2018 Volume 66 Issue 3 Pages 217-224
Despite the critical need for lifelong treatment of inherited and genetic diseases, there are no developmental efforts for most such diseases due to their rarity. Recent progress in gene therapy, including the approvals of two products (Glybera and Strimvelis) that may provide patients with sustained effects, has shed light on the development of gene therapy products. Most gene therapy products are based on either adeno-associated virus-mediated in vivo gene transfer to target tissues or administration of ex vivo gene-transduced hematopoietic cells. In such circumstances, there is room for different approaches to provide clinicians with other therapeutic options through a variety of principles based on studies not only to gain an understanding of the pathological mechanisms of diseases, but also to understand the physiological functions of target tissues and cells. In this review, we summarize recent progress in gene therapy-mediated enzyme replacement and introduce a different approach using adipocytes to enable lifelong treatment for intractable plasma protein deficiencies.
Many patients with genetic and acquired disorders caused by plasma protein (enzyme) deficiencies are currently treated with enzyme (protein or factor) replacement if such therapeutic enzymes (proteins) are available for clinical use. For example, insulin, coagulation factors, and some lysosome enzyme agents, which are the defective proteins in those life-threatening clinical settings, have been developed as native or recombinant proteins. Although those protein products have been proven to be effective in the treatment of target diseases, several concerns remain. One is sheer medical cost. The expense is mainly due to the production process and instability of the products. Another concern is decreased QOL among patients because protracted, continued treatment via repeated administration is required. Although long-acting protein products have been developed, repeated administration is still inevitable. An additional concern is that recombinant protein products are not available for all rare inherited diseases.
In enzyme replacement therapy (ERT) using protein products, repeated injections result in violent fluctuations of plasma concentrations of the products between the therapeutic and subtherapeutic levels (Fig. 1) in patients. The plasma concentration may reach the subtoxic range after high-dose bolus injection. The marked, repeated fluctuations in plasma protein concentrations between injection intervals may affect the metabolic pathways of organs/cells, leading to deleterious effects in patients. To resolve these problems, gene therapy1–3) is the most attractive treatment option in such diseases through sustained, hopefully lifelong, supplementation with the therapeutic proteins. After treatment with gene therapy, the therapeutic genes are expressed and gene products secreted through the administration of a viral vector (in vivo gene therapy) or therapeutic gene-transduced cells (ex vivo gene therapy), which meet the need to achieve continuous effective plasma concentrations (Fig. 1). This review focuses on and discusses current attempts to develop enzyme or protein replacement through gene therapy in genetic inherited diseases.
Changes in plasma concentrations of therapeutic proteins after bolus administration and in gene therapy are illustrated. Violent fluctuations in the concentration occur after bolus injection and may reach subtoxic concentrations depending on the characteristics of the protein. In contrast, stable therapeutic concentrations can potentially be achieved after a single administration in gene therapy.
The most impressive outcomes of gene therapy have been reported in patients with immunodeficiencies as a result of monogenic disorders, including adenosine deaminase deficiency-severe combined immunodeficiency (ADA-SCID),4,5) γc chain deficiency (X-SCID),6,7) X-linked chronic granulomatous diseases (X-CGD),8) and Wiskott–Aldrich syndrome (WAS).9,10) Among these diseases, some patients who were administered with γ-retroviral vector-mediated therapeutic gene-transduced hematopoietic cells developed leukemia in X-SCID11) and WAS12,13) and developed myelodysplasia in X-CGD14,15) associated with clonal expansion of cells with vector integration. On the other hand, no events indicative of myelodysplasia or leukemic transformation were reported in gene therapy of ADA-SCID patients.5) Although those observations emphasized the need to address potential risk and safety concerns with the use of retroviral vectors, the gene therapy trials showed clinical benefits with restoration of the immune system in treated children, which are encouraging researchers to seek safer viral vectors. In 2016, a γ-retrovirus-mediated ex vivo gene therapy for ADA-SCID (Strimvelis, GlaxoSmithKline) was approved in Europe.16)
Among immunodeficiency syndromes, ADA-SCID patients may be treated by enzyme replacement therapy with polyethylene-glycol-modified bovine ADA (PEG-ADA),17) which is available in some countries. The treatment improves immune function and decreases the incidence of severe infection. PEG-ADA-treated patients showed an increase in B lymphocyte counts, followed by enhancement of T lymphocyte function. However, the majority showed a decrease in total lymphocytes and circulating T cells after a few years.18)
Hemophilia is an X-linked bleeding disorder that occurs in approximately 1 in 5000 male births, which is caused by mutations in blood clotting factor VIII (FVIII, for hemophilia A) or factor IX (FIX, for hemophilia B). The absence or reduction of FVIII or FIX impairs coagulation cascades and leads to frequent spontaneous bleeding in patients with clotting activities less than 1% of normal. Without treatment, bleeding events may become life threatening. These pathologic conditions can be treated with plasma-derived or recombinant factors, with significant improvement in morbidity and mortality. However, patients need frequent (two or three times weekly) administration of those factors to maintain minimal therapeutic levels, which is highly invasive. Furthermore, it is difficult to administer such treatments in the majority of patients. Therefore, hemophilia is one of most typical clinical conditions3,19–21) for which gene therapy-mediated ERTs are desirable, since there is no need for regulated gene expression and relatively low plasma concentration levels are sufficient to show clinical benefits.
Under these circumstances, a therapeutic approach using gene therapy is being developed as a long-lasting treatment and even cure for hemophilia. Adeno-associated virus (AAV)-mediated FIX gene delivery in recent clinical trials has targeted the liver, the natural site for FIX production. Recombinant AAV2 was utilized via hepatic artery injection in severe hemophilia B patients.22) However, FIX expression was eventually lost due to the cytotoxic T cell response.21,23,24) To resolve the problem, serotype AAV8 has been a research focus, and FIX-expressing AAV8-pseudotyped AAV was utilized in clinical trials.25,26) Plasma FIX levels were measurable in all participants and were sustained for multiple years, thus reducing requirements for FIX infusions. Some patients showed a mild increase in transaminase levels, which was resolved by prednisolone administration with no recurrence of the increase. A clinical trial using AAV8 harboring FIX-Padua,27) a naturally occurring hyperactive FIX variant, was started. Although one patient receiving a mid-range dose has shown sustained FIX expression (20–25% of normal), which appears curative,3,28) participants treated with the highest dose exhibited transaminitis, a T cell response to viral capsid antigen, and lost FIX expression. Although the immune response against viral capsid antigen is the main obstacle to be overcome, current AAV technology is promising to achieve stable therapeutic and even curative levels of FIX. Treatment for hemophilia A is also under development. The main hurdle has been the large coding sequence of FVIII, which now seems to have been overcome by means of deleting the B-domain dispensable for FVIII function and/or replacing the B-domain with a small linker sequence for efficient secretion.3,20,21)
Lysosomal storage diseases (LSDs) are a group of more than 50 inborn errors of metabolism caused by a deficiency of one of the lysosomal enzymes or impairments in the lysosomal transport system. Lysosomes are catabolic organelles that degrade and recycle a range of complex substrates, including glycosaminoglycans, sphingolipids, glycogen, and proteins, through the actions of a variety of lysosomal enzymes. Impaired functions of the enzymes result in the accumulation of substrates and subsequent cellular and organ dysfunctions. The clinical consequence varies among the diseases depending on the enzymes affected.
The development of treatments for LSD patients was drastically changed from symptomatic treatment after the highly successful introduction of ERT for Gaucher disease in the early 1990 s.29,30) This approach has been extended to several other LSDs, including Fabry disease, Pompe disease, various forms of mucopolysaccharidosis, and lysosomal acid lipase deficiency. However, the treatment of a single LSD patient may cost as much as several hundred thousand U.S. dollars per year, which may limit patients’ access to the therapy and affect national healthcare expenditure. These approaches are intended to increase the activity of the defective enzymes. Therefore, long-acting ERTs using more stable systems such as hematopoietic stem cell transplantation or gene therapy should be developed to meet patient needs.31,32)
In addition, most LSDs affect the nervous system and lead to physical and neurological disabilities, which impact patient life expectancy. Gene therapy is now considered as potential treatment not only for LSDs with severe neurological complications but also neurological diseases such as amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease.33–35) In clinical trials, in addition to enzymes affected in those LSDs, several secreted neurotrophic factors such as nerve growth factor, neurturin, and glial cell-derived neurotrophic factor have been utilized as candidate therapeutic proteins through in vivo and ex vivo gene delivery (Table 1).
| Protein | Indication |
|---|---|
| Acid-alpha glycosidase (GAA) | Pompe disease |
| Adenosine deaminase (ADA) | Adenosine deaminase deficiency |
| Alpha and beta human hexosaminidase | Tay-Sachs disease |
| Alpha-1 antitrypsin (ATA) | Alpha-1 antitrypsin deficiency |
| Cystic fibrosis | |
| Alpha-galactosidase | Fabry disease |
| Alpha-L-iduronidase (IDUA) | Mucopolysaccharidosis I (Hurler syndrome) |
| Angiopoietin-1 (Ang-1) | Critical limb ischemia |
| Peripheral artery disease | |
| Arylsulfatase A | Metachromatic leukodystrophy |
| Beta-D-glucuronidase | Mucopolysaccharidosis VII |
| Brain-derived neurotrophic factor (BDNF) | Obesity with MC4R function-altering mutations or Prader–Willi syndrome |
| Huntingdon disease | |
| Cathepsin A | Galactosialidosis |
| Certolizumab | Ulcerative colitis |
| Ciliary neurotrophic factor (CNTF) | Achromatopsia |
| Amyotrophic lateral sclerosis | |
| Huntingdon disease | |
| Macular degeneration | |
| Macular telangiectasia type 2 | |
| Retinitis pigmentosa | |
| CLN2 (tripeptidyl peptidase) | Late infantile neuronal ceroid lipofuscinoses |
| Collagen type 7 A1 (COL7A1) | Recessive dystrophic epidermolysis bullosa |
| Erythropoietin (EPO) | Chronic kidney disease with anemia |
| Factor IX | Hemophilia B |
| Factor VIII | Hemophilia A |
| Fibroblast growth factor (FGF) | Coronary artery disease |
| Critical limb ischemia | |
| Intermittent claudication | |
| Ischemic heart disease | |
| Peripheral artery disease | |
| Severe peripheral artery occlusive disease | |
| Stable angina pectoris | |
| Stable exertional angina | |
| Follistatin | Becker muscular dystrophy, sporadic inclusion Body myositis |
| Duchenne muscular dystrophy | |
| Glial cell-derived neurotrophic factor (GDNF) | Amyotrophic lateral sclerosis |
| Parkinson’s disease | |
| Glucocerebrosidase (GC) | Gaucher disease |
| Hepatocyte growth factor (HGF) | Coronary artery disease, atherosclerosis, myocardial ischemia |
| Critical limb ischemia | |
| Ischemic heart disease | |
| Peripheral arterial disease | |
| Iduronate-2-Sulfatase (IDS) | Mucopolysaccharidosis II (Hunter disease) |
| Insulin-like growth factor-1 (IGF-1) | Cubital tunnel syndrome |
| Interleukin-2 (IL-2) | SCID |
| Interleukin-4 (IL-4) | Severe inflammatory disease of the rectum |
| Interleukin-10 (IL-10) | Ulcerative colitis |
| Severe inflammatory disease of the rectum | |
| Laminin 5-beta3 | Inherited autosomal recessive/junctional epidermolysis bullosa |
| Lecithin-cholesterol acyltransferase | LCAT deficiency |
| Lipoprotein lipase | Lipoprotein lipase deficiency |
| N-Acetyl-alpha-glucosaminidase (NAGLU) | Mucopolysaccharidosis IIIB (Sanfilippo B syndrome) |
| Nerve growth factor (NGF) | Alzheimer’s disease |
| Neuropeptide Y (NPY) | Epilepsy |
| Neurturin (NTN) | Parkinson’s disease |
| N-Sulfoglucosamine sulfohydrolase (SGSH) | Mucopolysaccharidosis IIIA (Sanfilippo A syndrome) |
| Sulfatase modifying factor 1 (SUMF1) | Mucopolysaccharidosis IIIA (Sanfilippo A syndrome) |
| Pigment epithelium-derived factor (PEDF) | Retinitis pigmentosa |
| Platelet-derived growth factor (PDGF) | Age-related macular degeneration |
| Coronary artery disease | |
| Venous leg ulcer | |
| Proenkephalin | Intractable pain |
| Retinoschisin | X-linked retinoschisis |
| Serine peptidase inhibitor, Kazal type 5 (SPINK5) | Netherton syndrome |
| Soluble Flt-1 receptor (sFLT-1) | Macular degeneration |
| Stromal cell-derived factor (SDF-1) | Heart failure |
| Peripheral artery disease | |
| Wound healing, advanced peripheral artery disease, infrapopliteal lesions | |
| Transforming growth factor-beta1 (TGF-beta1) | Degenerative arthritis |
| Vascular endothelial growth factor (VEGF) | Chronic critical leg ischemia |
| Congestive heart failure | |
| Coronary artery disease | |
| Critical limb ischemia | |
| Diabetic peripheral neuropathy | |
| End-stage renal disease (stenosis prevention) | |
| Ischemic heart disease | |
| Ischemic lower limb | |
| Myocardial ischemia | |
| Peripheral artery disease | |
| Peripheral neuropathy | |
| Peripheral vascular disease | |
| Raynaud disease caused by systemic scleroderma | |
| Refractory angina pectoris | |
| Restenosis (accelerated endothelialization and reduced neointimal thickening) |
Secreted proteins investigated in gene therapy clinical trials for the treatment of monogenic, ocular, neurological, cardiovascular, and inflammatory diseases are summarized with the target pathological conditions, according to Gene Therapy Clinical Trials Worldwide provided by the Journal of Gene Medicine (http://www.abedia.com/wiley/).
Degenerative retinal diseases such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), and age-related macular degeneration cause incurable blindness. Early work in gene therapy for ophthalmologic diseases targeted inherited monogenic diseases such as LCA, since the gene mutations responsible such as the mutation of the RPE65 protein had been identified so that the underlying pathological mechanisms were elucidated. LCA type 2 was the first retinal disease treated with AAV-mediated gene therapy in clinical trials,36–38) and the successful results encouraged researchers to develop broader applications not only for inherited retinal diseases but also for other general degenerative retinal diseases.3,39,40)
Although the clinical trial data are promising, some issues must be resolved.39,41) The retinal pigment epithelium, which is affected in LCA, is susceptible to AAV-mediated gene transduction. In contrast, pathological conditions in most inherited retinal degenerative disorders are caused by gene mutations of photoreceptor-specific proteins, causing the primary death of these cells with very rapid onset.41) Despite great efforts to increase the efficiency by AAV-mediated rhodopsin gene transduction, the effect was not long lasting, suggesting that the expression of rhodopsin was still not sufficient to block the progression of retinal degeneration completely in a mouse model of RP.42,43) Therefore, long-term efficacy may be achieved through a combined approach targeting both the gene defect and affected cellular signaling pathway. Although it is still necessary to elucidate the precise mechanisms underlying the disease pathology, there must be room for various possibilities, including that secreted proteins function to inhibit the apoptosis of photoreceptors.
Gene therapy, which transfers additional functional gene copies, has been considered and under initial development for decades to treat monogenic disorders. The therapeutic gene products are intended to function either inside or outside cells, the natural locations of the proteins. For example, in X-SCID gene therapy, the introduced γc gene product must function inside the transduced cells, and only then do the cells mature into T cells. On the other hand, it is possible to supply therapeutic proteins that function in plasma from outside cells to treat most of the clinical conditions described above. Lysosomal enzymes have a mannose-6-phosphate moiety and can enter cells to function through its receptor pathway, and LSDs have been recognized as clinically important targets for ERTs. Therefore, most plasma protein deficiencies and LSDs are candidates for gene therapy-mediated lifelong ERTs. Candidates for therapeutic proteins evaluated in gene therapy clinical trials are summarized with their target diseases in Table 1. In designing therapeutic approaches to the treatment of clinical conditions that require the supplementation of therapeutic proteins, various choices for target cells and tissues are available as long as the protein is secreted from the target cells. In addition, both in vivo and ex vivo strategies are possible avenues.
In the former strategy, although recent advances in AAV-mediated gene delivery have shown remarkable progress, gene transduction efficiency may be affected by the susceptibility of target tissues and cell types to the vector as well as possible preexisting neutralizing antibody against AAV in individual patients. In the latter strategy, such unexpected effects can be minimized by preparing the recipient cells in vitro, and gene transduction efficiency is controllable and checked prior to administration. Thus, it is necessary to develop cell manipulation strategies to transduce therapeutic genes efficiently and express their products stably to circulate in plasma.
In the field of lipoprotein metabolism, three different diseases have been targeted for the development of gene therapy. Hepatocyte-targeted retroviral vector-mediated ex vivo low-density lipoprotein (LDL) receptor gene transduction to treat familial hypercholesterolemia was performed in early clinical trials.44,45) However, the clinical benefits were not sufficient considering the invasiveness of hepatectomy for the preparation of target hepatocytes and ineffective cell engraftment.46) The therapeutic approach has shifted to AAV-mediated in vivo methodology.47) Whereas the LDL receptor is not a secreted protein, the subsequent two clinical conditions for which the gene therapy approach has been applied are caused by plasma protein deficiency.
Lipoprotein lipase deficiency (LPLD) is a rare recessive disorder, characterized by severe hypertriglyceridemia, chylomicronemia, and risk of recurrent and potentially fatal pancreatitis. AAV1 expressing the hyperfunctional LPL variant (S447X)48) was utilized for the development of in vivo gene therapy49–53) and was the first gene therapy product approved by the European Medicines Agency (Glybera, uniQure).54) In October 2012, the European Commission granted marketing authorization for Glybera under exceptional circumstances as a treatment for adult patients diagnosed with LPLD. However, in April 2017, uniQure announced that it was not pursuing renewal of the gene therapy product marketing authorization in Europe which was scheduled to expire on October 25, 2017.55)
Lecithin : cholesterol acyltransferase (LCAT) deficiency56,57) is also a rare recessive disorder characterized by low high-density lipoprotein (HDL)-cholesterol levels and markedly reduced cholesteryl ester in lipoproteins. Patients often develop severe complications such as corneal opacity, anemia, and proteinuria, which are suggested to be caused by abnormal lipid deposition. Proteinuria often progresses to renal failure, which determines the poor prognosis of patients. A clinical trial of recombinant LCAT enzyme replacement has recently been reported in a patient with familial LCAT deficiency.58) Bolus injection of recombinant LCAT resulted in transient normalization of plasma lipids, and clinical parameters related to anemia and renal function improved. The peak plasma concentration of LCAT reached around 30 to 40 µg/mL in the patient with the highest dose (9.0 mg/kg), which is 6- to 8-fold higher than that in healthy individuals. In contrast, long-lasting LCAT replacement via gene therapy has been developed using both in vivo59) and ex vivo60) methodologies, and a clinical trial of ex vivo retroviral vector-mediated gene therapy using adipocytes as target cells has been in development in Japan.
Previous efforts to develop ex vivo gene therapy using nonhematopoietic cell lineages as target cells showed no obvious clinical benefits in clinical trials in diseases like hemophilia.61–63) Therefore, a novel protein-secreting factory system utilizing different cell types would provide another therapeutic approach to the field of gene therapy-mediated ERTs. In the development of novel gene-transfer/transplantation strategies, concepts that would allow target cells to reside and survive at transplanted sites have been considered. Clinical experience has demonstrated that aspirated fat is a suitable autologous tissue transplantation source for the correction of tissue defects in plastic and reconstructive surgery with minimal risk.64–66) Adipose tissue is well vascularized and reported to be an important endocrine and secretory organ,67–70) which may provide a cell-based gene therapy with efficient systemic delivery of therapeutic proteins71) (Fig. 2). It was reported that approximately 10% of fat cells are renewed annually,72) indicating that they have a relatively long lifespan of approximately 10 years. In the development of ex vivo gene therapy, a critical issue is the risk of oncogenic transformation of ex vivo gene-transduced cells by a genome-integrating viral vector, as reported in certain immune deficiencies.11–15) Adipogenic potential has been demonstrated to suppress tumorigenic activity of ink4a knock-out mesenchymal stem cells.73) Considering the risk of genotoxicity, cells with more adipogenic potential would be safer vehicles for ex vivo gene therapy applications. For further risk management, it was shown that transplanted ex vivo-manipulated adipocytes can be easily excised,74) suggesting that the occurrence of unexpected or abnormal side effects in transplanted patients or cells could be avoided.
The therapeutic strategy for adipocyte-based enzyme replacement therapy utilizing ex vivo gene transfer is depicted. Adipose tissue is obtained by lipoaspiration from patients. ccdPAs are propagated in ceiling culture, followed by therapeutic gene transduction. ccdPAs stably secreting therapeutic proteins are expanded and harvested. The harvested cells are subcutaneously transplanted with the appropriate scaffold. In this strategy, the transplanted cells reside and eventually differentiate into mature adipocytes at the transplantation sites.
Two sources for cell preparations have been reported using collagenase-digested fat tissue. One is the stromal vascular fraction (SVF), which is obtained as a sediment after centrifugation of collagenase-digested adipose tissue.75,76) Adherent cells from the SVF are now recognized to be adipose tissue-derived mesenchymal stem cells (ASCs), which can differentiate into multiple lineages, suggesting their suitability for stem cell-based regenerative therapy.77) The heterogeneity of the cell preparations, however, might not be suitable for stable gene-transfer applications. The other cell source is the floating mature adipocyte fraction after centrifugation. Thus, ceiling culture78,79) using the buoyant properties of mature adipocytes enabled us to prepare more homogeneous cells, designated as ceiling culture-derived proliferative adipocytes (ccdPAs).60) ccdPAs showed trace levels of the mature adipocyte surface marker CD36 after preparation. Furthermore, ccdPAs showed increased lipid droplet accumulation with higher adipogenic marker gene expression in comparison with ASCs upon stimulation to induce differentiation.80) These observations suggest that ccdPAs meet the requirements for establishing a novel cell factory system through stable engraftment as therapeutic protein-secreting mature adipocytes.
ccdPAs were shown to be efficient vehicles for γ-retroviral vector-mediated gene transduction. Human lcat gene-transduced ccdPAs secreted functional LCAT protein in vitro, correlated with the copy number of the transduced gene.60) The secreted LCAT protein clearly ameliorated the disturbed HDL profile81) and abnormal LDL profile82) in patient serum caused by LCAT dysfunction as shown in in vitro incubation experiments, suggesting its feasibility as a therapeutic strategy.
To achieve clinical efficacies using ex vivo-prepared cell-based transplantation therapy, it is important to select suitable scaffolds that allow the target cells to survive, mature, and secrete therapeutic proteins at transplantation sites. Fibrin gel, clinically available as a tissue sealant, has been evaluated as a scaffold for the transplantation of ccdPAs. ccdPAs showed spontaneous accumulation of lipid droplets without any artificial stimulation in an in vitro three-dimensional culture system using fibrin gel.83) lcat gene-transduced murine ccdPAs were transplanted into mice with fibrin gel, which demonstrated that the gel increased cell survival and LCAT secretion through inhibition of the apoptosis of transplanted cells.84) In the above-mentioned in vitro evaluation, lcat gene expression was correlated with cell differentiation,83) suggesting that LCAT secretion would increase upon maturation of the transplanted ccdPAs into adipocytes after transplantation.
Therapeutic approaches based on gene therapy have been evaluated in different types of diseases. The clinically promising results may offer the hope of treating or even curing patients. Regardless of researchers’ strenuous efforts, potential treatment strategies have been suggested for a very limited number of diseases. There are several different approaches to developing treatments for diseases in which ERTs are applicable. First, in vivo AAV-mediated gene transfer to target tissue is now the focus of most clinical trials in this area, which manipulates the target tissue or organ to secrete therapeutic proteins. In addition, recent progress has also indicated several possible means to escape from the host immune response against AAV,85) the main obstacle to AAV-based gene therapy. Although this approach is now being taken in many clinical development efforts, there were reports of AAV vector integration into animal model genomes with subsequent genotoxicities.86,87) In addition, AAV genome sequences have been found in human hepatocellular carcinoma samples near known cancer driver genes, although at a low frequency.88)
A second approach is ex vivo gene therapy using genome-integrating viral vectors, which can target any type of cells if they secrete sufficient levels of therapeutic proteins for treatment. Most approaches target hematopoietic cells that circulate in blood, since other cell types do not serve as efficient targets. Thus, therapeutic genes should be transduced into stem cell lineages to maintain their efficacy due to the relatively short life span of blood cells. In this approach, if unexpected side effects such as leukemia occur, it is not easy to remove the abnormal cells completely. Considering these limited choices of therapeutic strategies, there is a critical need for the development of different approaches providing various options to researchers/patients. Adipocyte-based ex vivo gene therapy-mediated ERTs are another potential therapeutic option, in which gene-transduced cells reside at transplanted sites to provide a continuous supply of therapeutic proteins. Evaluation of the first clinical trial with autotransplantation of lcat gene-transduced ccdPAs in patients with LCAT deficiency has only started recently. Hopefully, this novel adipocyte-based strategy will provide opportunities to develop a new field of ex vivo gene therapy-mediated lifelong ERTs.
The authors thank our collaborators whose names appear in the references. The FIH clinical trial in the LCAT deficiency syndrome is currently supported by a research grant from the Japan Agency for Medical Research and Development (AMED, grant number 17im0110606h0004).
This review summarizes the results of joint research collaborations between Chiba University (MK, YS, and KY) and CellGenTech, Inc. (MA), where MK and KY are supported in part by research funding from CellGenTech, Inc.
