeutics against the novel SARS-CoV2 virus have dominated global news and drug development efforts since the novel coronavirus has changed the lifestyle of almost every person on the planet. The current standard of care for patients infected with SARS-CoV2 includes oxygen therapy and ventilation to assist in respiration along with dexamethasone (a steroid) and remdesivir, an antiviral therapy that has so far shown limited efficacy. Given the high incidence rate and hospitalization rate, there is a strong momentum to repurpose existing antiviral therapies that have known safety profiles to treat COVID-19.
Typical antiviral drugs target viral proteins, so the long-term efficacy of these drugs can reduce if the targeted viral proteins mutate such that they are no longer inhibited by the antiviral therapy. A new approach to developing therapies against SARS-CoV2 is to target host cell machinery. Coronaviruses like SARS-CoV2 are large RNA viruses so once they infect the cell via attachment of the spike protein to cell surface receptors, the first step is for the genomic RNA to be uncoated from the viral capsid and translated to functional proteins. Some of the proteins form the viral replication transcription complex, while others are involved in mRNA translational control and proteolytic cleavage. Essentially, the virus hijacks the host cell translational machinery to start its replication cycle.
A recent report from Kris White and colleagues at the Icahn School of Medicine at Mount Sinai showcases an example of repurposing an oncology therapeutic, plitidepsin (Aplidin®), for COVID-191. Plitidepsin inhibits eEF1A or eukaryotic Elongation Factor 1A that is a critical component of the translation machinery. Plitidepsin is a member of the didemnins class of compounds and is a cyclic depsipeptide (which is a peptide that forms a cyclic structure via an ester bond). It was originally extracted from Aplidium albicans, a rare sea squirt found in the shallow waters off the coast of Ibiza, Spain and is being clinically tested to treat multiple myeloma patients in conjunction with dexamethasone. In a phase III trial, patients treated with plitidepsin and dexamethasone had a 35% reduction in disease progression compared to dexamethasone alone2. Additionally, plitidepsin was found to have a good safety profile with the most common side effects being fatigue, muscle pain and nausea3.
Plitidepsin was tested in in vitro and in vivo models of SARS-CoV2 and was found to be over 25-fold more potent than remdesivir that has received emergency use authorization to treat patients with COVID-19. Through the use of drug resistant mutant eEF1A, the researchers identified that the effect on SARS-CoV2 was due to the inhibition of eEF1A function in the translational machinery. Plitidepsin was also found to reduce viral protein expression in infected cell lines. Following the cell line data, the researchers tested the effects of plitidepsin in 2 mouse models of SARS-CoV2 and showed reductions in viral load and lung inflammation in plitidepsin treated mice1. PharmaMar, the company that developed plitidepsin for cancer indications has recently completed a clinical trial where the efficacy of plitidepsin on COVID-19 was evaluated on 46 COVID-19 patients who had required hospitalization. The study results were dramatic and showed an average 70% reduction in viral load 15 days post treatment along with reduction in inflammation and clinical improvement.
Based on these reports that demonstrate efficacy, plitidepsin appears to be a viable therapeutic for COVID-19 with a good safety profile. This is another example of a therapy identified in a marine animal that can be a game changer in the fight against disease.
Progeria or Hutchinson-Gilford syndrome is a rare disease characterized by accelerated dramatic aging. It is estimated that one in 4 million live births have progeria, and currently about 400 children have been diagnosed with the disease. Progeria does not develop at birth and symptoms appear about a year after birth, and the average lifespan of progeria patients is 14 years. Along with characteristic physical features such as a large head, small facial features and baldness, children with progeria suffer from joint issues and heart diseases that can lead to fatal heart attacks or stroke. In 2003, scientists discovered that a single point mutation (GGC > GGT) in the Lamin A gene was the genetic disease driver of progeria1. The point mutation resulted in the truncation of the Lamin A protein causing destabilization of the nuclear membranes in cells. The truncated Lamin A protein is also called progerin. The impact of nuclear membrane destabilization results in dysregulated transcription, mitochondrial dysfunction and accelerated cell death and senescence. The effects are prominently seen in tissues subject to external forces such as cardiovascular and musculoskeletal tissues.
There is a genomic test to identify the presence of point mutations in the Lamin A gene (LMNA) clinically, and this facilitates early diagnosis and treatment. In November 2020, the first therapy for progeria was approved by the FDA2 – lonafarnib (Zokinvy) was developed by Eiger BioPharmaceuticals and is a farnesyltransferase inhibitor. Lonafarnib acts by inhibiting the farnesylation of the progerin protein (truncated Lamin A) so that it does not bind to the nuclear membrane and this helps reduce the destabilization of the nuclear membrane3. Lonafarnib was found to increase the lifespan of progeria patients by 2.5 years in the 11 year follow up time frame of the trial cohort compared to natural history controls. Due to its inhibitory effect on truncated Lamin A protein, lonfarnib is also being investigated as a potential therapy for other rare laminopathies.
Recently, researchers at Harvard University and the Broad Institute published a ground-breaking new study using CRISPR based DNA editing technology to correct the point mutation in Lamin A4. Conventional CRISPR Cas9 system nicks both strands of DNA at specific locations allowing the insertion or deletion of a DNA sequence but it does not correct point mutations. David Liu’s lab at the Broad Institute has advanced CRISPR technology to develop single strand base editing capabilities, which were successfully shown to correct the point mutation in Lamin A. Base editing technology uses engineered bacterial deaminase enzymes that convert an adenine (A) base to cytosine (C) and a guanine (G) to thymidine (T). The deaminase enzymes are targeted to the DNA sequence that requires editing by the Cas9 enzyme that performs the same function in conventional CRISPR technology.
The researchers delivered the base editing system via adeno-associated viruses (AAV) to correct the error in the Lamin A gene in mouse models of progeria, resulting in an increase in the amount of normal Lamin A protein in the heart and muscles. This correction resulted in doubling of the lifespan of treated mice compared to control despite the efficiency of base correction being in the 20-60% range5. The study demonstrated a critical point that 100% efficiency of correction is not required to see improvement in the disease phenotype. While minimal off target effects were detected in this study, safety issues must be thoroughly investigated before using base editing in human patients.
Nevertheless, this study demonstrates that pinpoint accuracy of DNA sequence correction can be a ground breaking approach to fix disease causing point mutations and improve patient quality of life and increase life span6.
Idiopathic pulmonary fibrosis (IPF) is a rare but serious lung disease with an estimated 5,000 new cases each year and over 100,000 patients in the US1. IPF is characterized by the development of thick scar tissues in the interstitial spaces in the lungs that results in reduced gas exchange over time. Over time, the air sacs or alveoli in the lungs are replaced with stiff scar tissue. Essentially, IPF is the result of a disbalance between epithelial cells and fibroblasts resulting in increased fibrosis in lung tissues. It has been suggested that IPF develops due to repeated injury by unknown factors to the lung epithelial cells resulting in wound formation. As the name suggest, a definitive disease driver has not been identified for IPF but risk factors have been identified including a family history of interstitial lung disease, smoking, gastroesophageal reflux disease (GERD), age (older than 50 years) and gender (75% of IPF patients are male).
Oxygen therapy and lifestyle management help delay disease progression but if IPF progresses to a severe stage, a lung transplant may be the only available option but there are some pharmaceutical options. Currently, there are 2 drugs on the market for IPF – nintedanib (Ofev®) from Boehringer Ingelheim and pirfenidone (Esbriet®) from Roche. Nintedanib is a broad tyrosine kinase inhibitor that binds to and inhibits activation of tyrosine kinase receptors like FGFR (fibroblast growth factor receptor), VEGFR (vascular endothelial growth factor receptor) and PDGFR (platelet derived growth factor receptor), that are important for fibroblast proliferation and migration as well as the development of the extracellular matrix (ECM)2. Pirfenidone is an anti-inflammatory agent that also reduces fibroblast proliferation and inhibits the production of specific collagen forms. While pirfenidone have been shown to extend life span by 2.5 years3, and nintedanib and pirfenidone have been shown to slow the decline in lung function.
In the past couple of years, promising new therapies for IPF have been moving into the clinic. PRM-151 is currently in phase III clinical trials. This therapy was originally developed by Promedior, which was acquired by Roche in 20194. PRM-151 was shown to delay and reverse pulmonary fibrosis in phase II trials suggesting that this therapy may have disease modifying potential. PRM-151 is a recombinant protein called pentraxin-2 that is associated with normal wound repair that would minimize fibrosis and scar tissue formation. Another new therapy from Galapagos NV is being tested in a proof-of-concept Phase II trial in 68 IPF patients5. The novel therapy is GLPG1205 that is an antagonist of a G-protein coupled receptor called GPR84 that has been implicated in chronic inflammatory diseases.
Additionally, there is a new therapy that is going into the clinic – Endeavor Medicines recently raised $62 million series A funding to evaluate taladegib, a small molecule inhibitor of the Hedgehog pathway in IPF patients in phase II trials6. The company plans to first evaluate the efficacy and safety of taladegib as a monotherapy and then test in combination with currently available therapies such as nintedanib or pirfenidone. Hedgehog signaling is a well-studied signaling pathways involved in development and the Sonic Hedgehog (SHH) pathway is involved in lung development including lung branching and the survival of the mesenchyme cells. A 2012 study confirmed that the Hedgehog pathway is reactivated in IPF and the downstream transcription factors GLI1 and GLI2 were accumulated in the nuclei of fibrotic cells7. Furthermore, when fibroblasts derived from IPF patients were cultured in vitro and treated with recombinant SHH, they showed a remarkable resistance to apoptosis, which may play a role in increasing lung fibrosis.
These new therapies that have disease-modifying potential could be the much-needed breakthrough that IPF patients have been waiting for.
7 Bolaños AL, Milla CM, Lira JC, Ramirez R, Checa M, Barrera L, García-Alvarez J, Carbajal V, Becerril C, Gaxiola M, Pardo A, Selman M. Role of Sonic Hedgehog in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 303: L978 –L990, 2012.
20 | Apr | 2021
The question often asked of business leaders is “what keeps you up at night?” One of the answers to that question was made obvious last year and continues to be on the list. COVID. Through management oversight, diligence, and some luck, we’ve been able to weather the pandemic storm, so far. As Dr. Fauci is fond of reminding us “don’t spike the ball on the 5 yard line”. With the focus now on moving forward with the broader availability of vaccines, the question now is whether we should consider mandating vaccines.
Many schools and universities have already made the decision to require vaccination. I wouldn’t suggest that we set company policy by what comes out of the Vatican, but the Pope was recently quoted as saying it was our moral obligation to be vaccinated. While the average age of an employee at Biomere falls within the range of what the CDC might consider to be at lower risk of becoming seriously ill, we recently have taken the step to incentivize all employees to get their shots by offering a $50 gift card to everyone receiving their first dose by July 4th (some symbolism in the date). We will cross the bridge over mandating the vaccine once we gather further research and deliberate with some outside consultation on what is in the best interests of our employees, their families, our clients, animals, and the business. Just one more thing to consider when going through the list of items in the middle of the night.
01 | Apr | 2021
CAR-T or chimeric antigen therapy T-cells are a major breakthrough in personalized cancer therapies. The premise of CAR-T is that a patient’s T-cells are isolated, genetically engineered to express a receptor that binds to tumor cells and reintroduced into the circulation to specifically attack and kill tumor cells. This approach has been successful and currently 2 CAR-T therapies are commercially available for hematological cancers. The first therapy, Kymriah® (tisagenlecleucel) was approved in 2018 for certain pediatric and young adult patients with refractory or relapsed acute lymphoblastic leukemia (ALL)1. Yescarta® (axicabtagene ciloleucel) was the second CAR-T therapy approved for certain diffuse large B-cell lymphomas (DLBCL), a specific type of non-Hodgkin’s lymphoma2. While CAR-T therapies have been successful in hematological cancers, the treatment of solid tumors has been more challenging and several novel approaches are being used to develop next-generation CAR-T therapies for solid and hematological cancers. One such approach is the use of gamma delta T cells as the source for genetically engineered CAR-T cells.
Gamma delta T-cells are a rare population (1-5%) of T-cells in the peripheral blood. These cells express T-cell receptors that are composed of gamma and delta chains in contrast to the more abundant T-cells that express T-cell receptors composed of alpha and beta chains. Gamma delta T-cells are a part of the innate immune system and have the unusual and important characteristic of being activated in an MHC-independent manner. Conventional T-cells require a foreign antigen to be presented by the MHC (major histocompatibility complex) to activate a response restricting the response. Gamma delta T-cells have also been reported to have T-cell receptor independent activation in response to phosphorylated metabolites that are produced in tumor cells due to dysregulated metabolism. Another attractive characteristic of gamma delta T-cells is the preference to attack tumor cells compared to normal tissues. Gamma delta T-cells express NK (natural killer) cell receptors such as NKp44 and NKp30 that bind to ligands overexpressed on the cell surface of many tumor cells but have low expression on normal cells. Additionally, the gamma delta T-cells secrete high levels of cytokines and chemokines to induce an inflammatory response and activate other immune cells.
One of the important endpoints in immunotherapy trials is the presence of tumor infiltrating lymphocytes (TILs). Several studies have been published to identify gamma delta T-cells infiltrated in tumors. The most commonly used methods for this analysis are transcriptomic analysis of bulk tumors, immunohistochemistry analysis using an antibody against a pan-gamma delta T-cell marker and phenotypic studies. The presence and percentage of gamma delta T-cells varies between tumor types with one study reporting up to 20% of TILs being identified as gamma delta T-cells. Some studies have shown that gamma delta T-cells tend to localize around the tumor periphery suggesting that activating tumor infiltration will drive T-cell mediated tumor killing. More studies across various tumor indications will drive understanding of the presence of gamma delta T-cells in and around tumors.
The MHC independence is a major reason why gamma delta T-cells are being evaluated for T-cell based immunotherapies in an allogeneic setting. Currently, CAR-T cells are being used in an autologous setting where the patient is the T-cell donor, limiting scale up and increasing cost. In contrast, allogeneic CAR-T therapies will help increase scale of use and manage costs but the challenge is the develop of graft vs host disease in patients treated with CAR-T cells derived from other donors. Gamma delta T-cells have the potential to support allogeneic T-cell therapies and avoid graft vs host disease. It is evident that there is continued clinical interest in using gamma delta T-cell therapies to treat various tumor indications. In the past couple of years, a few Phase I clinical trials have been initiated and one of the interesting trials that is in progress is sponsored by Incysus Therapeutics where gamma delta T-cells plus standard of care chemotherapy are being tested in glioblastoma multiforme3. Given the success of Kymriah and Yescarta in hematological cancers, there are likely to be more clinical trials using engineered gamma delta T-cells for various tumor indications in the future.
Golf is often used as a metaphor for life. How a person plays the game provides insight into how they handle challenges in their personal and professional lives. There was even a book written on that exact topic about former President Trump. I happen to come across an interesting tidbit about an old golfer that you’ll recognize if you’re a fan, Chi Chi Rodriguez, who was competing in the US Open, played that year at Hazeltine Country Club outside Minneapolis. Tied for second place after the opening round, Rodriguez eventually finished 27th, a few strokes ahead of Jack Nicklaus, Arnold Palmer, and Gary Player. His caddy for the tournament was a 17-year-old local named Tommy Friedman. That’s right, the same Thomas Friedman, famed author of the book The World Is Flat.
Everyone likes to talk about globalization and the harmonization of processes when bringing new products to different markets across the globe. Regardless of the industry, it is essential that companies be integrated, and people be experienced in navigating local and international regulations. It is essential that we be able to communicate and work across cultural differences. Obvious stuff, one would think but hasn’t always been the case when companies look to expand their global footprint. Over the last few years, JOINN has performed over 60 IND enabling programs that were registered with the USFDA supporting submissions for a total of 27 Chinese pharmaceutical companies. This represents close to 50% of comparable projects that have been conducted by all Chinese CROs combined over the same period of time.
Flattening the world through effective integration is important if we are to provide our clients with an option for better and more efficient drug development. This is a centerpiece to JOINN and Biomere’s global strategy.
02 | Mar | 2021
The development of oncolytic viruses to target solid tumors is an area of intense preclinical and clinical interest. Oncolytic viruses (OVs) are engineered using well studied viruses such as vaccinia, adenovirus and herpes simplex virus as well as lesser-known viruses such as Maraba virus (originally isolated from Brazilian sandflies) and foamy viruses. Viruses are engineered to have specific characteristics including tissue tropism (the ability to naturally infect specific organs), tumor selectivity, immunogenicity and a payload that can stimulate the immune system. GM-CSF is one of the most widely used payloads in OVs as it boosts the immune system and increases the production of T-cells.
OVs kill tumor cells through multiple mechanisms – tumor cells are directly lysed post infection releasing tumor antigens, immune mediators, cytokines etc. which induce an immune response. The payload in the viruses express therapeutic proteins that further activate the immune response and recruit cytotoxic T cells to the tumor to mediate killing. OVs have also been shown to mediate an abscopal effect where distant uninfected tumors regress in response to OV infection of one tumor site. Given the multi-pronged approach to tumor killing, OVs are actively being developed as stand-alone therapies and as combination therapies with immunomodulators and checkpoint therapies.
One challenge with OVs is the balance between the induction of an antiviral response and an antitumor response. An antiviral response typically starts with the synthesis of proinflammatory cytokines including type I interferons, followed by the priming of T-cells by viral antigen presentation leading to viral clearance. In order for OVs to be maximally efficacious, it is important to manage the antiviral response and subsequent viral clearance. Many OV therapies in development are administered directly into the tumor with the intention of triggering direct tumor lysis and stimulating immune cells in the local tumor microenvironment. Systemic administration of OVs is more challenging due to the presence of anti-viral antibodies that reduce viral titer and contribute to viral clearance. Some of the approaches include masking viruses in polymeric materials or in extracellular vesicles as well as using novel viruses that humans have not been exposed to and therefore do not have pre-existing immunity. A good example of a novel OV is the Maraba virus that is being developed by Turnstone Biologics.
To date, Imlygic® (talimogene laherparepvec) is the only OV therapy for recurrent melanomas1 but there are about 100 active or completed clinical trials using OVs either as single agents or in combination with existing chemotherapies, monoclonal antibodies or radiation2. Melanomas, gastrointestinal cancers including pancreatic tumors and brain tumors (glioblastomas, astrocytomas etc.) are the most popular indications in clinical trials but there is increasing interest in other tumor indications that have an unmet clinical need such as triple negative breast cancer. A recent report3showed that the combination of an oncolytic reovirus (pelareorep) combined with either atezolizumab, letrozole or trastuzumab in women with different types of breast cancers showed an increase in tumor infiltrating lymphocytes or TILs across all breast cancer subtypes. This is a favorable result as an increase in TILs correlates to a better response to immune checkpoint inhibitors and is clinical evidence that OVs can prime the immune system to attack tumors.
While there is limited clinical information on OV efficacy as most of the ongoing trials are in phase I or I/II, there is a growing body of preclinical knowledge on OV engineering and its application as a mono or combination therapy in solid tumors. Interested in learning more about OV engineering? Check out our recent webinars on cell and gene therapies.
Levodopa or L-dopa was approved 50 years ago as a treatment for Parkinson’s disease (PD) to replace dopamine in the brain and slow disease progression. Levodopa has been prescribed to millions of PD patients as the first line of treatment. The drug is a modified amino acid (L-dihydroxyphenylalanine) that is able to cross the blood brain barrier where it is metabolized into dopamine and taken up by dopaminergic neurons.
Age-related macular degeneration or AMD presents in two forms – the more prevalent dry AMD and the less prevalent neovascularized or wet AMD (nAMD). Neovascularized AMD develops when abnormal blood vessels grow under the macula and leak blood and fluids that damage photoreceptor cells. This form of AMD represents 10-15% of all AMD patients, but 90% of the patients develop vision loss. Currently, nAMD is treated with anti-VEGF therapies like bevacizumab (Avastin®) and ranibizumab (Lucentis®) that are injected into the eyes every few weeks. While these therapies are effective, they require frequent injections and are expensive. Due to this trend, there is a large clinical need for improved and affordable therapies for nAMD. An interesting retrospective study in 2016 reported that PD patients who were prescribed L-dopa were less likely to develop age-related macular degeneration (AMD), and those who developed AMD had a later onset compared to the mean age of onset for AMD.
What if levodopa, which is a safe and well tolerated therapy, could help delay the need or frequency of anti-VEGF injections? To answer this question, two proof of concept studies were performed in Tucson, Arizona. In the first study, 20 newly diagnosed nAMD patients were dosed with Levodopa and then tested for visual improvement and acuity over 32 days. The second study was a dose range study with 35 patients. Both studies showed that levodopa induced significant improvement in vision and retinal anatomy including central retinal thickness and retinal fluid. The dose ranging study reported limited adverse events suggesting that levodopa is well tolerated and a viable option for advanced AMD patients.
How does levodopa work in the retinal pigment epithelia? A G-protein coupled receptor (GPCR) called GPR143 is expressed in retinal pigment epithelial cells and the ligand for this GPCR is levodopa. GPR143 is involved in melanin synthesis via the biogenesis, organization and transport of melanosomes in pigment epithelial cells. One of the signaling factors that is expressed in retinal epithelial cells is PEDF (pigment epithelium-derived factor), an anti-angiogenic factor that is downregulated along with melanin in aged populations. nAMD patients tend to be older so the downregulation of PEDF and upregulation of VEGF induces the formation of abnormal blood vessels in nAMD patients. Levodopa acts by flipping the angiogenesis balance – PEDF expression is upregulated and VEGF expression is downregulated.
It’s important to note that levodopa is likely not a replacement for anti-VEGF therapies and more work needs to be done including expanded clinical trials that include a control arm, and segmentation of the results by racial diversity and other known factors that contribute to nAMD development. These studies show that levodopa has the potential to be a safe and effective adjunct therapy to help manage the use of anti-VEGF injections in the treatment of neovascularized AMD. Interested in learning more about the clinical results? Check out the paper published in July 2020 and the proof of concept clinical trial 1 and clinical trial 2.
20 | Jan | 2021
CROs are not the engines that drive innovation. Instead, they serve as an integral part of a large and complex machine that must, even under the most trying of times, function flawlessly. Last year was as trying as it gets (hopefully) and 2021 is setting up to be equally as challenging. Challenging times provide for unique opportunities for those best prepared. While I do not pretend to be any more of a clairvoyant than the next person, an obvious key to success in 2021 starts with doing everything possible to keep employees safe while maintaining operations at full capacity. These are not mutually exclusive and must happen in parallel, one without the other leads to a failed year and wasted opportunity.
As a service provider to the bio-pharmaceutical industry, it is critical that a lab be able to meet the demands of its clients both from a capabilities and scheduling perspective. The current global pandemic should remind us all that we cannot become complacent when it comes to the discovery and development of new therapies, not just for the treatment of a virus but all diseases. Those that truly embrace a sense of urgency in their missions will be the ones that thrive during 2021 and beyond. In order to reduce this to practice, it will be important that CROs have relationships with key vendors that allow for access to important resources such as animals. COVID-19 caused travel restrictions and importation bans in 2020 that will continue into 2021. These produced a choke hold on a critical component in the preclinical supply chain leading to an industry-wide shortage of supplies that will favor those that can find solutions. This will benefit certain global companies that have strategic locations and relationships in place that provide access and availability of critical supplies.
With much of the industry’s focus on a virus and the development of a vaccine, manipulation/modulation of the immune system will dominate the science we support. Not just for the treatment of a virus but as a means for treating a wide array of conditions ranging from and beyond neurology, nephrology, gastroenterology, dermatology, rheumatology, and xenotransplantation. For new viruses or early phase work, labs with virology experience and expertise will have competitive advantages. Gene therapy will also continue to be a major driver of demand for CROs. Since much of this work requires the use and availability of non-human primates, the importance of availability and access to this resource will be paramount in 2021.
04 | Jan | 2021
Vedere Bio was founded in June 2019 with $21 million series A funding and was acquired by Novartis in a lucrative deal valued at up to $280 million ($150 million upfront)1 18 months later. This is exceptional even in the fast-paced M&A world and one contributing factor may be that Vedere’s technology has the potential to be a game changer in gene therapy. Vedere’s novel optogenetics platform could be used to develop novel gene therapies for retinal disorders like age-related macular degeneration (AMD) and retinitis pigmentosa that can lead to blindness. It’s well known that cataracts and retinal eye diseases are the most common causes of permanent blindness, and while cataracts are treated surgically, retinal eye diseases typically do not have a standard treatment regimen. In developed countries, retinal diseases are the most common cause of irreversible blindness and AMD is the most common retinal eye disease in older people. AMD does have a few therapeutic options such as laser photocoagulation and anti-angiogenic therapies (for wet AMD) but there is an unmet clinical need for long-term therapies and the more prevalent dry form of AMD has very limited therapeutic options. Gene therapies are being actively investigated but one of the complications is the fact that there are several therapeutic targets for retinal disease – more than 250 different genetic mutations have been reported for retinitis pigmentosa alone. Gene therapy that targets a specific disease driver gene would be beneficial only to the patients with that mutation, thus limiting the addressable patient population.
Vedere Bio’s technology is unique in that it does not depend on the presence of specific genetic mutations and can address a broader patient population. Some retinal diseases like AMD and retinitis pigmentosa can cause widespread death of photoreceptor cells (rods and cones) resulting in vision loss. Vedere’s strategy is to target retinal cells that are not destroyed during the disease process. The technology was originally developed at UC Berkeley in the labs of Ehud Isacoff and John Flannery and focuses on the development of adeno-associated virus (AAV) vectors that express light sensing opsin proteins and can be directly injected into the vitreous space. The goal of this approach is to reverse blindness by using an AAV expressing green cone opsin targeted to retinal ganglion cells in the inner retina. Normally, these cells are not sensitive to light but the presence of the green cone opsin protein makes them light sensitive, so they are able to function as surrogates for photoreceptor cells and generate electrical signals for the brain to interpret as vision.
Another unique feature is the AAV vector that was engineered to specifically infect cells in the inner retina. The AAV serotype 2 viruses with tissue specific opsin expression infect the retinal ganglion cells in the inner retina– the tissue specific expression simplifies the delivery method as the virus can be directly injected into the vitreous space instead of the subretinal area, which is a more complicated process. The use of the green cone opsin is a technological innovation as optogenetic methods have used microbial opsins that have high response rates but need a strong light stimulus which could damage the retina. Conversely, rhodopsin and melanopsin from retinal ganglion cells are sensitive but have a slow response to light. The medium wavelength green cone opsin solves both challenges as it is sensitive to dim light and has a fast response rate. An added benefit is that the green cone opsin protein allows visual adaptation in normal light for 3D object visualization.
This opens up the possibility that people with advanced retinal disease may be able to see again and regain a better quality of life so Vedere’s innovative technology could be a true game changer in ocular gene therapy.
Interested in reading more about the development and testing of the AAV in the rd1 mouse model of blindness? Check out the original paper from March 2019.
