Industry updates from the field of stem cell research and regenerative medicine in December 2022

Business development

Collaboration agreement: Actinium & Columbia University

Actinium Pharmaceuticals (NY, USA; www.actiniumpharma.com), a company developing targeted radiotherapies, has entered into a research collaboration with Columbia University (NY, USA; www.columbia.edu) to study Actimab-A, its clinical-stage CD33 targeting radiotherapeutic, with engineered hematopoietic stem cells (eHSCs) modified by CRISPR/Cas9 gene editing technology to knock out CD33 expression [1]. Actimab-A has been studied in over 150 acute myeloid leukemia patients in six clinical trials. It has the most clinical experience of any Actinium-225 based drug candidate in development. Actinium-225 is an alpha-particle emitting radioisotope that has the most potent cell killing ability of any medical grade isotope but has a short pathlength that limits potential off-target effects. eHSCs are intended to engraft and reconstitute patients’ blood and immune systems with cells that do not express cancer specific targets such as CD33. This would then allow a patient to receive CD33 targeting therapy post-transplant to eradicate any residual CD33 positive leukemia cells and prevent relapse while sparing newly formed blood cells that do not express CD33.

Collaboration agreement: Kite & Arcellx

Kite (CA, USA; www.kitepharma.com), a Gilead Company (CA, USA; www.gilead.com) and Arcellx (MD, USA; www.arcellx.com), have announced a global strategic collaboration to co-develop and co-commercialize Arcellx’s lead late-stage product candidate, B-cell maturation antigen (BCMA) specific CAR-modified T-cell therapy, CART-ddBCMA, for the treatment of patients with relapsed or refractory (r/r) multiple myeloma [2]. Multiple myeloma is an incurable disease for most patients and the need remains for effective, safe and broadly accessible therapies.

Currently in phase II clinical development, CART-ddBCMA is an investigational cell therapy product comprising autologous T cells that have been genetically modified to target multiple myeloma [3]. CART-ddBCMA utilizes Arcellx’s novel D-Domain binder. Kite and Arcellx will jointly advance the CART-ddBCMA asset.

Upon closing, Arcellx will receive an upfront cash payment of US$225 million and US$100 million equity investment as well as other potential contingent payments. The companies will share development, clinical trial and commercialization costs for CART-ddBCMA and will jointly commercialize the product and split US profits 50/50. Outside the USA, Kite will commercialize the product and Arcellx will receive royalties on sales. Kite will be responsible for the development and commercialization costs for any product under the collaboration that is not co-commercialized. After completion of the technical transfer, Kite will be responsible for manufacturing.

Licensing agreement: Kite & Daiichi Sankyo

Kite (CA, USA; www.kitepharma.com), a Gilead Company (CA, USA; www.gilead.com) and Daiichi Sankyo (Japan; www.daiichisankyo.com) have revised their 2017 partnership agreement, which gave Daiichi Sankyo exclusive rights to develop, manufacture and commercialize Yescarta^® (axicabtagene ciloleucel) in Japan [4]. Kite was acquired by Gilead later in 2017, after the Daiichi Sankyo partnership agreement. Daiichi Sankyo and Kite have now agreed that the Marketing Authorization for Yescarta will be transferred to the Japan subsidiary of Gilead (Japan; www.gilead.co.jp/en/), in 2023. A Kite Cell Therapy Business Unit at Gilead in Japan will manage the sales and promotion activities of the product in Japan after the marketing authorization transfer.

Kite’s manufacturing facility in CA, USA, has been approved by Japanese regulatory authorities to manufacture Yescarta for the Japanese market, and it is expected that supply will commence in early 2023. The first axicabtagene ciloleucel treatment center in Japan was authorized in December 2021, and there are now six hospitals in Japan authorized to administer the therapy. Currently, the Japan Ministry of Health, Labour and Welfare (MHLW; www.mhlw.go.jp/english/) has approved Yescarta for the initial treatment of patients with r/r large B cell lymphoma: diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, transformed follicular lymphoma and high grade B-cell lymphoma [5]. Yescarta should be used only in patients who have not received prior transfusion of CAR T cells targeted at CD19 antigen.

Yescarta is a CAR T-cell therapy directed against a cell membrane protein CD19, which harnesses a patient’s own immune system to fight cancer. Axicabtagene ciloleucel is made by removing a patient’s T cells from their blood and engineering them in the lab to express chimeric antigen receptors so that they can recognize and destroy cancer cells when they are infused back to the patient’s body. The CAR T therapy is manufactured specifically for each patient and administered only once.

Partnership agreement: Alzamend & ISCI

Alzamend Neuro (GA, USA; www.alzamed.com), an early clinical stage biopharmaceutical company focused on developing novel products for the treatment of Alzheimer’s disease, bipolar disorder, major depressive disorder and post-traumatic stress disorder, is partnering with the Miller School of Medicine, Interdisciplinary Stem Cell Institute at the University of Miami (FL, USA; https://med.miami.edu/en/centers-and-institutes/interdisciplinary-stem-cell-institute) for its phase I/IIA clinical trial of ALZN002, a patented method using a mutant peptide sensitized cell as a cell-based therapeutic vaccine that seeks to restore the ability of a patient’s immunological system to combat Alzheimer’s [6]. ALZN002 is a proprietary ‘active’ immunotherapy product, which means it is produced by each patient’s immune system. It consists of autologous dendritic cells, which are activated white blood cells taken from each individual patient that are then engineered outside of the body to attack Alzheimer’s related amyloid beta proteins. These dendritic cells are pulsed with a novel amyloid-beta peptide (E22W) designed to bolster the ability of the patient’s immune system to combat Alzheimer’s; the goal of this treatment approach is to foster tolerance to treatment for safety purposes while stimulating the immune system to reduce the brain’s beta-amyloid protein burden, resulting in reduced Alzheimer’s signs and symptoms.

Clinical trials

Mesenchymal stromal/stem cells

Novadip

Novadip Biosciences (Belgium; https://novadip.com), a clinical stage biopharmaceutical company developing a new class of regenerative tissue products to accelerate healing of large bone defects and injuries in a single treatment, has announced positive data from its phase I/II clinical trial evaluating the safety and clinical activity of its investigational product, NVD-003, in patients with severe bone non union of the lower limb following trauma [7].

In this study, NVD-003, an autologous tissue engineered product generated from the patients’ own adipose stem cells, was applied in nine patients with bone non-union of the lower limb who had previously undergone several surgical procedures; in one case, a patient had undergone 14 previous procedures. The US FDA defines a non-union as a fracture that is at least 9 months old and has not shown any signs of healing for three consecutive months despite surgical intervention. A total of eight patients (89%) presented clinical healing during the 2 years of follow-up post-GS. The median and mean time to clinical healing were 6 and 9 months, respectively. All patients achieved total weight bearing at 6 months and seven patients (78%) were walking normally at 2 years.

Immune cells

AvenCell

AvenCell Therapeutics (MA, USA; https://avencell.com) has announced updated safety and efficacy data from its lead CD-123-directed Universal CAR (UniCAR) T cell candidate [8,9]. Of 16 patients treated with AVC-101, five patients (31%) achieved complete response with incomplete count recovery or minimal residual disease negative conversion and the overall response rate was 56% (n = 9). AVC-101 is an investigational CD-123-directed cell therapy targeting acute myeloid leukemia, that utilizes AvenCell’s proprietary Universal Targeting platform, a regulatable CAR T cell technology that can turn CAR T cells ‘OFF’ and ‘ON’ by means of a separately infused targeting module (TM). These TMs provide the antigen specificity to redirect and activate gene-modified T cells, engineered to express a universal CAR against tumor antigens. TMs consist of a highly flexible antigen-binding moiety, linked to a small peptide motif recognized by the UniCAR effector T cell.

Kite

Kite (CA, USA; www.kitepharma.com), a Gilead Company (CA, USA; www.gilead.com), announced 3 year follow-up data from the pivotal ZUMA-5 study for Yescarta (axicabtagene ciloleucel) in r/r indolent non-Hodgkin lymphoma, showing continued response in 52% of all enrolled patients and prolonged duration of progression-free survival in the phase II study [10].

The company also announced 2 year follow-up data from the ZUMA-1 safety cohort (Cohort 6) evaluating use of prophylactic corticosteroids in patients with r/r large B-cell lymphoma. A new analysis showed that the toxicity management strategy demonstrated improved long-term safety without compromising durability of response or survival in patients treated with Yescarta. Patients in the cohort received dexamethasone 10 mg orally on the day of Yescarta infusion and each of the two following days.

Kite has also announced findings from follow-up analyses of two pivotal studies (ZUMA-2 and ZUMA-3) of the CAR T-cell therapy Tecartus^® (brexucabtagene autoleucel) [11,12].

A comparison of 2-year follow-up from ZUMA-3 and SCHOLAR-3, a retrospective historical control study, evaluating Tecartus (KTE-X19, autologous anti-CD19 CAR T cell therapy) versus standard of care in adult patients with r/r B-cell acute lymphoblastic leukemia (B-ALL). Adults with r/r B-ALL received a single infusion of KTE-X19 (1 × 10⁶ CAR T cells/kg). After 26.8 months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase II was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with >75% blasts.

A separate exploratory analysis of ZUMA-2 was designed to identify factors associated with long-term response to Tecartus in adults with r/r mantle cell lymphoma (r/r MCL), comparing patients who remained in ongoing response at 24 months (47%; n = 29; ‘ongoing responders’) and those who had relapsed (48%; n = 30; ‘relapsed responders’). A greater proportion of ongoing responders had an Eastern Cooperative Oncology Group (ECOG) score of 0 compared with relapsed responders (79 vs 57%) and the incidence of high risk features was similar between the two groups. Levels of CAR T cells were approximately double in ongoing versus relapsed responders (median 102.4 cells/μl [range: 0.3–2241.6] vs median 59.9 cells/μl [range: 1.6–2589.5]). The analysis indicated that the patients with lower ECOG score and less tumor burden achieved a longer response. The ECOG score describes a patient’s level of functioning in terms of their ability to care for themselves, daily activity and physical ability (walking, working, etc.). It ranges from 0 to 5, with 0 denoting perfect health and five death.

Orca bio

Orca Bio (CA, USA; https://orcabio.com), a late-stage biotechnology company developing high precision cell therapies for the treatment of cancer, genetic blood disorders and autoimmune diseases, has presented updated positive clinical data on its lead investigational cell therapy, Orca-T [13–16]. Updated data from phase Ib/II trials include 151 patients with acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndromes and other hematologic malignancies. Across all 151 patients, there was an increase in graft-versus-host disease (GvHD), relapse-free survival (RFS) or GRFS, rates and OS rates at 1 year with Orca-T compared with an independent cohort. Results demonstrated that patients conditioned with busulfan, fludarabine and thiotepa regimen and treated with Orca-T experienced:

• 87% RFS at 1 year among all groups, including minimal residual disease positive acute leukemia patients.

• 81% GRFS at 1 year.

• 0% non relapse mortality and only 5% moderate-to-severe chronic GvHD at 1 year.

• 94% OS at 1 year.

In pooled results from all patients treated with Orca-T, patients experienced:

• 70% GRFS at 1 year compared with 21% in the CIBMTR-based cohort.

• 4% non relapse mortality at 1 year compared with 10% in the Center for International Blood and Marrow Transplant Research (CIBMTR)-based independent control cohort.

• 88% OS at 1 year compared with 68% in the CIBMTR-based cohort.

The Company has also announced that interim clinical data from its phase I multicenter trial of its second investigational cell therapy, Orca-Q [17–19]. Orca-Q is an investigational high-precision cell therapy that is a proprietary composition of enriched CD34⁺ stem cells combined with specific T cell subsets. The findings presented are from patients with acute myeloid leukemia, ALL, myelodysplastic syndromes and chronic myeloid leukemia who were matched to haploidentical allogeneic donors, defined as matched across at least 4/8 but fewer than 7/8 HLA.

 loci. Historical controls from the literature of patients who received standard of care haploidentical alloHSCT with PTCy GvHD prophylaxis were used for comparison purposes.

Interim results from the phase I single-arm, open-label trial showed:

• A reduction of grade 2–4 acute GvHD (aGvHD) at 6 months as compared with literature controls (13 vs 21–63%), with only one patient developing grade 3 aGvHD and no incidence of grade 4 aGvHD;

• No patients experienced moderate-to-severe chronic GvHD (cGvHD), compared with 24–33% in the literature control. There was only one case of mild cGvHD;

• GRFS was 75% at 1 year after Orca-Q, which compares favorably to a GRFS of 46% in patients in the literature control.

Patients treated with Orca-Q also experienced a low adverse event profile, suggesting Orca-Q has the potential to offer a new treatment option for patients undergoing haploidentical alloHSCT.

PeproMene bio

PeproMene Bio (CA, USA; https://pepromenebio.com), a clinical stage biotech company developing novel therapies to treat cancers and immune disorders, has announced that the first patient treated in its Phase I r/r B-cell non-Hodgkin Lymphoma (r/r B-NHL) clinical trial of PMB-CT01 has reached complete response at 1 month post-treatment [20,21]. Despite high initial efficacy of CD19-CAR T cell treatment for B-cell lymphoma and leukemia, there is a significant unmet medical need for those patients who unfortunately relapse. PMB-CT01 is a first-in-class B cell activating factor receptor (BAFFR) targeted, autologous CAR T-cell therapy. BAFF-R, a TNF receptor superfamily member, is the main receptor for BAFF expressing almost exclusively on B cells. Since, BAFF-R signaling promotes normal B-cell proliferation and appears to be required for B-cell survival, it is unlikely tumor cells could escape immune responses via loss of BAFF-R antigen. This unique characteristic makes BAFF-R CAR T therapy a great potential treatment of B cell malignancies. BAFF-R CAR-T was constructed using the anti-BAFF-R single-chain fragment variable antibodies with the 2nd generation signaling domains containing CD3ζ and 4–1BB. BAFFR-CAR T cells kill human lymphomas and leukemias in vitro as well as in animal models. PeproMene has licensed intellectual property relating to PMB-CT01, from City of Hope (CA, USA; www.cityofhope.org).

Other

Editas

Editas Medicine (MA, USA; www.editasmedicine.com), a clinical stage genome editing company, has announced positive, initial clinical data from the first two patients with sickle cell disease (SCD) treated with EDIT-301 in the phase I/II RUBY trial [22,23]. EDIT-301 is under development for the treatment of severe SCD. The clinical data include safety data from the first two patients and efficacy data from the first patient treated.

Both treated patients demonstrated successful neutrophil and platelet engraftment. Patient 1 achieved neutrophil engraftment at 23 days after EDIT-301 infusion and platelet engraftment at 19 days after EDIT-301 infusion. Patient 2 achieved neutrophil engraftment 29 days after EDIT-301 infusion and platelet engraftment 37 days after EDIT-301 infusion. Additionally, neither patient has experienced any vaso-occlusive events since treatment with EDIT-301, at 5 and 1.5 months follow-up, respectively.

At 5 months post-treatment, the first patient treated with EDIT-301 has a total hemoglobin of 16.4 g/dl, a fetal hemoglobin (HbF) of 45.4% and a mean corpuscular HbF of 13.8 pg/red blood cell, exceeding the 10.0 pg/red blood cell threshold to suppress red blood cell sickling. Additionally, HbF increase in the first patient was highly pancellular, with F cells steadily increasing to reach greater than 95% of red blood cells.

EDIT-301 was well-tolerated in the two patients and demonstrated a safety profile consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant. No serious adverse events occurred, and no adverse events reported were related to treatment with EDIT-301.

EDIT-301 uses AsCas12a, a novel, proprietary, highly efficient and specific gene editing nuclease, to edit the promoter regions of gamma globin gene 1 and 2 to increase the expression of HbF to mimic the natural mechanism of hereditary persistence of fetal hemoglobin to treat SCD. The RUBY trial marks the first time AsCas12a was used to edit human cells in a clinical trial.

Regulations, approvals, acquisitions…

Acquisitions & mergers

Kite & Tmunity

Kite (CA, USA; www.kitepharma.com), a Gilead Company (CA, USA; www.gilead.com), has signed an agreement in which Kite will acquire Tmunity (PA, USA; www.tmunity.com), a clinical-stage, private biotech company focused on next-generation CAR T-therapies and technologies [24]. The acquisition of Tmunity complements Kite’s existing in-house cell therapy research capabilities by adding additional pipeline assets, platform capabilities and a strategic research and licensing agreement with the University of Pennsylvania (UPenn; PA, USA: www.upenn.edu).

The acquisition will provide Kite with preclinical and clinical programs, including an ‘armored’ CAR T technology platform, which potentially could be applied to a variety of CAR T's to enhance antitumor activity, as well as rapid manufacturing processes. Tmunity’s prostate-specific membrane antigen and prostate stem cell antigen assets are not part of the Kite acquisition and will be spun-out by Tmunity as part of the transaction.

As part of the acquisition, Kite will assume responsibility for continuing the research and development collaboration between Tmunity and UPenn, also known as the Amended Research License Agreement, which includes research funding to UPenn along with options and licenses to certain cell engineering and manufacturing technologies invented and developed in certain UPenn laboratories. Upon closing, the Amended Research License Agreement will be extended until 2026 with an option to extend further.

Green light

bluebird bio

bluebird bio (MA, USA; www.bluebio.com) has announced that the FDA lifted its partial clinical hold for patients under the age of 18 in studies evaluating lovotibeglogene autotemcel (lovo-cel) for SCD [25–27]. In December 2021, lovo-cel clinical studies were placed on a partial hold for patients under the age of 18. The hold related to an investigation by bluebird bio into an adolescent patient with persistent, non transfusion dependent anemia following treatment with lovo-cel. Results from a detailed investigation of this case were presented alongside details from another case of persistent anemia in an adult patient following treatment with lovo-cel. Both patients had two α-globin gene deletions (‐α3.7/‐α3.7), also known as alpha-thalassemia trait and notably are the only patients in the study with this specific genotype. Following these cases, this genotype was added to exclusion criteria for ongoing studies.

BioCardia

BioCardia (CA, USA; www.biocardia.com), a developer of cellular and cell-derived therapeutics for the treatment of cardiovascular and pulmonary diseases, has announced FDA approval of its Investigational New Drug (IND) application to initiate a first-in-human phase I/II clinical trial of its NK1R+ allogeneic mesenchymal stromal/stem cells therapy for the treatment of patients with ischemic heart failure [28].

This trial is designed for patients with New York Heart Association Class II and III ischemic heart failure with reduced ejection fraction whose own cell composition makes them ineligible for the Company’s Phase III CardiAMP^® Heart Failure Trial studying autologous cell therapy [29].

IASO

IASO Biotherapeutics (China; www.iasobio.com), a clinical stage biopharmaceutical company engaged in discovering, developing and manufacturing innovative cell therapies and antibody products, has announced that the IND application for its CT103A (equecabtagene autoleucel), BCMA CAR-T, has been approved by the FDA for use in US clinical trials for r/r multiple myeloma [30]. CT103A contains a fully human single-chain variable fragment, allowing it to bypass potential anti-CAR immunogenicity of the host while retaining antitumor activity. Results from a clinical phase I/II study in China showed excellent safety and efficacy of CT103A [31].

Capital market & finances

Angiocrine biosciences

Angiocrine Bioscience (CA, USA; https://angiocrinebioscience.com), a clinical-stage biopharmaceutical company has announced that the California Institute for Regeneration Medicine (CIRM; www.cirm.ca.gov) has approved investing US $15 million in the phase III registration study AB-205-301 (E-CELERATE), a multicenter, randomized, double-blind, placebo-controlled study of AB-205 in adults with lymphoma undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation [32,33]. AB-205 is an experimental engineered cell therapy consisting of allogeneic E4ORF1+ human umbilical vein endothelial cells (E-CEL^® cells). AB-205 is an advanced reparative medicine product being developed by Angiocrine and is currently being studied in a single, pivotal phase III registration trial. This late-stage trial is designed to evaluate the efficacy and safety of AB-205 in the treatment of systemic multi-organ stem cell niche damage from high dose chemotherapy and prevent the emergence of severe transplant related complications.

Autolus

Autolus Therapeutics (UK; www.autolus.com), a clinical-stage biopharmaceutical company developing next-generation programmed T-cell therapies, has announced that Blackstone Life Sciences (MA, USA; www.blackstone.com) has committed to make two pre-agreed milestone payments of US $35 million each to Autolus, totaling US$70 million [34]. The first Blackstone milestone of US $35 million is being paid earlier than anticipated as a result of the joint steering committee’s review of Autolus’ interim analysis of pivotal FELIX Phase II clinical trial of obecabtagene autoleucel (obe-cel) in r/r adult ALL [35,36]. The study has met its primary end point; based on 50 patients evaluated for efficacy, the overall remission rate for obe-cel was 70%. Obe-cel showed comparable expansion and initial persistence (median follow-up 6.4 months) to the data observed in the prior ALLCAR19 study [37].

The second Blackstone milestone of US $35 million is a pre-agreed manufacturing milestone as a result of completion of planned activities demonstrating the performance and qualification of Autolus’ obe-cel’s manufacturing process.

Autolus and Blackstone entered into a strategic collaboration and financing agreement in November 2021, whereby funds managed by Blackstone agreed to provide up to US$250 million in equity and product financing to support Autolus’ advancement of obe-cel, its CD19 CAR T cell investigational therapy product candidate, as well as next generation product candidates of obe-cel in B-cell malignancies.

Autolus also announced underwritten public offering in the USA of 75,000,000 American Depositary Shares (ADSs) representing 75,000,000 ordinary shares at a public offering price of US$2.00 per ADS, for total gross proceeds of US$150.0 million [38,39]. All ADSs sold in the offering were offered by Autolus. In addition, Autolus has granted the underwriters a 30 day option to purchase up to an additional 11,250,000 ADSs at the public offering price, less underwriting discounts and commissions. The underwriters have partially exercised their option to purchase an additional 6,927,102 ADSs, at a price per ADS of US$2.00, resulting in additional gross proceeds to Autolus of approximately US$13.9 million [40]. After giving effect to the issuance of these additional shares, Autolus has sold a total of 81,927,102 ADSs in the offering for aggregate gross proceeds of approximately US$163.9 million.

Calidi biotherapeutics

Calidi Biotherapeutics (CA, USA; https://calidibio.com), a clinical-stage biotechnology company that is pioneering allogeneic stem cell-based platforms to revolutionize oncolytic virus immunotherapies, has announced that the California Institute for Regenerative Medicine (CIRM; www.cirm.ca.gov) has awarded the company a US$3.1 million grant to support continued development of the company’s Supernova-1 (SNV1) pre-clinical program through IND application [41]. In addition, CIRM has awarded City of Hope (CA, USA; www.cityofhope.org) a US$12 million grant to fund a Phase I physician sponsored clinical trial evaluating Calidi’s licensed oncolytic virotherapy NeuroNova platform in patients with recurrent high-grade glioma, a form of advanced brain cancer.

SNV1 is composed of allogeneic, adipose derived mesenchymal stromal/stem cells loaded with the oncolytic vaccinia virus Cal1, targeting a variety of solid tumors including metastatic/unresectable melanoma, triple negative breast cancer and advanced head and neck squamous cell carcinoma.

Gamida cell

Gamida Cell (Israel; www.gamida-cell.com), a company developing nicotinamide enabled cell therapies for patients with hematologic and solid cancers and other serious diseases, announced the closing of a senior secured convertible term loan of US$25 million [42]. The proceeds from the term loan, together with the net proceeds from Gamida Cell’s US$20 million public offering of ordinary shares announced in September 2022 and its existing cash and cash equivalents and trading financial assets, are expected to: fund commercial readiness and initial launch activities to support launch of their product omidubicel, if approved; fund the continued development of its NK product pipeline, including clinical stage asset GDA-201; and be used for general corporate purposes, including general and administrative expenses and working capital.

SonoThera

SonoThera™ (CA, USA; www.sonothera.com), a biotechnology company dedicated to treating the root cause of human diseases through genetic therapy, has completed a US$60.75 million Series A financing round [43]. The financing will support the continued development of SonoThera’s ultrasound guided, nonviral, gene therapy platform and treatments, designed to provide patients with genetic medicines. SonoThera’s ultrasound-guided platform uses sonoporation, a microbubble mediated biophysical process to non-invasively deliver genetic payloads of diverse formats and sizes, selectively targeting a wide range of organs within the body. Unlike traditional gene therapies, the technology does not require viral vectors which can be immunogenic and lead to both safety and efficacy challenges.