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The principal investigator at Seattle Children’s Research Institute discussed her lab’s work on using ultrasound mediated gene delivery to target hemophilia A. 

Carol Miao, PhD, on Using UMGD to Target Liver Sinusoidal Endothelial Cells

The principal investigator at Seattle Children’s Research Institute discussed her lab’s preclinical research with UMGD for the treatment of hemophilia.

Carol Miao, PhD, on the Potential of Ultrasound Mediated Gene Delivery

The principal investigator at Seattle Children’s Research Institute discussed the continuing need to share preclinical research at conferences even as more gene therapies enter the clinic.

Carol Miao, PhD, on the Importance of Continuing Preclinical Research in Gene Therapy

The principal investigator at Seattle Children’s Research Institute discussed the potential of new delivery methods and gene editing to overcome the limitations of AAV vector-based gene therapies.

Carol Miao, PhD, on Bringing Together Novel Gene Editing Tools and Delivery Methods

The principal investigator at Seattle Children’s Research Institute discussed her lab’s preclinical research on nonviral delivery methods for gene editing tools in the context of treating hemophilia A.

Carol Miao, PhD, on Delivering Gene Editing Tools With Nonviral Methods in Hemophilia A Models

The principal investigator at Seattle Children’s Research Institute discussed the preclinical research on delivery methods for genomic medicines that her lab presented at ASGCT’s 2023 meeting.

Carol Miao, PhD, on Exploring New Delivery Methods for Gene Replacement Therapy and Gene Editing

The associate professor of medicine at University of Colorado discussed data presented at ASCO 2024. 

Manali Kamdar, MD, on Liso-Cel's Ongoing Benefit in the Treatment Lanscape for LBCL 

“Especially with follicular lymphoma, the response rates are just stellar. The median follow up is a little under 3 years right now, but at this point in time, the median duration of response and responders [are great]. Personally, for the people I enrolled on the trials, they're all in a complete remission, they've gone back to life, they have not relapsed. They're young patients and older patients across all age groups. It's really gratifying as a clinical trial to see just the power of the construct.”

Lisocabtagene maraleucel (liso-cel), approved under the name Breyanzi for patients with primary refractory/relapsed (r/r) large B-cell lymphoma (LBCL) based off of data from the phase 3 TRANSFORM (NCT03575351) and TRANSCEND trials (NCT02631044), continues to demonstrate deep and durable responses in patients with r/r LBCL and superiority over standard of care.

Manali Kamdar, MD, associate professor of medicine – hematology, University of Colorado School of Medicine - Anschutz Medical Campus, and UCHealth Blood Disorders and Cell Therapies Center, investigator on TRANSCEND, TRANSFORM, and other investigations on liso-cel, presented updated, 3-year data from TRANSFORM at the 

2024 American Society of Clinical Oncology (ASCO) Annual Meeting

, held May 31 to June 4, in Chicago, Illinois. CGTLive® spoke with Kamdar to learn more about liso-cel's ongoing benefit in the treatment landscape of LBCL. She also shared her enthusiasm for data presented on liso-cel for treating Richter transformation.

Click here to view more coverage from the 2024 ASCO meeting.

1. Kamdar MK, Solomon SR, Arnason J, et al. Lisocabtagenemaraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study. Presented at: 2024 (ASCO) Annual Meeting; May 31 - June 4; Chicago, Illinois. Abstract #7013
2. Winter AM, Bharadwaj S, Herrera AF, et al. Real-world outcomes of lisocabtagene maraleucel (liso-cel) in patients (pt) with Richter transformation (RT) from the Center for International Blood and Marrow Transplant Research (CIBMTR). Presented at: 2024 (ASCO) Annual Meeting; May 31 - June 4; Chicago, Illinois. Abstract #7010

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Afamitresgene autoleucel (afami-cel; Adaptimmune Therapeutics) is an investigational MAGE-A4–targeted autologous engineered T-cell receptor (TCR) SPEAR T-cell therapy intended to treat 

The therapy is currently being reviewed by the FDA, which accepted Adaptimmune’s biologic license application (BLA) for the therapy in January 2024 after the company completed its rolling BLA submission in December 2023.

 The BLA was the first of its kind for an engineered T-cell therapy for a solid tumor indication submitted to the agency. The Prescription Drug User Fee Act (PDUFA) target action date is August 4, 2024.

Afami-cel is being evaluated in the pivotal SPEARHEAD-1 clinical trial (NCT04044768), which has met its primary efficacy endpoint of overall objective response (ORR) compared to natural history.

“This could be the first, to my knowledge, the first FDA approved TCR therapy for solid tumors - there's really very little affinity for CAR T-cells in solid tumors at this point, either. And so that's really exciting, soft tissue sarcoma is heterogeneous, with at least 50 subtypes of soft tissue sarcoma. So, treatment development for sarcoma is hard, and it's been relatively slow. So, this is super exciting to see this underserved population really take the first step and hopefully broaden out to other tumor types,” primary investigator John A. Charlson, MD, associate professor of medicine, Medical College of Wisconsin, told 

Looking Forward to A Potential First Cell Therapy Approval for Sarcomas

Patients with SS in SPEARHEAD-1 had an 39% ORR and a median duration of response (DOR) of around 12 months. Recent data from the trial with updated positive survival data were presented at 

the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting

, held in Chicago, Illinois, in June, by investigator Brian Van Tine, MD, PhD, professor of medicine and pediatrics at Washington University in St. Louis.

The new data demonstrated that responders had a 1-year survival rate of 90% and a 2-year survival rate of 70%. The median overall survival (OS) rate overall was 17 months although the median OS has not yet been reached for responders. Comparatively, second-line treatment of advanced synovial sarcoma has historically yielded a median OS of under 12 months. The new data also included transient cases of cytokine release syndrome but no new, long-term safety signals.

“We've learned that there's issues with cytokine release syndrome, which is why this has to be given impatient by people that know what they're doing. But compared to getting chemotherapy once every 3 weeks, it's much safer and much better tolerated in the long term. And so, we're really trying to spread the message that everybody should know their (HLA) status. I think as these become more prevalent, and the targets become more available, hopefully everybody will eventually have access to something like this," Van Tine told 

Besides the primary endpoint of ORR, secondary endpoints included the safety and tolerability of ADP-A2M4 by assessing treatment-related adverse events (AEs) and serious AEs using CTCAE version 5.0 over 2.5 years. The safety assessment also involved measuring replication-competent retrovirus in genetically engineered T-cells through PCR-based assays in peripheral blood for 15 years and analyzing T-cell clonality and insertional oncogenesis in peripheral blood mononuclear cells for 2.5 years. Efficacy endpoints included determining the best OR per RECIST v1.1, assessing time to response, DOR, progression-free survival (PFS), and OS, with PFS and OS monitored for 2.5 years and 15 years, respectively. Quantitative measures of genetically engineered T-cells in PBMCs were taken by qPCR and flow cytometry, assessing both the amount and the time taken to achieve peak expansion of these cells over 2.5 years. Additionally, the development and validation of an in vitro diagnostic assay for screening MAGE-A4 antigen expression as a companion diagnostic were conducted over 2.5 years.

SPEARHEAD-1 enrolled participants between the ages of 16 and 75 years (10 years at selected sites) with a diagnosis of advanced SS or myxoid liposarcoma/myxoid round cell liposarcoma confirmed by cytogenetics. Participants had previously received an anthracycline or ifosfamide-containing regimen and had measurable disease according to RECIST v1.1 prior to lymphodepletion. They were HLA-A02:01, HLA-A02:02, HLA-A02:03, or HLA-A02:06 positive, and their tumors showed MAGE-A4 expression confirmed by a central laboratory. In North America, the tumor showed MAGE-A4 expression of ≥1+ staining in ≥10% of cells by immunohistochemistry. Participants had an ECOG Performance Status of 0 or 1, or a Lansky Score ≥60% for those aged 10 to 16 years old, and a left ventricular ejection fraction (LVEF) of ≥50%. Additional protocol-defined inclusion criteria also applied.

Exclusion criteria for the study included the presence of HLA-A*02:05 in either allele and prior or planned receipt of various therapies or treatments before leukapheresis or lymphodepleting chemotherapy, such as cytotoxic chemotherapy, tyrosine kinase inhibitors, immune therapy, anti-cancer vaccines, gene therapy using an integrating vector (except lentiviral vectors), corticosteroids, any immunosuppressive therapy, investigational treatments or participation in interventional clinical trials, allogeneic hematopoietic stem cell transplant, radiotherapy to the target lesions, and major surgery. Participants with a history of allergic reactions to compounds similar to fludarabine, cyclophosphamide, or other agents used in the study, autoimmune or immune-mediated diseases, symptomatic central nervous system metastases, prior malignancy not in complete remission, clinically significant cardiovascular disease, uncontrolled intercurrent illness, active infections with HIV, hepatitis B, hepatitis C, or human T cell leukemia virus, and those who were pregnant or breastfeeding were also excluded. Additional protocol-defined exclusion criteria applied.

1. Adaptimmune announces U.S. FDA acceptance of biologics license application for afami-cel for the treatment of advanced synovial sarcoma with priority review. News release. Adaptimmune Therapeutics plc. January 31, 2024. Accessed February 2, 2024. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/260/adaptimmune-announces-u-s-fda-acceptance-of-biologics
2. Adaptimmune completes submission of rolling biologics license application (BLA) to U.S. FDA for afami-cel for the treatment of advanced synovial sarcoma. News release. Adaptimmune. December 6, 2023. Accessed February 2, 2024. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/258/adaptimmune-completes-submission-of-rolling-biologics
3. Adaptimmune reports better outcomes for people with synovial sarcoma who received afami-cel compared to historical Control. News release. Adaptimmune. October 31, 2023. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/253/adaptimmune-reports-better-outcomes-for-people-with
4. Van Tine BA, Ganjoo KN, Blay JY, et al. The SPEARHEAD-1 trial of afamitresgene autoleucel (afami-cel [formerly ADP-A2M4]): Analysis of overall survival in advanced synovial sarcoma. Presented at: ASCO 2023 Annual Meeting; June 2-6; Chicago, Illinois. Poster #497

The Prescription Drug User Fee Act (PDUFA) target action date is August 4, 2024.

SPEARHEAD-1 Supports Potential TCR-T Approval for Synovial Sarcoma 

Leukodystrophies are a group of inherited neurological disorders in which genetic mutations affect the myelin sheath, and are categorized as rare diseases, with a prevalence of around 1 in 7000 live births. Researchers have identified more than 50 types of leukodystrophies, with some common types including adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), Krabbe disease or globoid cell leukodystrophy, and 

Despite their rarity, leukodystrophies are a prime target for gene therapy as most affected patients have a single gene mutation responsible for the disease phenotype. Substantial progress has been made in the field, with 2 gene therapies approved for leukodystrophies in the United States (US) in 2022 and 2024: bluebird bio’s elivaldogene autotemcel (eli-cel/Skysona) for cerebral ALD and Orchard Therapeutics’ atidarsagene autotemcel (arsa-cel/Lenmeldy) for early-onset MLD.

Although these leukodystrophy gene therapy approvals have enriched the market in the United States, the same access to these products cannot be found in Europe, where price negotiations and reimbursement agreements have struggled to reckon with prohibitively high price tags—eli-cel is available for $3 million and arsa-cel for $4.25 million in the US. The US approval of eli-cel followed its 2021 approval by the European Medicines Agency, however, by the end of the year, bluebird announced that it was 

withdrawing its European Union (EU) marketing authorization

 along with its United Kingdom (UK) filing for the therapy following price disputes in Germany with another approved but now unavailable for the European market gene therapy product, betibeglogene autotemcel (Zynteglo), making eli-cel only available in the US.

Arsa-cel has been approved under the name Libmeldy in the European Union, United Kingdom, Iceland, Liechtenstein, and Norway since in 2020. The therapy nearly followed the same path as eli-cel in Europe, although the agencies finally came to an agreement after years of price negotiations, the latest of which only concluded early in 2024.

 Although approved for use in all 27 member states of the EU, arsa-cel is permanently reimbursed in only 11

“These therapies are complex and production is expensive. The research and development is long and complex, because these are personalized treatments... But these also are treatments that are given once and they're potentially curative. So, it will be really important in the future to reduce the cost associated with the manufacturing, the cost associated with the development. But these types of treatments are potentially breakthroughs. So, we really need to find a balance between moving further with research and accessibility of these new treatments to patients,” Alessandro Aiutti, MD, PhD, the deputy director of clinical research and head of the Clinical Research Unit at San Raffaele Telethon Institute for Gene Therapy, the group leader of Pathogenesis and therapy within the primary immunodeficiencies unit, and a full professor at the Università Vita-Salute San Raffaele, as well as the chief of clinic at the Pediatric Immunohematology Unit of San Raffaele, told 

Arsa-cel is available under a limited distribution model that includes 5 centers of excellence trained as qualified treatment centers (QTCs) across Europe. Aiutti was involved with clinical trial investigations for the therapy at San Raffaele, which is now a QTC for administering the therapy. 

Orchard is planning to implement arsa-cel's rollout in the US under a similar limited distribution model, with 5 QTCs administering the therapy in the country. As of March 2024, the M Health Fairview Masonic Children’s Hospital in Minnesota is in the final stages of qualification, and Children’s Healthcare of Atlanta, Children's Hospital of Philadelphia, Texas Children’s Hospital, and UCSF Benioff Children’s Hospital San Francisco are in the qualification process.

“These are rare diseases, it's important that you have centers of excellence that are QTCs where there's expertise from both a clinical perspective, but also a nursing, laboratory perspective. We have key relationships with the manufacturing laboratory, and also, of course, the sponsors. That's been really important in the onboarding of this product at our hospital,” Madeleine Powys, MBBS, a former locum consultant of pediatric BMT and leukemia at Royal Manchester Children’s Hospital (RMCH), now at Children's Hospital at Westmead, in Sydney, Australia, told 

 about her experience with Libmeldy at RMCH. “So, there's been an enormous amount of effort put into the training of the staff—the clinical staff, the laboratory staff, and our nursing staff—on the various complex steps that need to occur to make sure that the product is safely collected, manufactured and delivered into our patients.”

ALD and MLD, like many other leukodystrophies, primarily affect infants and young children, creating an extremely time-sensitive environment for gene therapies to have the most effect, similar to approved gene therapy onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy (SMA). Such conditions necessitate newborn screening to identify patients and administer gene therapy sooner and may lead to more clinical benefit, as such is the case of Zolgensma, wherein treated children with presymptomatic SMA were found to 

 Notably, MLD has not yet joined X-linked adrenoleukodystrophy on the US Recommended Uniform Screening Panel (RUSP).

"With lentiviral therapies, you have to harvest the bone marrow of a baby. If the disease starts really early, the earliest they can get into the baby is like 5 to 6 months,” Maria Escolar, MD, the chief medical officer of Forge Biologics, told 

. Forge is developing gene therapy FBX-101 to be infused intravenously after hematopoietic stem cell transplant in children with Krabbe disease. Krabbe was added to the RUSP in February 2024.

Fast identification of patients is made especially important when manufacturing of ex vivo gene therapy takes weeks—both arsa-cel and eli-cel are autologous, lentiviral, ex-vivo gene therapies. For reference, Orchard Therapeutics stated in January 2023 that the average time for manufacturing and release of arsa-cel was 44 days.

“[Newborn screening] is super important because the transplant only works when you're presymptomatic. So, if those babies get identified, we want them to get the transplant, hopefully, in the first month of life. And then those babies could then get gene therapy, and many [can be helped]... We hope that these babies get referred very quickly so that we can prevent both the damage in the brain and, in the future, also prevent the peripheral nerve disease,” Escolar said.

Looking Ahead for Leukodystrophy Gene Therapies

Besides FBX-101, a number of gene therapies are in development for other leukodystrophies. These include gene therapy programs for Canavan disease by Aspa Bio, a subsidiary of BridgeBio Pharma, and Myrtelle, and SwanBio Therapeutics’ gene therapy program for 

These therapies are all currently being evaluated in recruiting phase 1/2 trials: these are Aspa’s CANaspire trial (NCT04998396) of BBP-812, Myrtelle’s trial of rAAV-Olig001-ASPA, and SwanBio’s PROPEL trial (NCT05394064) of SBT-101. FBX-101 is similarly being evaluated in the currently recruiting REKLAIM phase 1/2 trial (NCT05739643). These gene therapies have all shown some promise so far to show a benefit for patients with leukodystrophies and hope to face a smoother path to approval and market than paved by trailblazers eli-cel and arsa-cel.

1. Leukodystrophy. Webpage. Cleveland Clinic. June 3, 2021. https://my.clevelandclinic.org/health/diseases/6034-leukodystrophy
2. bluebird bio Receives FDA Accelerated Approval for SKYSONA® Gene Therapy for Early, Active Cerebral Adrenoleukodystrophy (CALD). News release. bluebird bio. September 16, 2022. https://finance.yahoo.com/news/bluebird-bio-receives-fda-accelerated-035100645.html
3. FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 18, 2024. Accessed March 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystroph
4. bluebird bio. Form 8-K. October 21, 2021. https://investor.bluebirdbio.com/node/14816/html
5. NHS in yet another negotiated discounted deal for game-changing Libmeldy drug. News coverage. VWV.org. March 11, 2022. https://www.vwv.co.uk/news-and-events/blog/pharma-life-sciences-law/nhs-libmeldy-drug
6.Beneluxa Initiative announces successful conclusion of Libmeldy price negotiations, directly benefiting patients in three countries. News release. Beneluxa. January 2024. https://beneluxa.org/Libmeldy_conclusion
7. Orchard Therapeutics Outlines U.S. Launch Plans for Lenmeldy™ (atidarsageneautotemcel), the Only Approved Therapy for Children with Early-onset Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 20, 2024. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-outlines-us-launch-plans-lenmeldytm
8. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogeneabeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nature Medicine. Published online June 17, 2022. doi10.1038/s41591-022-01866-4
9. Recommended Uniform Screening Panel. Webpage. Health Resources & Services Administration. August 2023. https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp
10. U.S. panel adds rare brain disease to newborn screening list, after push from families. News article. Quinn Eastman. Science. February 2, 2024. Accessed May 22, 2024. https://www.science.org/content/article/u-s-panel-adds-rare-brain-disease-newborn-screening-list-after-push-families
11. Orchard Therapeutics Highlights Recent Progress Across HSC Gene Therapy Portfolio and Outlines Key 2023 Milestones. News release. Orchard Therapeutics. January 9, 2023. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-highlights-recent-progress-across-hsc-gene


CGTLive takes a look at the path gene therapies have blazed in leukodystrophies, the challenges they’ve faced, and the road they’ve paved. 

Navigating a Novel Therapy Frontier: Gene Therapy's Stunted Impact on Leukodystrophies 

Parkinson disease (PD) can be caused, in different cases, by a number of complex factors including genetics, lifestyle, environmental factors, and other factors that may not even be known. As such, developing new treatments for PD is highly complex, as well, and, unfortunately, not much progress has been made in the past few decades.

 recently reached out to Ignacio Mata, PhD, an associate professor of neurology at the Cleveland Clinic Lerner Institute, to learn more about the current state of PD research, and where more work is needed. Mata discussed the importance of detecting the disease in patients earlier and the potential of slowing or stopping disease progression in patients with genetic forms of PD via targeted approaches.

 Can you discuss the current landscape of care for PD and the unmet needs that remain for this patient population?

 So full disclosure, I'm not a doctor. I'm a PhD, obviously, so I do research in genetics, mostly. So, I don't deal with patients on the day-to-day. But, PD is a very complex disease. I think neurologists will agree that it is very complex from the symptoms' point of view. It's also very complex from the biology point of view, right? There are at least 20-some genes that cause familial forms of PD, there are about 100 additional genes that are risk factors for PD, and then in addition to that, you have all the environment, lifestyle, and other factors. It makes for a very complex disease to study and a very complex disease to treat.

We've had the same drug for over 2 or 3 decades now, which is great to treat the symptoms. Obviously, there are some issues with the current treatments, but they can give good quality of life to patients, especially for 5 to 10 years, depending on the patient. There are also surgical procedures, like deep brain stimulation, that can also be used once the drugs stop working as well as they should. But we don't have any treatment for slowing or stopping the disease. I think that has been the major focus in a lot of the research that people in the field are doing. There's been a lot of clinical trials with many different types of therapies that have been used. So far, we haven't been successful, which is very similar to what is happening with the Alzheimer disease (AD) field, as well.

What could be driving that lack of success in introducing novel disease-modifying therapies?

Again, I think part of it is due to the complexity of the disease. I think part of it is also that the disease when it appears as we recognize it in the case of PD, is usually with the motor symptoms. When it appears, more than 80% of the dopaminergic neurons are already gone. So the disease has been going on maybe 10, 15, or 20 years already in the patients. So by the time they show up in the clinic, the disease is very progressed. Although it looks like the symptoms are mild at the beginning, biologically it has been going on for a while.

So another hypothesis that has been thrown out there is that maybe we're catching these people too late. We don't have any biomarkers, currently. I think there are some in the pipeline with α-synuclein aggregation that maybe will allow us to identify people before they develop the symptoms. In other people, I think that the therapies that we're trying, especially with those trying to avoid synuclein aggregation, might not be the correct ones. I think the same thing is true for AD, as well. I think for those 2 diseases, some people in the field believe that maybe the hypothesis is incorrect, and maybe we should be providing normal α-synuclein, instead of trying to avoid aggregation, as that might be the byproduct of all the damage that is happening. So, there are a lot of different hypotheses that are going around.

I think having ongoing clinical trials is important. I think the closest that we are right now to something that may slow or stop the progression are those that are targeted for people that have a genetic form of PD, where the biology is at least mostly understood and is caused in some of those cases by 1 single variant. [W]e can understand what is happening biologically and we can try to compensate for what the deficit is. So I think there's definitely a huge need for new therapies, and especially those that help us to slow down or stop the progression.

Ignacio Mata, PhD, an associate professor of neurology at the Cleveland Clinic Lerner Institute, pointed out that genetic forms of PD are relatively well-understood compared to other types.

Genetic Forms of Parkinson Disease May Hold Most Potential for Targeted Treatment

The chief scientific officer of Caribou Biosciences discussed the company’s platform for genome editing.

Steve Kanner, PhD, on Caribou’s chRDNA Technology

“[Hybrid RNA-DNA] technology enables us to maintain very high genome edits on-target, but we do not detect the off-targets within the limits of detection of the assay, in comparison to an all-RNA guide of the same sequence.”

Early efforts in genomic medicine largely saw success with adeno-associated virus vector-based gene therapies, several of which have now been approved by the FDA. Interest in more precise methods of genome modification for therapeutic purposes has continued; however, with CRISPR-based approaches to gene editing being particularly popular. One company currently working on novel CRISPR-based gene editing products is Caribou Biosciences, which originally developed its platform for ex-vivo editing of cell therapy products. Although, more recently, the company has been looking into the potential for in vivo applications of this same platform technology, which it refers to as Cas12a CRISPR hybrid RNA-DNA (chRDNA) genome-editing technology. The company recently presented proof-of-concept data from mouse model work with the platform at 

the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting

, held May 7 to 10, 2024, in Baltimore, MD.

 held shortly after the close of the conference, Steve Kanner, PhD, the chief scientific officer of Caribou Biosciences, discussed the company’s chRDNA technology and how it works. He explained that in the early research on the use of CRISPR-based technology for genome–editing, it was found that all-RNA guides, which are used by bacteria in nature, carry a substantial risk of off-target effects, which can be dangerous in a mammalian therapeutic context. Caribou, on the other hand, is seeking to overcome this risk with the use of hybrid RNA-DNA guides, which preclinical research were able to achieve on-target edits without producing detectable off-target edits. Kanner also spoke about how lipid nanoparticles (LNPs) were used to transport the chRDNA technology to mice’s liver cells via intravenous infusion in the research presented at ASGCT this year. He concluded by noting that modification of the mice’s liver genes was successfully detected.

Click here to view more coverage of the 2024 ASGCT Annual Meeting.

REFERENCE
1. Losa-Llabata M, Rajmane P, Stanaway L, et al. Cas12a CRISPR hybrid RNA-DNA (chRDNA)-mediated i

 genome-editing technology for efficient and functional hepatic gene disruption. Presented at: ASGCT Annual Meeting 2024, May 7-10; Baltimore, Maryland. Abstract #278

RG6501 (OpRegen) allogeneic retinal pigment epithelium (RPE) cell therapy has continued to be well-tolerated in patients with

secondary to age-related macular degeneration (AMD) in extended follow-up data from a phase 1/2 trial (NCT02286089). Patients with less advanced GA also experienced gains in best-corrected visual acuity (BCVA).

Data from the trial were presented at the 2024 Retinal Cell & Gene Therapy Innovation Summit, held on May 3, 2024, in Seattle, Washington, by David Telander, MD, PhD, a staff physician at Retinal Consultants Medical Group, in Sacramento, California.

“The products approved recently for the treatment of GA secondary to AMD have not demonstrated a compelling functional benefit, so there remains a need for treatments that can positively affect patient vision,” Brian M. Culley, the CEO of Lineage, said in a statement.

“We are encouraged by the apparent durability of visual performance being achieved by patients in this study, notably in the 5 patients who received a thorough coverage ofOpRegen cells across the majority of their atrophic areas and who had experienced a cessation or reversal of their areas of atrophy, evidenced by outer retinal structural improvements on optical coherence tomography (OCT). Dry AMD has traditionally been considered to be an irreversible and progressively degenerative disease leading to vision loss. However, these data suggest thatOpRegen RPE cells may provide a one-time treatment which could slow or even reverse this damage by way of direct support to the patients’ remaining retinal cells, including those near or within atrophic areas. We look forward to additional, future clinical data updates on the OpRegen program from our partners, Roche and Genentech.”

Arshad Khanani, MD, on Comparing Wet AMD Gene Therapy 4D-150 to Aflibercept in a Randomized Clinical Trial

Investigators observed improvements in BCVA, specifically, in 10 patients in cohort 4 with less advanced GA 12 months after treatment, which persisted through 24 months. These participants had a mean change in BCVA of +5.5 letters on Early Treatment Diabetic Retinopathy Study (ETDRS) assessment at 24 months post-treatment. In 5 participants with extensive OpRegen bleb coverage of their GA area, the mean change in BCVA was +7.4 ETDRS letters at 24 months.

These participants also maintained or improved external limiting membrane (ELM) and RPE drusen complex (RPEDC) structure on optical coherence tomography OCT. RPEDC area improvements were maintained compared with baseline in treated eyes from 12 months (+2.6 mm

; n = 4). In untreated fellow eyes, RPEDC area had mean decreases at 12 months (–1.1 mm

; n = 4). Similarly, ELM mean area increased in treated eyes from 12 months (+0.4 mm

; n = 4) compared with decreases in untreated fellow eyes from 12 months (–1.3 mm

No serious treatment-related adverse events (AEs) were reported. The most frequent ocular AEs reported in all patients on study treatment were conjunctival hemorrhage/hyperemia (71%) and ERM (67%), and most AEs were mild (87%).

“These data suggest that OpRegen RPE cells may counteract RPE cell dysfunction and loss in GA by providing support to the remaining retinal cells within atrophic areas; such effects are durable through at least 24 months after a single administration,” Telander said during his presentation.

1. Reubinoff B, Barak A, Boyer D, et al. OpRegen® Retinal Pigment Epithelium (RPE) Cell Therapy for Patients with Geographic Atrophy (GA): Month 24 Results from the Phase 1/2a Trial. Presented at: 2024 Retinal Cell & Gene Therapy Innovation Summit, May 3, 2024; Seattle, Washington.
2. OpRegen® (RG6501) Phase 1/2a Clinical Study 24-Month Visual Acuity Results Featured at 2024 Retinal Cell & Gene Therapy Innovation Summit. News release. Lineage Cell Therapeutics. May 6, 2024, https://www.businesswire.com/news/home/20240506017390/en/OpRegen%C2%AE-RG6501-Phase-12a-Clinical-Study-24-Month-Visual-Acuity-Results-Featured-at-2024-Retinal-Cell-Gene-Therapy-Innovation-Summit

RG6501/OpRegen was well-tolerated, with no serious treatment-related AEs reported in follow-up data from a phase 1/2 trial.

Carol Miao, PhD

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