Category Archives: Gene therapy

Atsena Therapeutics

ATSN-101 demonstrated clinically meaningful improvements in vision with no drug-related serious adverse events

Data presented at the American Academy of Ophthalmology 2022 Annual Meeting

DURHAM, N.C., Oct. 03, 2022 (GLOBE NEWSWIRE) -- Atsena Therapeutics, a clinical-stage gene therapy company focused on bringing the life-changing power of genetic medicine to reverse or prevent blindness, announced positive results from the Phase I/II clinical trial of ATSN-101, its lead investigational gene therapy product formerly known as SAR439483, for the treatment ofGUCY2D-associated Leber congenital amaurosis (LCA1).

The data demonstrated that subretinal delivery of ATSN-101 was well tolerated and patients treated with the highest dose (1.0E11 vg/eye) saw clinically meaningful improvements in vision, as measured by full-field stimulus testing (FST) and multi-luminance mobility testing (MLMT), at more than one-month post treatment.

As of the July 25, 2022, data cut-off date, 15 patients, including three pediatric patients, were treated with ascending doses of ATSN-101. Patients treated with the highest dose (N=9) demonstrated a significantly larger mean change from baseline in retinal sensitivity and a trend toward a larger mean change in best-corrected visual acuity (BCVA) in treated eyes as compared with untreated eyes. In addition, three of four patients tested on MLMT demonstrated at least two-level improvement from baseline light levels. No drug-related serious adverse events were reported, and most treatment-emergent adverse events were mild and transient.

Patients with LCA1 have profound visual impairment or blindness at birth, but their retinal structure remains intact, which indicates an opportunity to confer meaningful improvements following delivery of a subretinal gene therapy such as ATSN-101, said Kenji Fujita, MD, Chief Medical Officer of Atsena Therapeutics. Were encouraged by these data that demonstrate ATSN-101 improved visual function while maintaining a favorable safety profile. We look forward to launching a pivotal trial for the evaluation of ATSN-101, which will lay the groundwork for successful registration and commercialization. We also look forward to advancing other promising programs in our gene therapy pipeline to reverse or prevent blindness for people with inherited retinal diseases.

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The data were presented on Saturday, Oct. 1, in a Late Breaking Developments session during the Retina Subspecialty Day at the American Academy of Ophthalmology Annual Meeting (AAO 2022) in Chicago, by Christine Nichols Kay, MD, Clinical Ophthalmology Advisor for Atsena.

About GUCY2D-associated Leber congenital amaurosis (LCA1)LCA1 is a monogenic eye disease that disrupts the function of the retina. It is caused by mutations in the GUCY2D gene and results in early and severe vision impairment or blindness. GUCY2D-LCA1 is one of the most common forms of LCA, affecting roughly 20 percent of patients who live with this group of inherited retinal diseases. There are currently no approved treatments for LCA1.

About Atsena TherapeuticsAtsena Therapeutics is a clinical-stage gene therapy company developing novel treatments for inherited forms of blindness. The companys ongoing Phase I/II clinical trial is evaluating a potential therapy for a form of LCA, one of the most common causes of blindness in children. Its additional pipeline of leading preclinical assets is powered by an adeno-associated virus (AAV) technology platform tailored to overcome significant hurdles presented by inherited retinal disease, and its unique approach is guided by the specific needs of each patient condition to optimize treatment. Founded by ocular gene therapy pioneers Dr. Shannon Boye and Sanford Boye of the University of Florida, Atsena is based in North Carolinas Research Triangle, an environment rich in gene therapy expertise. For more information, please visitatsenatx.com.

Media Contact:Tony Plohoros6 Degrees(908) 591-2839tplohoros@6degreespr.com

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Atsena Therapeutics Announces Positive Results from Phase I/II Clinical Trial of ATSN-101 for the Treatment of GUCY2D-associated Leber Congenital...

Gene therapy is a novel therapeutic approach to managing various inherited and acquired diseases. Gene therapy has already successfully managed (i) inherited diseases such as Leber's congenital amaurosis (LCA), X-linked severe immunodeficiency disease, beta thalassemia, hemophilia, and chronic granulomatous disease; and (ii) acquired diseases such as multiple myeloma, B-cell lymphoma, advanced melanoma, prostate cancer, and many others [1]. The eye is an ideal organ for gene therapy. This is attributed to the fact that it is small, easily accessible, and isolated; it has a blood-retinal barrier; and the other eye can act as a control. It requires a lower dose of vectors. There is little to no chance of systemic infection using viral vectors [2]. Gene therapy can be either ex vivo or in vivo. Ex-vivo gene therapy is when the host cells are collected, cultured, genetically modified, and transplanted back into the host. In vivo means when the genetically modified information is transferred to targeted host cells via viral or non-viral vectors [3]. The viral vectors use the inherent property of viruses to infect the host cell's genomes. The pathological genetic sequence is replaced by the therapeutic genes, which can produce the desired therapeutic effect.

The non-viral vectors transfer either DNA plasmids or small DNA and RNA molecules by physical or chemical methods. Physical methods include electroporation, sonoporation, hydroboration, needles, and DNA ballistics. The chemical methods include using vectors like inorganic particles, lipids, polymers or peptide particles [4]. Ocular gene therapies can be used for various inherited retinal diseases like Lebers congenital amaurosis, X-linked retinitis pigmentosa (RP), choroideremia, X-linked retinoschisis, Stargardt disease, and Usher syndrome, which are discussed in this review [3]. Various clinical trials for corneal gene therapy are also being done for corneal dystrophies, herpes simplex virus keratitis, Sjogren syndrome, and others [5]. Ocular gene therapy is not only used for inherited diseases but also acquired diseases like glaucoma. Few clinical trials have been conducted for glaucoma where the therapeutic gene, i.e., siRNA, antagonizes adrenergic receptor synthesis to lower the intraocular pressure [6]. Even if much progress has been made in ocular gene therapy, there are several challenges that we have yet to overcome. This includes uncertainty about the longevity and irreversibility of the therapy. Other challenges include gene therapy complications like ocular inflammation, insertional oncogenesis, or therapeutic failure.

Gene Replacement/Gene Augmentation

Gene augmentation is most commonly used for autosomal recessive disorders. In these disorders, a defect or absence of a single copy of the gene leads to loss-of-function mutation and thus to an inadequate amount of protein synthesis. In gene augmentation, the abnormal copy of the gene is replaced by the normal copy of the gene via therapeutic vectors. This therapeutic gene can be transferred either as mRNA or as a DNA copy [7]. DNA needs to be injected directly into the nucleus of the cells. It also increases sustained production of the protein, hence it is preferred. The complications of using mRNA include instability of the mRNA molecule due to changes in sequence within it and the induction of immune responses. The disadvantage of gene augmentation is that it cannot be used in an already degenerated retina. This technique has been successfully used for Food and Drug Administration (FDA) approved Phase 3 trial of Luxturna, a gene product used to treat Leber's congenital amaurosis targeting gene RPE65. The RPE65 gene encodes for retinoid isomerohydrolase, an enzyme of the visual cycle synthesized by the retinal pigment epithelium (RPE) [7,8].

Gene Silencing/Gene Editing

This mechanism is used for autosomal dominant inherited diseases. Here, the mutation is a gain-of-function mutation. The disease occurs due to the expression of undesired proteins or gene products of the mutated gene. The aim is to prevent the mutated gene from expressing and encoding the undesired protein. This can either be allele-specific or non-specific. In allele-specific, only the mutated allele is targeted. In allele non-specific, both the mutated and the functional allele are silenced and, by gene augmentation, replaced with the normal gene. It can be done at three levels of the genetic machinery: (1) DNA, (2) RNA, and (3) transcription [3].

CRISPR/Cas9

CRISPR are clustered regularly interspaced short palindromic repeats of prokaryotic DNA. The virus genome follows each repetitive sequence from a previous infection, known as spacer DNA. Cas9 is a CRISPR-associated protein 9 that specifically cuts DNA at these recognizing sites, leading to gene silencing [9]. When used for genome editing, Cas9 endonuclease, along with guide RNA, is injected into the nucleus of target cells. The RNA-guided endonuclease cuts the double-stranded DNA at targeted sites, activating the DNA repair system [3]. This technique has been used therapeutically for autosomal dominant RP [10].

Other DNA-based genome editing techniques are transcription activator-like effector nucleases (TALENs) and zinc finger nucleases (ZFN) [11]. There are ongoing clinical trials to treat acquired immune deficiency syndrome using the ZFNgenome editing technique targeting the C-C chemokine receptor type 5 gene (CCR5 gene) of CD4+T cells (T helper cells). CCR5 is present on the surface of these cells and acts as a coreceptor for the human immunodeficiency virus. In this trial, the CCR5 gene was silenced by genome editing using the ZFN technique[12].

These techniques work either by eliminating mRNA molecules or preventing their translation.

Small Interfering RNA

RNA interference (RNAi) is a post-transcriptional gene silencing technique that uses sequence-specific siRNA to cleave targeted RNA. The RNAi pathway starts with long pieces of dsRNA being cleaved into small interfering RNA by the endoribonuclease dicer enzyme. This step can be skipped by directly administering siRNA into the targeted cell cytoplasm. Once in the cytoplasm, the siRNA gets incorporated into a protein complex called the RNA-induced silencing complex (RISC). The double-stranded siRNA gets cleaved into sense and antisense strands. The antisense strand guides the RISC to the targeted mRNA and cleaves it, preventing gene expression. RNA interference is currently under trial for managing age-related macular degeneration, glaucoma, RP, and diabetic retinopathy [3,13].

Antisense Oligonucleotide

These are complementary strands of the targeted mRNA molecule. It causes the downregulation of gene expression by two mechanisms. An antisense oligonucleotide binds to the targeted mRNA and forms a complex. The mRNA and antisense oligonucleotide complex are cleaved by RNaseH1 activity. The other mechanism acts by translation inhibition, preventing exon splicing, 5'mRNA capping, or destabilizing the RNA. Currently, the antisense oligonucleotide is under trial for ocular gene therapy for Lebers Congenital Amaurosis acting on the gene CEP290. This gene encodes for centrosomal protein 290 [14,15].

Characteristics of the vectors are summarized in Table 1.

Several ongoing clinical trials are conducted by ocular gene therapy ranging from retinal to corneal diseases [20]. Table 2 summarizes a few clinical trials, including completed and ongoing trials, which are discussed further.

LCA is a childhood-onset autosomal recessive disease that leads to vision loss. It occurs due to the mutation of several genes, especially RPE65, encoding for retinoid isomerohydrolase, which is predominantly expressed in the retinal pigmented epithelium. This mutation leads to a deficiency of the enzyme retinoid isomerase, which is responsible for chromophore formation. Chromophore forms visual pigments in photoreceptors of the retina. This leads to visual impairment [18].

The first approved ocular gene therapy by the FDA is the phase 3 trial of Luxturna sub-retinal injection for LCA in both eyes. The gene product was AAV2-hRPE65v2 (voretigene neparvovec-rzyl), and the vector was adeno-associated virus 2 (NCT00999609) [21]. The inclusion criteria consisted of participants being three years or older, being a diagnosed case of LCA with RPE65 mutation, visual acuity of less than 20/60 in both eyes with the best possible correction. The subjects should be evaluated by multi-luminance mobility testing (MLMT). The most important inclusion criteria were the presence of viable retinal cells as determined by optical coherence tomography (OCT). The outcome was measured by MLMT, which is used to measure functional vision changes. The MLMT score ranged from 0 to 6, with six being where the subject was able to pass MLMT with low light intensity. The MLMT score change was a difference between the baseline score and the score measured after a year. The other measures for the trial's outcome were full-field light sensitivity threshold testing and visual acuity. The trial results indicated that the MLMT change score in the interventional group was 1.8 as opposed to the control group, with an MLMT change score of 0.2. This indicated an improvement in functional vision by Voretiegene Neparvovec gene replacement therapy [8].The adverse effect has been described in Table 3.

The only serious complications were convulsions in one participant out of 20 participants with a history of pre-existing seizure disorder and adverse drug reactions in a participant with a history of complicated oral surgery and pre-existing seizure disorder. The gain in visual function has been present for over three years. However, the durability of the intervention is still not determined [8]. Other clinical trials for LCA are mentioned in Table 4.

RP is a group of disorders that cause progressive retinal dystrophy and vision loss. It is one of the most common causes of vision loss. One in every 4000 individuals worldwide is affected by RP. RP can be either autosomal dominant, autosomal recessive, or X-linked. Autosomal recessive is the most common. More than 70 genes are found to be concerned with the development of retinitis pigmentosa [18].

Optogenetic Therapy for Advanced Retinitis Pigmentosa

The clinical trial (NCT03326336) is the most advanced novel ongoing clinical trial for the management of advanced stages of retinitis pigmentosa, combining gene therapy, engineering, and mechanics. It does not target mutated photoreceptors; thus, the mutation is independent. It targets retinal ganglion cells, bypassing the rest of the pathway. The ganglion cells are injected with an optogenetic vector, AAV2.7m8, which encodes for light-sensing proteins CrimsonR and tdTomato. This transgene vector is injected via a single intravitreal injection followed by the use of engineered goggles, GS030MD, that sense light changes in their vicinity and project them into the genetically modified ganglion cells. The objective of this clinical trial was to check the safety of the gene product and the recovery of vision. The clinical trial till now has reported partial vision recovery in one out of 15 participants. The participant, using light-stimulating goggles following gene therapy, could perceive and locate the objects. The therapy was well tolerated, and no intraocular inflammation or other changes were noted. This indicates that optogenetic gene therapy, along with light-stimulating goggles, can be used to partially restore vision in advanced RP [22,23].

Autosomal Dominant Retinitis Pigmentosa

RHO (Rhodopsin) gene was responsible for about 25% of all cases of autosomal dominant retinitis pigmentosa (ADRP). The RHO gene transcribes the RHO protein. RHO protein is the visual pigment present in the rods' outer segments. There are two possible clinical scenarios in ADRP. In class A, there is an early presentation with severe progressive loss of rods. The main aim of the therapy here is to preserve the functions of the cones. In class B, there is a slow progression, and the functions of the rods are well preserved. Here, the main aim of the therapy will be the preservation of the rods. The most common mutation in the RHO gene is the substitution from proline to histidine at the 23rd position (P23H) [10]. The ongoing clinical trial, NCT04123626, targets the P23H mutation of the RHO gene. The gene product used here is QR-1123. It is an antisense oligonucleotide, which is an ssDNA molecule complementary to the targeted P23H mRNA, which increases expression of the wild type of the RHO protein in photoreceptors [24].

MERTK-Associated Retinitis Pigmentosa

One of the other genes involved in the pathogenesis of RP is the MER tyrosine kinase gene (MERTK). The photoreceptors in the retinal epithelium recycle their outer segments. The shed outer segments of the photoreceptors are phagocytized by MERTK [25]. The current clinical trial for MERTK-associated RP (NCT01482195) delivers unilateral subretinal rAAV encoding MERTK protein. This trial aimed to assess the safety of the gene product rAaV2-VMD2-hMERTK. The collected data indicated that three out of six participants showed visual improvement, which lasted for two years in two of these participants. The adverse effects of this clinical trial are summarized in Table 5. Other than these adverse effects, the clinical trial was found to be safe.

Age-related macular degeneration is one of the most common causes of irreversible blindness. It consists of two phases: (1) dry or non-neovascular and (2) wet or neovascular. During the non-neovascular phase, there is atrophy of the retinal cells in patches, called geographic atrophy, leading to loss of central vision. During the neovascular phase, there is the formation of new blood vessels originating from the choroid into the sub-retinal space. These vessels cause leakage of fluid into the subretinal space as they lack tight junctions. The subretinal space is filled with fluid, leading to oedema and reversible vision loss. However, if this fluid build-up continues for several months, it may cause irreversible vision loss [27]. The vascular endothelial growth factor is responsible for the proliferation of new vessels. Hence, the current standard therapy for neovascular macular degeneration is intravitreal drug administration of anti-VEGF agents. However, considering the economic and social burden this therapy puts on because of the repeated intravitreal injections, complications, high drug cost, and repeated imaging, ocular gene therapy for sustained drug delivery have become necessary [28].

The current clinical trials can have two mechanisms: either by the sustained release of anti-angiogenic factors or by gene silencing for factors that cause overexpression of VEGF [29]. The current trials are summarized in Table 6.

Pigment Epithelium-Derived Factor

The first clinical trial for neovascular age-related macular degeneration was conducted by targeting the gene for pigment epithelium-derived factor (PEDF) protein. The NCT number for the clinical trial is NCT00109499 [30]. PEDF is usually present in the eye, acting as an anti-angiogenesis factor. Its levels are altered in neovascular macular degeneration. The transgene was delivered via the intravitreal route as AAV2 expressing PEGF. The adverse effects occurred in 25% of the cohort population and were limited to mild ocular inflammation and a slight increase in intraocular pressure, which were easily manageable. The results of this trial had a dose-related effect. The cohorts receiving the dose of 108 particle units showed no increase in the lesion and a significant decrease in neovascularization. Whereas the cohorts receiving doses less than 108 showed an increase in the size of lesions by one disk area at 12 months. This suggests that this ocular gene transfer is a feasible approach and further studies should be carried out [31].

Aflibercept

Aflibercept is an anti-VEGF factor that acts as a receptor for VEGF-A, VEGF-B, and placental growth factors, preventing neovascularization. Aflibercept is a fusion protein encoded by different genes [29]. The clinical trial (NCT03748784) studied the safety and efficacy of the gene product ADVM-022, responsible for the sustained release of aflibercept. The vector used here is AAV-2, administered by the intravitreous route. After 34 weeks, ADVM-022 was well tolerated. Only mild ocular inflammation was observed and resolved by steroid eye drops. Consistent improvements were seen on OCT, and patients maintained vision throughout [32].

Endostatinand Angiostatin

Endostatin and angiostatin inhibit angiogenesis endogenously. The clinical trial (NCT01301443) is a dose escalation study to determine the safety and efficacy of a lentiviral vector administered subretinally for sustained expression of endostatin and angiostatin [33]. The procedure caused a macular hole in one of the participants. However, it was very well tolerated by others. Eight participants showed sustained expression of angiostatin and endostatin for a period of 2.5 years, whereas two participants showed sustained release for four years [29,34].

sFLT-1

FLT-1 is a receptor gene that endogenously inhibits VEGF-A, preventing angiogenesis. Currently, there are two clinical trials that focus on viral vector-delivered sFLT-1.

The clinical trial (NCT01494805) delivers rAAV.sFlt-1 via the AAV2 vector subretinally, which encodes naturally occurring FLT-1. No particular adverse effects were seen. It was found to be safe and tolerable, especially among the geriatric population, and could help decrease the frequency of anti-VEGF injections. However, no significant improvement in visual acuity or other exploratory points was observed [28,35].

The other clinical trial (NCT01024998) delivered AAV2-sFLT01 via the vector AAV-2 by the intravitreous route. The viral vector encoded a fusion protein of sFLT-1 domain two and the Fc domain of Immunoglobulin G1. It was a dose escalation study, which showed that the gene product was well tolerated at all doses. It was observed that 5 out of 10 participants who were administered higher doses showed a detectable amount of sFLT-1 levels. The participants, who did not express sFLT-1, had an antibody titre of 1:400 against the AAV-2 vector. The clinical trial did not particularly show any improvement in visual acuity or retinal thickness [28,29,36].

One of the major setbacks of ocular gene therapy is inflammation. The eye is considered a site of immune privilege due to varying factors like the retinal-blood barrier. However, the immunogenicity of viral vectors, their capsids, the transgene, and the transgene product as a foreign body can activate immune responses. Various factors affect the severity of the immune response, such as viral vectors used, administration route, and viral dose, including several others [37].

Type of Vector

AV is currently only used for the gene therapy of retinoblastoma as it is highly immunogenic. It causes severe inflammation and destruction of the transduced cell. Being a double-stranded virus, it binds strongly to TLR9 and activates a stronger immune response.

AAV has several serotypes which have different levels of immunogenicity. Most of the population normally has pre-existing antibodies against AAV2, and a small part of the population has antibodies against AAV8. However, cross-reactivity between serotypes is possible. AAVs only generate favourable immune responses, hence they are the preferred vector for ocular gene therapy [37].

LV generates a stronger immune response than an adeno-associated virus but is preferred when more genetic material needs to be transduced [18,38].

Route of Administration

Different routes of delivery expose the vector to different systemic and local biodistribution. The intravitreal route is the most commonly used but shows a higher immune response. This is because the viral particles from the vitreous, through Schlemms canal and reach the systemic circulation and lymphatic flow and can activate an immune response. The subretinal space is relatively immune-privileged and shows a very mild immune response [37].

Viral Dose

According to Timmers et al., the relationship between the viral dose and ocular inflammation depends upon the site of inflammation. In the anterior chamber, the dose escalation did not show any effect. However, in the vitreal chamber, dose escalation showed a greater degree of immune response [39].

The basis of gene therapy is to replace or inactivate a faulty gene or administer a gene product that can prevent the disease process. Ocular gene therapy, in particular, has proven to be a promising tool to treat many inherited retinal diseases like RP, LCA, choroideremia, Stargardt disease, and acquired diseases like nAMD, glaucoma, and diabetic retinopathy. Several clinical trials are being conducted, though in their early stages, have shown promising results. The aim of any clinical trial is to assess the safety and efficacy of the gene product. Something to be concerned about when it comes to the safety of ocular gene therapy is inflammation. There are several factors that affect it such as the vectors used, the route involved, and the dose of the gene product. The subretinal route generates a milder immune response compared to the intravitreal route. AAVs are currently preferred, though newer viral vectors should be considered. As we already know what factors affect it, vectors and delivery methods need to be developed to prevent ocular inflammation. Factors that influence the selection of a vector are immunogenicity, size, the amount of genetic material it can carry and the adverse effects it generates, if any. There are several unanswered questions when it comes to the sustainability of ocular gene therapy. We still do not know how long the effect of gene therapy will last, what factors will affect it and how they can be influenced. Another issue that needs addressing is the long-term adverse effects of gene therapy.

As we have seen in the review, there are several gene targets when it comes to nAMD. A combined approach with several gene targets for such diseases can be developed. A thorough study of the molecular genetics of the disease needs to be done to have a positive outcome in such a case. Though ocular gene therapy has made massive progress in retinal diseases, gene therapy for other ocular diseases like uveitis, corneal graft rejection, and corneal genetic dystrophies needs to be addressed. Ocular gene therapy is an emerging and promising field that can change the trajectory of how ocular diseases will be treated in the future.

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Ocular Gene Therapy: A Literature Review With Focus on Current Clinical Trials - Cureus

Voretigene neparvovec (Luxturna, Spark Therapeutics) is the first causal treatment for biallelic RPE65 mutationassociated retinal disease, which regularly progresses to legal blindness. The one-time gene therapy aims to deliver the correct coding sequence of the human RPE65 gene to the retinal pigment epithelium and is performed via subretinal injection following vitrectomy.

The therapy was approved by both the European Medicines Agency (in 2018) and US Food and Drug Administration (in 2017) after data from the supporting pivotal phase 3 study revealed statistically significant functional vision improvement in patients in terms of increased light sensitivity. The findings also showed improved ability to navigate a mobility course at different levels of environmental illumination.

New gene therapies such as these raise the hope of treating a previously incurable disease with a favorable adverse effect profile. However, as with any new therapeutic product, there are limited real-world data, so it is natural that uncertainties regarding the durability and benefit-risk ratio exist.

Recent reports of retinal atrophy development in the postoperative course of the disease have led to concerns that voretigene neparvovec could lead to potentially devastating consequences in the long-term. It is therefore necessary to closely follow-up treated patients with multimodal imaging approaches in order to assess retinal morphology and gain further knowledge on the factors possibly contributing to atrophy development.

RPE65 mutationassociated disease

The RPE65 gene encodes a key enzyme in the retinoid cycle and is responsible for the regeneration of the light-sensitive component of rhodopsin, our visual purple.1 When light enters the eye, it hits the photoreceptors in the retina leading to a conversion of the light signal into a chemical signal.2

This so-called photoisomerization of the vitamin A derivative 11-cis-retinal (to all-trans-retinal) cannot take place unless there is sufficient functional 11-cis-retinal available. Because 11-cis-retinal decays after initiation of the visual process, it must be perpetually regenerated by specific metabolic processes in the retinal pigment epithelium to initiate and maintain the visual process.3

Mutations in the RPE65 gene result in deficiency or severely functionally impaired isomerohydrolase activity, causing a severe rod-cone dystrophy.4 The clinical courses of RPE65-associated retinal dystrophy are thought to result from different residual activity of the enzyme.

Clinically, the 2 most common forms of RPE65-related retinal disease are Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy. In both forms, visual impairment is first noticed at birth and during the first years of life, respectively, and worsens over time, eventually leading to complete blindness.5

LCA is considered the most severe form of early childhood blindness and was first described by Theodor Leber in 1869.6 Affected infants usually show lack of eye contact and nystagmus and/or present with conspicuous pressing of their eyeballs with fingers, fists, or toys (oculo-digital phenomenon).

Parents may report that their child frequently trips over objects or bumps into obstacles, especially in dim light. Early-onset severe retinal dystrophy that manifests after infancy also has a very poor prognosis and, like LCA, usually leads to blindness in the third to fifth decade of life.

To date, it is known that LCA can be caused not only by alterations in the RPE65 gene, but also by mutations in a further 24 genes (see: https://sph.uth.edu/retnet/sum-dis.htm#A-genes). However, mutations in the RPE65 gene might also manifest in the form of retinopathia pigmentosa (RP20).7

In the subtype of RP20, a noticeable deterioration of visual acuity usually occurs in young adulthood or adolescence while concentric loss of visual field is already advanced.7 Common to all forms of RPE65 mutationassociated retinal disease is a pronounced night blindness, which presents as one of the earliest and most characteristic symptoms of the disease, and a progressive, irreversible retinal degeneration.

The night blindness can be explained by the functional impairment of the rods, which are already affected at the earliest disease stages. Rods, unlike cones, are completely dependent on 11-cis-retinal regeneration through the retinoid cycle of the retinal pigment epithelium. Cones are less affected in early stages of the disease because they can rely on 11-cis-retinal from other sources, such as Mller cells, which explains their better function in early disease stages.8-10

Gene therapy surgery and mechanism of action

Voretigene neparvovec consists of the capsid of an adeno-associated viral vector serotype 2 (AAV2) containing a correct coding sequence (cDNA) of the human RPE65 gene and regulatory elements.11 This is provided in the form of frozen concentrate, which must be prepared into a vector solution by trained personnel.

Subsequently, the therapy is provided in a syringe containing the vector solution that must be applied within 4 hours after preparation. Following vitrectomy, delivery of the vector solution is performed by using a small injection cannula by placing it onto the retina and applying slight pressure to create a retinotomy through which the fluid can pass into the subretinal space (see Figure 1).

The injection may be performed manually with the help of an assisting surgeon or using a foot pedalcontrolled injection device. Patients receive a single dose of 1.5 x 1011 vector genomes of voretigene neparvovec in each eye; the intended target volume is 300 l.

The injection forms 1 or more fluid-filled bubbles under the retina (blebs). These are reabsorbed within 24 to 48 hours after subretinal delivery, as the drug is taken up by the target cells, the retinal pigment epithelium. Uptake into the target cells is receptor mediated.

Once in the nucleus, the single-stranded DNA is transcribed into double-stranded DNA, and the mRNA is subsequently translated in the cytosol into the functional protein, the enzyme isomerohydrolase (illustrated in Figure 2).

Reports of atrophy development following administration

Data from the clinical studies leading to approval of voretigene neparvovec showed that there are certain risks associated with the gene therapy procedure. However, most of the treatment-related adverse events were transient and mild. These included elevated IOP (18%), cataract formation (18%), ocular inflammation (8%), retinal tears (8%), dellen (8%), and retinal deposits (8%).12,13

The previously undescribed complication of chorioretinal atrophy development following treatment with voretigene neparvovec was recently reported by Gange and colleagues.14 Eighteen eyes of 10 patients developed perifoveal chorioretinal atrophy; in 80% of the cases this was seen bilaterally.

Atrophy was first identifiable anywhere between 1 week and 1 year postoperatively at an average of 4.7 months after treatment (follow-up period, 4-18 months). In 10 eyes, the atrophy occurred within and outside the area of the subretinal bleb, whereas in 7 eyes, it formed exclusively within the blebs area.

One eye showed atrophy only outside the bleb area. Despite atrophy development, functional results remained stable or improved in the majority of patients. Twelve of 18 eyes showed improved visual acuity (VA), whereas in 3 of the eyes VA did not change.

VA decreased in a further 3 eyes. After statistical analysis, no significant change in mean VA was found pre- versus postoperatively (P = .45). Although all 13 eyes with reliable Goldmann visual field tests showed improvement (expansion or gain of isopters), paracentral scotomas caused by the atrophy were seen in 3 eyes.

Another recent publication reported progressive atrophy development in 13 eyes of 8 patients.15 All eyes developed atrophy within the bleb area and 3 patients additionally developed atrophic changes outside the bleb.

The mean duration of the patients follow-up period was 15.3 months (range, 6-27). First signs of developing atrophy as detected by reduced autofluorescence were identifiable in 5 of 8 eyes as early as 2 weeks after treatment, which represented the earliest postoperative visit.

At month 3 following therapy, all 13 eyes showed areas of retinal atrophy. Notably, the atrophy area enlarged over time and in 6 of 7 eyes with existing follow-up data after 1 year, atrophy development progressed even after 1 year. Functional improvement shown by increased light sensitivity and perimetry seemed to be overall stable over the observational period despite atrophy development.

What could be the cause of atrophy?

Possible explanations for the development of atrophy include immune reactions against the vector genome (eg, promotor sequence as the CAG promotor in voretigene neparvovec, the expressed transgene, or manufacturing-related impurities) or against the capsid. Manufacturing-related factors could also include subtle deviations in the preparation of the gene therapy shortly before therapy administration at the respective treatment center.

Surgical factors may also play an important role. Mechanical stress and/or damage at the injection site as well as shear stress within the bleb may directly lead to damage of the retina or trigger deleterious stress responses. This may be particularly relevant in the setting of RPE65-related retinal disease and other inherited retinal dystrophies in which dystrophic changes and a more fragile, thinned retina may predispose to damage.

Patient-related factors should be considered as well. Age, gender, stage of disease, and immune status of the individual patient could influence the functional outcome and morphological state of the retina after treatment.

Conclusion

Early detection of inherited retinal diseases is becoming increasingly important, as earlier diagnoses enable more timely initiations of therapy and thus potentially lead to better prognoses for affected patients. Symptoms such as increased sensitivity to light (photophobia), night blindness, or nystagmus may indicate an inherited retinal disease and require a thorough ophthalmological work-up within a specialized ophthalmogenetic department.

If there is reasonable suspicion, molecular genetic testing should be carried out. This is crucial to determine whether therapy with voretigene neparvovec is applicable. Gene therapy with this product must only be performed in individuals with confirmed biallelic RPE65 mutationassociated retinal dystrophy and sufficient viable retinal cells.

Limited real-world data initially confirmed the tolerable safety profile seen in marketing authorization trials.16 However, the recent reports of progressive atrophy development following therapy are undoubtedly concerning.

In summary, currently available data are insufficient to draw definite conclusions about the causes of atrophy development and their functional consequences in the long-term. Experiences of other treatment centers, including reports of the exact surgical procedure and patient details as well as longer follow-up periods, are necessary to reach a more accurate picture on possible long-term effects of the therapy. This could have important implications for the selection of patients and will help in predicting the expectable treatment benefit for eligible patients.

Maximilian J. Gerhardt, MD

Stylianos Michalakis, PhD

Gnther Rudolph, MD

Claudia Priglinger, MD

Siegfried Priglinger, MD*

E: siegfried.priglinger@med.uni-muenchen.de

Drs Gerhardt, Michalakis, Rudolph, Priglinger, and Priglinger are based at the Department of Ophthalmology, Ludwig-Maximilians-University Munich in Germany.

*Corresponding author

References

1. Redmond TM, Yu S, Lee E, et al. Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Gen. 1998;20(4):344-351. doi:10.1038/3813

2. Palczewski K. G proteincoupled receptor rhodopsin. Annu Rev Biochem. 2006;75:743-767. doi:10.1146/annurev.biochem.75.103004.142743

3. Kiser PD, Golczak M, Palczewski K. Chemistry of the retinoid (visual) cycle. Chem Rev. 2014;114(1):194-232. doi:10.1021/cr400107q

4. Takahashi Y, Chen Y, Moiseyev G, Ma JX. Two point mutations of RPE65 from patients with retinal dystrophies decrease the stability of RPE65 protein and abolish its isomerohydrolase activity. J Biol Chem. 2006;281(31):21820-21826. doi:10.1074/jbc.M603725200

5. Weleber RG, Michaelides M, Trzupek KM, Stover NB, Stone EM. The phenotype of Severe Early Childhood Onset Retinal Dystrophy (SECORD) from mutation of RPE65 and differentiation from Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2011;52:292-302.

6. Leber T. ber Retinitis pigmentosa und angeborene Amaurose. Archiv fr Ophthalmologie. 1869;15:1-25.

7. Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis. Proc Natl Acad Sci U S A. 1998;95:3088-3093.

8. Wang JS, Kefalov VJ. An alternative pathway mediates the mouse and human cone visual cycle. Curr Biol. 2009;19:1665-1669.

9. Sato S, Frederiksen R, Cornwall MC, Kefalov VJ. The retina visual cycle is driven by cis retinol oxidation in the outer segments of cones. Vis Neurosci. 2017;34:E004.

10. Das SR, Bhardwaj N, Kjeldbye H, Gouras P. Muller cells of chicken retina synthesize 11-cis-retinol. Biochem J. 1992;285(pt 3):907-913.

11. European Medicines Agency. Summary of product characteristics: Luxturna. Accessed 7 June 2022. https://www.ema.europa.eu/en/documents/product-information/luxturna-epar-product-information_en.pdf

12. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390:849-860.

13. Maguire AM, Russell S, Wellman JA, et al. Efficacy, safety, and durability of voretigene neparvovec-rzyl in RPE65 mutationassociated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology. 2019;126:1273-1285.

14. Gange WS, Sisk RA, Besirli CG, et al. Perifoveal chorioretinal atrophy after subretinal voretigene neparvovec-rzyl for RPE65-mediated Leber congenital amaurosis. Ophthalmol Retina. 2022;6:58-64.

15. Reichel FF, Seitz I, Wozar F, et al. Development of retinal atrophy after subretinal gene therapy with voretigene neparvovec. Br J Ophthalmol. Published online May 24, 2022. doi:10.1136/bjophthalmol-2021-321023

16. Deng C, Zhao PY, Branham K, et al. Real-world outcomes of voretigene neparvovec treatment in pediatric patients with RPE65-associated Leber congenital amaurosis. Graefes Arch Clin Exp Ophthalmol. 2022;260:1543-1550.

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Will experience support use of first-ever retinal gene therapy? - Ophthalmology Times

Rejuvenate Bio is a gene therapy startup that seeks to reverse aging. In response to emailed questions, CEO and Co-founder Daniel Oliver talked about how he and his co-founder started the company and their vision for treating age-related conditions.

Why did you start this company?

The idea was formed in the George Church lab at Harvard Medical School. Our Co-founder and Chief Scientific Officer Noah Davidsohn was doing his postdoc in Georges lab where he got his dog Bear, his best friend. He immediately decided that he needed to make him live a longer healthier life because 10-12 years just isnt long enough.

Noah realized that these treatments were applicable across both animal and human health. As the science progressed, it was clear that the only way to properly advance this technology and create novel therapeutics to help both pets and human patients was to form a company to move it from the bench to the bedside and into the real world. I joined from another startup to help commercialize Rejuvenate Bios current technology.

How did you meet your co-founder?

We are friends from college at Caltech. We met at a point in life where the most important thing on our minds was making sure we got our applied mathematics class problem sets done before Thursday so we could hang out with our friends! We have been friends ever since, and we luckily took complimentary paths where Noah went the traditional science route and I went to business school.

Daniel Oliver

What need/problem are you seeking to address in healthcare?

Aging costs our healthcare system in the U.S. $1.3 trillion dollars annually. Aging is driven by a dysregulation in gene expression. You have the same DNA the day you are born as you do the day you die, but what genes are turned on or off change dramatically through time. These changes can be beneficial. They drive one through development and leave people in early adulthood, but there is no evolutionary mechanism to keep these systems regulated long term. That is why we see very similar changes in gene regulation patterns across humans and subsequently see similar prevalence of age-related conditions.

What does your technology do?

At Rejuvenate Bio, we are using combination gene therapy to reverse aging in people, increasing their quality of life while treating multiple age-related conditions. Rejuvenate Bio is creating gene therapies to address issues of gene expression. By utilizing gene therapy Rejuvenate Bio can precisely deliver genetic material to patients to re-regulate certain genes whose expression levels change through age.

Rejuvenate Bios technology originated in the lab of co-founder George Church, Ph.D., as part of co-founder Noahs postdoctoral research into the genetics of aging. Our initial pipeline products are based on three longevity genes with proven efficacy and unprecedented safety profiles validated by big pharma: FGF21, sTGFR2, and Klotho are the cornerstone of Rejuvenate Bios approach. They have previously been shown to increase health and lifespan in mice that were bred to overexpress them. By delivering combinations of these three genes we have treated multiple models of age-related disease, heart failure, kidney failure, diabetes and obesity in mice and heart failure and obesity in large animals.

We have also created key tools for the delivery and control of epigenetic modifying factors that hold the promise of re-regulating the entire gene expression profile.

What is your lead therapeutic?

RJB-01 is a combination liver directed AAV gene therapy that expresses the secreted factors FGF21 and TgfBr2. RJB-01 has shown the ability to increase heart function and decrease damage against three types of heart failure in animals. RJB-01 has also been shown to have positive metabolic effects across both mice and dogs. RJB-01 will initially go into cynical trials for Arrhythmogenic Right Ventricular Cardiomyopathy(ARVC) and Familial Partial Lipodystrophy (FPL). As RJB-01 enters clinical trials for humans, a canine version will become available for the treatment of Mitral Valve Disease in dogs through a partnership with Phibro Animal Health.

Do you have any clinical validation of your product?

Weve conducted extensive preclinical studies in mice and dogs. We now have more than two years of safety data in dogs as well as multiple experiments demonstrating the efficacy of the treatment in both cardiac and metabolic conditions.

What are your upcoming milestones?

We are driving towards initial clinical trials with RJB-01 and commercialization of the canine version of RJB-01.

Photo: tylim, Getty Images

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Rejuvenate Bio CEO highlights ambitious approach of using gene therapy to reverse aging - MedCity News

Visiongain has published a new report entitled Gene Therapy R&D 2022-2032. It includes profiles of Gene Therapy R&D and Forecasts Market Segment by Disease {Cancer, Rare Diseases (Oncologic, Non-oncologic), Cardiovascular Diseases, Ophthalmic Diseases, Haematology, Neurological, Diabetes Mellitus, Other Diseases)}, Vector {Viral (Retrovirus, Adenovirus, AAV, Lentivirus, Others), Non-viral (Naked DNA, Gene Gun, Electroporation, Lipofection)}, Techniques (Gene Augmentation Therapy, Gene Replacement Therapy), Participants (Small/Medium Pharma & Biotech, Universities & Research Institutes, Hospitals, Government & Public Bodies, Big Pharma) PLUS COVID-19 Impact Analysis and Recovery Pattern Analysis (V-shaped, W-shaped, U-shaped, L-shaped) Profiles of Leading Companies, Region and Country.

The gene therapy R&D market was valued at US$1,653.0 million in 2021 and is projected to grow at a CAGR of 30.1% during the forecast period 2022-2032.

Gene Therapies Are Projected to Provide Potential Benefits for a Range of Rare DiseasesThere are about 7,000 rare diseases reported, but only a few hundred have therapies approved. Gene therapy is especially important for patients with rare disorders, as more than 80% of them have a documented monogenic (single-gene) cause. Rather than treating the disease, conventional small molecule medications often work by reducing symptoms. When managing a chronic condition, this may indicate that the medication or drugs used to control the condition are administered on a daily basis. Gene therapy, on the other hand, has the ability to remedy structural genetic disorders, rather than merely treating symptoms.

In October 2021, the U.S. FDA, National Institutes of Health (NIH), ten pharmaceutical companies & five non-profit groups joined forces to pace up the development of gene therapies for addressing the 30 million rare diseases patient pool across the North American region. Only two genetic disorders now have FDA-approved gene treatments, despite the fact that there are about 7,000 rare diseases. Hence, partnerships between pharmaceutical companies to tackle rare diseases is likely to fuel the demand for gene therapy in rare diseases treatment during the forecast period.

Furthermore, gene therapies provide the potential of a one-time cure for a range of rare disorders for which there are actually no clear clinical alternatives. With multiple gene therapy drugs securing FDA clearance, recent developments in genetic engineering and recombinant viral vector production have fuelled interest in the field.

The Asia Pacific Has Witnessed an Increase in Early ApprovalsThe regulatory framework for supporting fast marketing authorizations for advanced medicines to address unmet medical needs has been developed by regulatory agencies as a result of the Asia-Pacific region's rapid growth in advanced therapy research and development. With the introduction of regulatory frameworks by the authorities, the region has witnessed an increase in early approvals of new medicines. These approvals showed that regional regulators are more prepared to review and authorize cutting-edge treatments. To introduce these cutting-edge medications into Asia-Pacific, numerous pharmaceutical companies are making use of these new regulatory paths to take a competitive edge in the market.

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Gene Therapy R&D Market Report 2022-2032

How has COVID-19 had a Significant Impact on the Gene Therapy R&D Market?All biopharmaceutical firms have been impacted by the COVID-19 pandemic, but many CGT companies have been hit particularly severely because of their complex manufacturing and distribution models and financial structures. Businesses' decisions will have a significant impact on both the present patients with CGT and those who stand to gain from the next wave of innovation being explored by CGT companies. The manufacturing and treatment supply of the CGT industry, as well as scientific and clinical advancement and business operations, have all been severely hampered by the COVID-19 problem. The COVID-19 impact, which has been more severe in some nations compared to others, has not affected some CGT enterprises very negatively. However, since the supply chains used to manufacture CGTs are complex and tightly regulated, CGT companies have discovered that they are especially susceptible to interruptions in regions where the new coronavirus has been widespread.

How this Report Will Benefit you?Visiongains 462 page report provides 169 tables and 228 charts/graphs. Our new study is suitable for anyone requiring commercial, in-depth analyses for the gene therapy R&D market, along with detailed segment analysis in the market. Our new study will help you evaluate the overall global and regional market for gene therapy R&D. Get the financial analysis of the overall market and different segments including service type, molecule type, and therapeutic area. We believe that high opportunity remains in this fast-growing gene therapy R&D market. See how to use the existing and upcoming opportunities in this market to gain revenue benefits in the near future. Moreover, the report would help you to improve your strategic decision-making, allowing you to frame growth strategies, reinforce the analysis of other market players, and maximise the productivity of the company.

What are the Current Market Drivers?

Increasing Investments Driving Market GrowthThe pandemic has highlighted the relevance of cell and gene therapies, as well as genetic medicines in specific. If the investment by venture capitalists maintains capital flows, the momentum will be maintained during the forecast years. Large biopharmaceutical firms are anticipated to invest or acquire innovative technologies & support valuation, even if the capital markets funding climate deteriorates; Visiongain anticipates that the gene therapy industry will continue to attract investor interest over the forecast period.

Even as private companies like enGene plan to go public, Generation Bio's valuation has grown to $2 billion due to non-viral gene therapy. Longer term, synthetic biology investments, such as transgene engineering, are expected. In cell-based treatment, we see more investment potential in solid tumors and off-the-shelf pluripotent stem cell technology.

Recognizing the promise of these cutting-edge developments, large pharmaceutical firms sought out partnerships with smaller, more agile biotech start-ups. Janssen (Johnson & Johnson) & Fate Therapeutics agreed to a US$100 million upfront deal to develop cell-based immunotherapies for hematologic and solid tumors. Biogen & Sangamo have agreed to a US$350 million upfront contract to create zinc finger protein-based gene regulation therapies for neurodegenerative diseases. These agreements aided in the receipt of US$3 billion in upfront fees from corporate alliances, as well as clinical and regulatory milestones worth billions more.

Technological Advancements to Fuel Market Growth Through 2032Gene therapy, both as a modern medical technique and as a biomedical business, has a bright future in terms of technology and industry promotion. Researchers may use genome editing technology to break, alter, and edit particular genes in a DNA sequence-specific manner. However, genome editing carries the possibility of unintentional editing of genes with identical DNA sequences, a phenomenon known as the off-target effect. Genome editing has the ability to create lasting changes in the genome.

Furthermore, the genome editing tool CRISPR-Cas9 is making waves in the scientific area. It has a wide range of possible uses and is quicker, less expensive, and more accurate than earlier methods of DNA editing. Animal research has been transformed by CRISPR/Cas9 technology, as has human gene therapy, medical research, and plant science study. This method has become increasingly useful in recent years for carrying out precise gene targeting and alterations, such as gene insertions and deletions, gene replacements, and single-base pair conversions. Over the forecast period, the market for gene therapy R&D is expected to grow as a result of significant breakthroughs in this field.

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Gene Therapy R&D Market Report 2022-2032

Where are the Market Opportunities?

Growing Number of Clinical Trials to Offer Lucrative Growth OpportunitiesWhile 2022 will be a significant year for gene treatments that target rare diseases, we also anticipate that clinical readouts on medicines that target common diseases will garner media attention. It was one of the pivotal events when Vertex Pharmaceuticals' cell therapy effectively cured one patient's type 1 diabetes in 2021. The first gene therapy approval for a prevalent illness in the U.S. & Europe may occur within the next several years due to Phase 3 studies for indications like congestive heart failure, critical limb ischemia, diabetic peripheral neuropathy & macular degeneration. Approximately, 59% of the 2,406 clinical studies in the area focus on prevalent diseases. Additionally, 62% of academic and government-sponsored studies are against 56% for commercial trials, demonstrating the industry's greater involvement in the study of rare diseases. In addition, when compared to university and government sponsors, the industry places more emphasis on rare haematological diseases like hemophilia and sickle cell anaemia as well as rare ophthalmological conditions like retinitis pigmentosa.

Nearly two-thirds of all trials for rare diseases focus on treating rare malignancies, which continue to be the main goal. Additionally, inherited haematological conditions like SCDs & hemophilia, ophthalmological indications like retinitis choroideremia & pigmentosa, and other rare monogenic disorders like mucopolysaccharidosis, Duchenne muscular dystrophy & Wilson disease have drawn interest from cell and gene therapy developers.

Even while the proportion of trials targeting both common and rare diseases is roughly similar over phases, the prominent diseases being targeted are evolving. Phase 3 studies that target a common disease include 23% of musculoskeletal problems, but just 7% of Phase 1 trials, including bone fractures, osteoarthritis, and sports injuries. Other common disease categories targeted include viral diseases like HIV and CNS disorders such as Alzheimer's & Parkinson's disease.

There is also a change in the predominant disease category toward focusing on more complicated, polygenic diseases. We are witnessing a gradual transition within the CNS disorders, from more complex, polygenic disorders like Alzheimer's disease, autism & even treatment-resistant bipolar disorder & depression, to conditions such as spinal cord injury (SCI), traumatic brain injury (TBI), and neuropathic pain.

Facility Expansion Anticipated to Offer Lucrative Growth ProspectsContract manufacturers, on whom new gene & cell therapy businesses rely for early-stage development, are experiencing a lack of viral vector manufacturing capacity as a result of the increase in clinical-stage start-ups. When these companies reach commercial scale, they frequently prefer to maintain total control over their manufacturing in order to avoid the difficulties of outsourcing. As a result, biotech firms began to create expansion plans, set up internal teams, and/or ask for site consultant guidance. These professionals support the strenuous search for suitable research and development facilities or, increasingly, new construction sites in competitive real estate markets.

These in-house capabilities allow gene and cell therapy companies to rapidly scale up production from clinical batches to commercial scale, even when therapies are still in the research and development stage. This also allows for co-location with drug research and development operations, ensuring smooth technology transfer and minimal disruption, particularly during clinical trials.

As a result, there is a pressing need for time-to-market, so the chosen emphasis is on existing buildings, which have become increasingly difficult to come by in developed biotech hubs due to market demand. These hubs provide benefits such as tailored university programs and the involvement of other gene and cell therapy companies (both rivals and potential collaborators), all of which combine to create a target-rich environment for the talent they are all looking for. While all ventures are cost-sensitive, venture-funded businesses are more concerned with cost, and the need to reduce both upfront and ongoing cash outlay.

Competitive LandscapeThe major players operating in the gene therapy R&D market are Astellas Pharma Inc., American Gene Technologies, Applied Genetic, Bayer, Benitec BioPharma, Biogen, Bluebird Bio, Bristol Myers Squibb, Calimmune, Inc. (CSL Behiring), Cellectis, F. Hoffmann-La Roche Ltd., GeneQuine Biotherapeutics, GenSight Biologics, Gilead Lifesciences, Inc., Novartis AG, OCUGEN, INC., Orchard Therapeutics, Oxford Biomedica, Pfizer, Inc., REGENXBIO Inc., Sangamo Therapeutics, Inc., Sanofi, Sarepta Therapeutics, Inc., Spark Therapeutics (Subsidiary of Roche), Takeda Pharmaceuticals, Taysha GTx, Transgene, UniQure NV, Voyager Therapeutics, and ViGeneron. These major players operating in this market have adopted various strategies comprising M&A, investment in R&D, collaborations, partnerships, regional business expansion, and new product launches.

Recent Developments

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Gene therapy R&D market is projected to grow at a CAGR of 30.1% by 2032: Visiongain Reports Ltd - GlobeNewswire

BOSTON--(BUSINESS WIRE)--Emulate, Inc., a leading provider of next-generation in vitro models, today announced the launch of its new adeno-associated virus (AAV) transduction application for the Liver-Chip that enables gene therapy researchers to test the delivery efficiency and safety of AAV vectors in a validated, human-relevant model of the liver and get results in weeks, not months, as with animal models. This technology allows them to rapidly iterate on AAV design to optimize delivery of gene therapies and accelerate development.

The ability to more rapidly optimize AAV design using this application is a game-changer for the gene therapy industry, said Emulate CEO Jim Corbett. We are excited to offer this novel application to researchers in biopharmaceutical, academic, and government entities around the world who are exploring gene therapy as a potential to treat a wide range of diseases such as cancer, cystic fibrosis, heart disease, diabetes, and metabolic disease.

Gene therapy involves replacing a faulty or missing gene by adding a new one inside the bodys cells to treat or prevent a genetic disease or disorder. Currently, this technique is primarily available in clinical trials, testing its potential to treat inherited disorders, cancer, and HIV/AIDS. The AAV vector is the most versatile and popular viral vector that researchers use as a delivery vehicle for gene therapy, as it efficiently targets different cell and tissue types and has been demonstrated to be safe and well-tolerated.

Due to the lack of suitable non-clinical models, scientists often struggle when designing new AAV vectors to ensure that the vector effectively and safely delivers the therapy to the right cells, in the right organ. Animal models are slow, costly, and tightly regulated, which limits the number of AAV delivery vehicles that can be tested and the ability to look at the individual contribution of each cell type. In addition, conventional in vitro models restrict the number of AAVs that can be tested as they are only a single cell type in a static petri dish and do not accurately reflect how cells behave inside the body.

The Emulate Liver-Chip provides the specific 3D multicellular architecture, physiological functions and mechanical forces necessary to recapitulate the relevant aspects of the liver, said Emulate Chief Scientific Officer Lorna Ewart, PhD. Now we have demonstrated it to be a more human-relevant model that researchers can use to assess and discriminate between the transduction efficiency of various AAV-based gene therapies in a concentration- and time-dependent manner, as well as evaluate the toxicity.

Information about the Emulate AAV transduction application for the Liver-Chip is available on the companys website and will be presented in a live webinar on October 6th.

About Emulate, Inc.

Emulate is igniting a new era in human health with industry-leading Organ-on-a-Chip technology. The Human Emulation System provides a window into the inner workings of human biology and diseaseoffering researchers an innovative technology designed to predict human response with greater precision and detail than conventional cell culture or animal-based experimental testing. Pioneered at the Wyss Institute for Biologically Inspired Engineering at Harvard University and backed by Northpond Ventures, Founders Fund, and Perceptive Advisors, Organ-on-a-Chip technology is assisting researchers across academia, pharma, and government industries through its predictive power and ability to recreate true-to-life human biology. To learn more, visit emulatebio.com or follow us on LinkedIn and Twitter.

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Emulate Announces New Gene Therapy Application Enabling Accelerated Development of Treatments for Genetic Diseases with Organ-on-a-Chip Technology -...

A new gene therapy being developed by CSL for haemophilia B has the potential to overhaul patient treatment times and, according to market watchers, unlock significant market share for the ASX-listed biotech giant

CSL started developing the treatment, known as EtranaDez, after inking a $655 million deal with genomic medicine company Uniqure back in 2020. The US Food and Drug Administration is expected to make a call on whether to give the product the green light by the end of this year.

CSL boss Paul Perreault told this masthead earlier this year he hoped to launch the product in the next calendar year. Credit:Jason South.

Patients with haemophilia B lack the blood clotting protein Factor-IX, and currently have to undergo regular intravenous treatments. EtranaDez aims to free up patients from the need for frequent treatment sessions, by instructing their cells to produce the clotting factor that they lack.

As the date of the FDAs decision approaches, experts have started to run the ruler over the potential benefits of the drug, with Boston-based independent non-profit, the Institute for Clinical and Economic Review (ICER), publishing a draft report on the treatment last week.

The groups panel of experts have reviewed the evidence for the treatment and run models for the cost-effectiveness of the drug, assuming a placeholder price of $2.5 million in the US market.

No prices are set yet for the product because it has not yet been approved, but the draft report suggests EtranaDez offers cost savings for a patient across their lifetime compared with other available treatments.

The ICER report also notes that gene therapies for haemophilia are a major step forward for patients who otherwise need regular and time-consuming injections.

CSL boss Paul Perreault told this masthead earlier this year the company was very excited for the treatment to be one of the next CSL research and development projects to hit the market.

It will be in the second half of this fiscal year when we look to hopefully get the approvals and launch that project, he said.

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CSL flexes gene therapy muscle with latest drug - Sydney Morning Herald

The FDA approved a tumor agnostic treatment for cancer, a lower dose MRI contrast agent, the first generic of Tazorac gel, and a gene therapy for a rare disease. Advisory committees vote down poziotinib for NSCLC and Pepaxto for multiple myeloma and give positive vote for microbiotic-based C. diff therapy. The agency has accepted sNDA for Tukysa for HER2 positive colorectal cancer.

FDA grants accelerated approval of Retevmo for tumor agnostic RET gene fusions.

The FDA has granted accelerated approval to Lillys Retevmo (selpercatinib) for adult patients with RET gene fusion. Tumor-agnostic data supporting approval demonstrated an overall response rate (ORR) of 44% across multiple tumor types in patients who have progressed on or following prior systemic treatment.

This indication is approved under accelerated approval based on ORR and duration of response (DOR). Continued approval for this indication is contingent upon verification of clinical benefit in a confirmatory trial.

The FDA also granted traditional approval of Retevmo to treat adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a RET gene fusion. This broadens the Retevmo label to include patients with locally advanced disease and converts the May 2020 accelerated approval for NSCLC to a traditional approval.

The two approvals are supported by data from the pivotal LIBRETTO-001 trial, which is the largest clinical trial of patients with RET-driven cancers treated with a RET inhibitor. The multicenter, open-label, multi-cohort study enrolled patients with locally advanced or metastatic RET-driven solid tumors, including NSCLC. Major efficacy outcomes were ORR and DOR.

FDA approves lower dose gadolinium-based contrast agent.

The FDA has approved Guerbets Elucirem (gadopiclenol), a new macrocyclic gadolinium-based contrast agent for use with magnetic resonance imaging (MRI). It is approved for use in adults and children aged 2 years and older to detect and visualize lesions with abnormal vascularity in the central nervous system (brain, spine and associated tissues) and the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system.

Elucirem will be marketed by Guerbet in the United States in bottle and pre-filled syringe form. It has been designed to allow it to be used at half the conventional dose of gadolinium compared with other non-specific gadolinium-based contrast agents. The approval is based on data from two phase 3 studies completed in March 2021, which demonstrated that Elucirem leads to non-inferior results in brain and body MRI at half the gadolinium dose of gadobutrol.

Bluebird bios gene therapy for CALD gets accelerated approval.

Shortly after approval of another gene therapy from bluebird bio, the FDA granted accelerated approval for the companys Skysona (elivaldogene autotemcel), also known as eli-cel, to treat early, active cerebral adrenoleukodystrophy (CALD).

The company also confirmed in a news release that the previous clinical hold on the eli-cel clinical development program has been lifted.

Bluebird has set the wholesale acquisition cost of Skysona at $3 million and expects commercial product to be available by the end of this year through a limited number of qualified treatment centers in the United States.

Last month, FDAalso approved Bluebird bios Zynteglo(betibeglogene autotemcel), also known as beti-cel, the first cell-based gene therapy to treat adult and pediatric patients with beta-thalassemia who require regular red blood cell transfusions.

FDA approves first generic of Tazorac gel.

The FDA has approved Cosette Pharmaceuticals abbreviated new drug application (ANDA) for the first generic versions of Almiralls Tazorac (tazarotene) gel, 0.05% and 0.1%, which is used to treat psoriasis, acne, and sun damage to skin. The company has received 180 days competitive generic therapy (CGT) exclusivity.

Tazarotene is a retinoid product related to vitamin A. Generics of the cream formulation are available from Cosette and Taro. The lowest retail price of the cream formulation is about $40 through mail order, according toGoodRx.

FDA advisory committee votes down Pepaxto for multiple myeloma

The FDAs Oncologic Drugs Advisory Committee (ODAC) voted 14 to 2 on Sept. 22, 2022, against whether the benefit risk profile of Oncopeptides Pepaxto (melphalan flufenamide) was favorable in adult patients with relapsed or refractory multiple myeloma.

In materials released ahead of the meeting, the FDA indicated that the confirmatory trial (OCEAN) demonstrated a worse overall survival and failed to verify clinical benefit. The committee reviewed data from the OCEAN trial, which compared Peptaxto/dexamethasone with pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Additionally, there were higher rates of deaths in Pepaxto arm than in the pomalidomide/dexamethasone arm. There were also higher rates of grade 3 and 4 adverse events in the Pepaxto arm.

Almost all patients (99.6%) reported treatment-emergent adverse events, including serious events such a bleeding, infections, thrombocytopenia (low platelet count), and neutropenia (low count of a specific white blood cell). Additionally, 53% of the 491 patients died during the studies with most of the deaths occurring more than 30 days after the last dose of Pepaxto.

FDA advisory committee votes against poziotinib for NSCLC.

The FDAs Oncologic Drugs Advisory Committee (ODAC) voted 9 to 4 on Sept. 22, 2022, against on whether the benefits of Spectrum Pharmaceuticals poziotinib outweigh its risks. The company was seeking accelerated approval of poziotinib for the treatment of patients with non-small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations. Poziotinib is a kinase inhibitor with a proposed dosage of 16 mg four times a day.

The committee members agreed there is an unmet need in this patient population, but many said after the vote that poziotinib doesnt appear to provide meaningful benefit beyond existing therapies, echoing concerns brought by the regulatory agency. The FDA expressed concerns about the toxicities associated with poziotinib, including high rates of treatment interruption and dose reduction, and very high rates of diarrhea, mucositis, and rash, as well as three fatal events of pneumonitis. In the ZENITH20 trial, poziotinib was poorly tolerated at the current proposed dosage (16 mg four times a day) with 57% of patients experiencing dose reductions and 85% of patients experiencing grade 3 to 4 adverse events.

FDA advisory committee gives positive vote for microbiota-based C. diff therapy.

The FDAs Vaccines and Related Biological Products Advisory Committee (VRBPAC) issued a positive vote on Sept. 22, 2022, for Ferring Pharmaceuticals RBX2660 (now with the brand name Rebyota) to reduce recurrence of C. difficile infection (CDI) after antibiotic treatment. RBX2660 is microbiota-based live biotherapeutic that contains live microorganisms that are used as active substances. RBX2660 is a fecal microbiota transplantation therapy that was developed by Rebiotix, a Ferring company.

The committee voted 13 to 4 indicating that the data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults 18 years of age and older following antibiotic treatment. The committee also voted 12 to 4 with one abstention that the data were adequate to support the safety of RBX2660.

C. diff is a serious disease that causes severe diarrhea, fever, stomach tenderness or pain, loss of appetite, nausea, and colitis. It has been estimated that up to 35% of cases recur after initial diagnosis and people who have had a recurrence are at significantly higher risk of further infection.

FDA accepts sNDA for Tukysa for HER2 positive colorectal cancer.

The FDA has accepted for priority review Seagens supplemental new drug application (sNDA) seeking accelerated approval for Tukysa (tucatinib). The company is seeking an indication in combination with trastuzumab for adult patients with HER2-positive colorectal cancer who have received at least one prior treatment regimen for unresectable or metastatic disease. The agency has set a target action date of Jan. 19, 2023.

Tukysa is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. The FDA approved Tukysa in April 2020 in combination with trastuzumab and capecitabine to treat adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

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FDA Updates for the Week of Sept. 19, 2022 - Managed Healthcare Executive

PTC Therapeutics is a global biopharmaceutical company committed to the development of treatments for rare diseases where significant unmet medical needs exist.

Gene therapies are bringing hope to patients living with ultra-rare diseases. Unlike some medicines that treat the symptoms of a disease, gene therapy targets the root cause, with the potential to transform a disease with a single treatment or a short treatment course.(1) However, there is work to do to ensure patients can benefit from these novel treatments and to ensure an environment where R&D continues to evolve and flourish.

Working together with biopharmaceutical companies, regulators, payers, HTA bodies and policymakers, we have an opportunity to forge new ground so patients, caregivers and health systems can realize the full benefit of medical innovation. We are at the frontier of an exciting therapy pipeline.

To ensure success, we will need to work together to identify solutions in three key areas.

Getting the right diagnosis for rare diseases can be notoriously difficult. Including supporting increased access to genetic testing.(2) We often hear of families who have visited an endless number of specialists to find out why their child is not meeting expected developmental milestones. That is why we provide support across the entire patient journey, from disease awareness, physician education and early diagnosis initiatives. The inclusion of more diseases in newborn screening panels is a potential solution and an important component of any national rare disease action plan, as disease outcomes are often better if patients are treated early.(3) Newborn screening is mandated by law in some countries, but not all.(4)

In Europe, an example of best practice can be found in Italy, where diagnostic methods have been centralized in screening centres. Italys mandatory national program includes 40 disorders with 100% coverage.(5) However, the availability of newborn screening and the number of conditions screened varies considerably across Europe; for example in some countries, screening is only performed for 1 condition.(6) In the US, as a comparator, it is recommended that babies are screened for 34 core conditions and 26 secondary conditions.(7)

Regulatory and HTA frameworks were set up for the well-known therapy model, where treatment is given and paid for across a lifetime and often, to large numbers of patients. Gene therapies dont fit this model. Typically given only once, for a value that stretches over a lifetime. Whats more, these innovative therapies are genetically personalized, and for conditions that are so rare, there may only be a handful of affected patients in a country. The overall impact on the national healthcare budget may therefore be minimal. An evaluation must reflect these small patient numbers to encourage innovation. It is encouraging to see that in the UK NICE (National Institute for Health and Care Excellence), will work to improve how it considers real-world evidence from patients when evaluating new treatments.(8) This is incredibly important in rare diseases where large clinical trials are not possible.

There needs to be more significance given to data collected through close patient follow-up in disease and product registries that build up vital long-term safety and efficacy data. Inaddition, the process for gathering this data needs to be more consistent, coordinated and efficient.(9)

With very small patient populations, real-world evidence that is gathered is important in order to understand the long-term benefit of the treatment and the impact on the patientsquality of life.

The collaboration of biopharmaceutical companies, regulators, payers, HTA bodies and policymakers is important to design clear and uniform guidance so that real-world data isinter-changeable, interoperable and consistently accepted across Europe.Hopefully, this is an area the newly launched proposal from the European Commission on European Health Data Space can improve, in addition to the EMAs DARWIN project whichwill provide a network of real-world evidence across the EU.(10,11)

There are many new and innovative treatments, including gene therapies, that are being developed for patients living with rare diseases, providing hope for patients, many of whom are children with disabling and life-limiting conditions and who currently have few or no treatment options.(12) The potentially long-lasting effects of gene therapies will greatly reduce and in some cases eliminate the need for ongoing treatments over a patientslifetime. We need to work together to improve the regulatory and accesslandscape across Europe to ensure that these transformative and innovative therapies reach patients and at the same time continue to advance medical science in Europe.

1) Goswami R, et al. Gene Therapy Leaves a Vicious Cycle. Front Oncol. 2019;9:297.2) Marwaha S, et al. A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Med. 2022;14(1):23.3) Kohlschtter A & van den Bussche H. [Early diagnosis of a rare disease in children through better communica-tion between parents, physicians and academic centers] Z Evid Fortbild Qual Gesundhwes. 2019;141-142:18-23.4) Loeber, JG. Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010. Int J Neonatal Screen. 2021;7(1):15.5) Sikonja J, et al. Towards Achieving Equity and Innovation in Newborn Screening across Europe. Int. J. Neonatal Screen. 2022, 8(2):31.6) Loeber JG. European Union Should Actively Stimulate and Harmonise Neonatal Screening Initiatives. Int J Neo-natal Screen. 2018;4(4): 32.7) National Conference of State Legislators (2017). State Newborn Health Screening Policies. Available at: https://www.ncsl.org/research/health/state-newborn-health-screening-policies.aspx (Accessed May 2022).8) NICE (2022) NICE publishes new combined methods and processes manual and topic selection manual for its health technology evaluation programmes Available at:https://www.nice.org.uk/news/article/nice-publishes-new-combined-methods-and-processes-manual-and-topic-selection-manual-for-its-health-technology-evaluation-programmes (Accessed May 2022).9) Kodra Y et al. Recommendations for Improving the Quality of Rare Disease Registries. Int. J. Environ. Res. Public Health 2018, 15(8):1644.10) European Commission. Questions and answers EU Health: European Health Data Space (EHDS). Available at: https://ec.europa.eu/commission/presscorner/detail/en/QANDA_22_2712 (Accessed May 2022).11) European Medicines Agency. Initiation of DARWIN EU Coordination Centre advances integration of real-world evidence into assessment of medicines in the EU. Available at:https://www.ema.europa.eu/en/news/initiation-darwin-eurcoordination-centre-advances-integration-real-world-evidence-assessment (Accessed May 2022).12) Bates M. Advances in Gene Therapy Offer Hope for Rare Disorders. IEEE Pulse 2019;10(6):9-12. EMEA Europe, Middle East and Africa, APAC Asia Pacific, R&D Research and Development, HTA Health Technology Assessment, EMA European Medicines Agency, EU Date of Preparation: September 2022 PTC/Corp/UK/22/0037.

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Preparing Europe for a new generation of innovative therapies - Open Access Government

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AVROBIO Receives Rare Pediatric Disease Designation From FDA For First Gene Therapy In Development For Cy - Benzinga