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Lysosomal Disorders

Oncology

1rem

Authors

Annaiz Grimm, BS, a research scientist at Seattle Children's Research Institute

The research scientist at Seattle Children's Research Institute discussed a potential alternative to standard of care immunosuppressive therapy.

Annaiz Grimm, BS, on Using EngTregs to Treat Autoimmune Disease 

Patient use of the 2 FDA-approved gene therapy products for sickle cell disease (SCD), Vertex Pharmaceuticals' and CRISPR Therapeutics’ 

 (exa-cel; marketed as Casgevy) and bluebird bio’s 

 (lovo-cel; marketed as Lyfgenia), in the commercial setting has remained low.

Despite the approval of both gene therapy products by the FDA occurring simultaneously on December 8, 2023, only 4 patients have begun treatment with lovo-cel in the commercial setting, while 20 patients are reported to have begun treatment with exa-cel. Alongside the number for lovo-cel, bluebird also pointed out that this year 4 patients have started on elivaldogene autotemcel (Lenti-D, Skysona), its marketed gene therapy for cerebral adrenoleukodystrophy, and 19 patients have started on betibeglogene autotemcel (beti-cel, Zynteglo), its marketed gene therapy for transfusion dependent thalassemia (TDT). As such, bluebird bio has reported 23 total cell collections for SCD/TDT gene therapies lovo-cel and beti-cel. The company expects that patient uptake of the 3 aforementioned therapies will continue to increase, with 85 patient starts expected across the therapies by the end of the year.

“We are seeing clear evidence that our commercial launch is accelerating, with over 20 cell collections completed in SCD and TDT to date in 2024, and more than 40 additional patients already scheduled to initiate the treatment journey for a bluebird gene therapy by the end of this year,” Andrew Obenshain, MBA, the chief executive officer of bluebird bio, said in a statement.

 “We are further encouraged by the commitment to provide patient access across both commercial and government payers, most recently conveyed through multiple positive Medicaid decisions and the growing number of published coverage policies for Lyfgenia, and we expect approximately 85 patient starts across our portfolio this year.”

Notably, unlike lovo-cel, exa-cel is indicated for both SCD and TDT. Since Vertex has not clarified the breakdown of patients treated with exa-cel for each disease, direct comparison is difficult. The approval in TDT came slightly later, with 

“Vertex delivered another strong quarter of revenue growth coupled with outstanding execution across the business, and we are increasing our full year product revenue guidance,” Reshma Kewalramani, MD, the chief executive officer and president of Vertex, said in an August 1, 2024, statement.

 “Our focus for the second half of the year remains on commercial execution in cystic fibrosis and the global launch of Casgevy, readying for the upcoming potential launches of the vanzacaftor triple in cystic fibrosis and suzetrigine in acute pain, while rapidly advancing a robust pipeline that is poised to deliver value for patients and shareholders for the long term.”

Beyond gene therapy for SCD and TDT, uptake of 

hemophilia gene therapies has also been slow

. Although BioMarin’s valoctocogene roxaparvovec (val-rox, marketed as Roctavian) was approved in June 2023, the first patient outside of clinical trials 

 until December 2023, at the Center for Inherited Bleeding Disorders (CIBD) in California.

 Just this month, BioMarin announced that 

 with regard to val-rox, with the company now mainly focusing on distributing the gene therapy in the United States, Germany, and Italy, the 3 countries in which it has been approved for use by relevant regulatory authorities and is reimbursed.

 UniQure and CSL Behring’s hemophilia B gene therapy, etranacogene dezaparvovec (marketed as Hemgenix), which was 

, has also been slow to be embraced by patients.

“We haven't seen a lot of patients dosed yet,” Steven W. Pipe, MD, a professor of pediatric hematology/oncology at CS Mott Children’s Hospital, told 

 regarding Hemegenix earlier in 2024. “And I don't think that’s related to either the enthusiasm of the clinicians or the patients, but really just the mechanics of how to deliver this in the clinical space, as opposed to the research trials... We've seen that a lot of the hemophilia treatment center sites have got their components together, their infrastructure and personnel so that they can actually start delivering this in the commercial setting. And so, I'm really looking forward to seeing this making a difference in patients' lives in a real world setting.”

REFERENCES
1. bluebird bio reports second quarter 2024 results and highlights operational progress and 2024 guidance. News release. bluebird bio, Inc. August 14, 2024. Accessed August 15, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-second-quarter-2024-results-and-highlights
2. Stock dive for bluebird as sickle cell gene therapy lags behind Vertex rival. News article. Anna Bratulic. FirstWord Pharma. August 14, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5885598
3. Vertex announces US FDA approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. Vertex Pharmaceuticals Incorporated. January 16, 2024. Accessed August 15, 2024. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene
4. Vertex reports second quarter 2024 financial results. News release. Vertex Pharmaceuticals Incorporated. August 1, 2024. Accessed August 15, 2024. https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-second-quarter-2024-financial-results
5. Center for Inherited Blood Disorders Administers Country's First Gene Therapy Infusion to Treat Hemophilia A. News release. Center for Inherited Blood Disorders. January 11, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5817834?from=article
6. BioMarin Announces Updated Strategy for ROCTAVIAN® to Focus on U.S., Germany and Ital. News release. BioMarin Pharmaceutical Inc. August 5, 2024. Accessed August 15, 2024. https://investors.biomarin.com/news/news-details/2024/BioMarin-Announces-Updated-Strategy-for-ROCTAVIAN-to-Focus-on-U.S.-Germany-and-Italy/default.aspx
7. FDA approves first gene therapy to treat adults with hemophilia B. News release. FDA. November 22, 2022. Accessed August 15, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b

bluebird bio has reported 23 total cell collections for SCD and TDT gene therapies lovo-cel and beti-cel and Vertex Pharmaceuticals has reported approximately 20 cell collections for SCD/TDT gene therapy exa-cel.

Topic

Uptake of Nononcology Gene Therapy Remains Slow in Hematology

(arsa-cel, OTL-200; Orchard Therapeutics) is a gene-edited cell therapy designed to restore arylsulfatase A (ARSA) enzyme activity in children with presymptomatic (PS) late infantile (LI), PS early juvenile (EJ), or early symptomatic (ES) early juvenile (EJ) metachromatic leukodystrophy (MLD).

 arsa-cel under the name Lenmeldy to become the first gene therapy for children with MLD to be approved in the United States, following its approval in the European Union, UK, Iceland, Switzerland, Liechtenstein and Norway under the name Libmeldy.1 Orchard Therapeutics previously announced that the FDA had accepted the biologics license application with 

The FDA’s decision was based on data from patients treated with arsa-cel across 2 clinical trials (NCT01560182; NCT03392987) and additional patients treated in expanded access frameworks. These patients had follow-up times ranging from 0.64 years to 12.19 years (median, 6.76).

“Metachromatic leukodystrophy, is a really important unmet need in the pediatric community. So, this is a disease that's rare, it affects about one in 40,000 children. And up until recently, we have had no curative treatment option for this,” Madeleine Powys, MBBS, Staff Specialist, Blood Transplant and Cell Therapies, The Children's Hospital at Westmead, told 

. "Autologous hematopoietic stem cell gene therapy has offered really promising new hope for these patients.”

Madeleine Powys, MBBS, on Lessons Learned With Libmeldy

Arsa-cel is currently being evaluated in 6 participants enrolled in a phase 3 clinical trial (NCT04283227). The trial enrolled participants with documented biochemical and molecular diagnosis of MLD, including low ARSA activity and identification of 2 disease-causing ARSA alleles, with novel mutations analyzed and excluded as common polymorphisms, alongside specific genotype criteria. Symptomatic individuals must have onset between 7 and 17 years of age, or pre-symptomatic participants must be less than 17 years at treatment initiation and have a sibling with late-juvenile MLD variant, along with normal cognitive and motor function, with seizures or disease signs revealed by instrumental evaluations not being exclusionary if present alone, and compliance with contraceptive use requirements if applicable, with signed informed consent or assent provided by the participant or guardian.

The exclusion criteria for the study include documented HIV infection, malignant neoplasia except localized skin cancer or hereditary cancer syndrome unless successfully treated with no recurrence, myelodysplasia, acute myeloid leukemia, or serious hematological disorders, current enrollment in other interventional trials, prior allogeneic HSPC gene therapy or gene therapy, symptomatic herpes zoster unresponsive to treatment, active tuberculosis unless on antibiotic prophylaxis, acute or chronic stable Hepatitis B or positive Hepatitis C RNA test result unless specific conditions are met, end-organ dysfunction, severe infection not responsive to treatment, or other severe diseases deemed inappropriate for the study by the investigator. Additionally, testing for other transmissible infectious agents may be considered, and participants with elevated liver enzymes or bilirubin may be included after discussion and agreement with the medical monitor.

The study’s primary measures involve assessing the OTpbmsL-200 Arylsulfatase A (ARSA) activity levels in cerebrospinal fluid (CSF) and the neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter brain regions, both evaluated at 24 months post-treatment, with changes from baseline being monitored.

Secondary measures involve evaluating changes in ARSA activity levels in CSF and neuronal metabolite ratio in white matter brain regions, assessing ARSA levels in peripheral blood mononuclear cells (PBMCs) and specific subtypes, comparing neuronal metabolite ratios to baseline, siblings, or untreated controls, determining engraftment through lentiviral positivity in bone marrow progenitors and vector copy number in BM cells and PBMCs, assessing severity scale for brain MRI, neurocognitive function, full neurological clinical examination, gross motor function classification, nerve conduction velocity, Vineland Adaptive Behavior Scale, and monitoring conditioning regimen and non-conditioning-related adverse events up to 8 years post gene therapy, along with hematological reconstitution, infusion-related reactions, immune response, abnormal clonal proliferation, replication-competent lentivirus, and integration site analysis findings over time.

, held February 4-9, in San Diego, California, by Vera Gallo, MD, staff pediatrician, San Raffaele Telethon Institute for Gene Therapy. The data were from 5 patients with LJ MLD that had follow-up ranging from 3.2 to 21.3 months (median, 17.3). At the time of treatment, 3 patients had PS MLD and 2 had ES MLD. The group included a 2.7-year-old girl (PS), a 9.9-year-old boy (ES), a 15.2-year-old boy (PS), a 6.6-year-old girl (PS), and 10.9-year-old boy (ES) as of the December 2023 cutoff date.

"This represents of course, the proof of principle that gene therapy with ex- vivo lentiviral gene therapy into stem cells can correct a lysosomal storage disorder (LSD)... and could be applicable to other LSDS. So we're working on new diseases to bring this approach of enzyme correction also to other LSDs," investigator Alessandro Aiuti, MD, PhD, deputy director, clinical research, and head, Clinical Research Unit, San Raffaele Telethon Institute for gene therapy, and Group leader, Pathogenesis and therapy, primary immunodeficiencies unit, and full professor, Università Vita Salute San Raffaele, and chief of clinic, Pediatric Immunohematology Unit, San Raffaele, told 

Data from these participants showed that they all had normal hematological reconstitution and engraftment that was consistent with arsa-cel outcomes seen in patients with early-onset MLD who have been treated in other settings. Time to neutrophil engraftment ranged from 26 to 42 days (median, 33) posttreatment and time to platelet engraftment ranged from 25 to 46 days (median, 26) posttreatment. ARSA activity reached supranormal levels in the PBMCs and in CD15+ cells and increased to normal levels in the CSF in 3 patients for whom central nervous system pharmacodynamic efficacy measures were available.At 90 days after administration of arsa-cel transduced bone marrow progenitors made up between 23.81% to 81.25% of bone marrow progenitors. At this time point, the PBMCs showed a median vector copy number (VCN) of 0.49 copies/cell and the CD15+ cells showed a median VCN of 0.82 copies/cell.

In terms of safety, there were no serious adverse events (SAEs) deemed potentially related to arsa-cel. One nonserious AE deemed potentially related to the therapy, a case of erythematous rash, occurred in 1 patient. No SAEs deemed potentially related to the Busulfan conditioning regimen occurred; although cases of febrile neutropenia, cytopenia, and stomatitis were deemed to have potential relation to the regimen. An SAE of upper respiratory tract infection occurred in 1 patient. One patient with prolonged thrombocytopenia who had previously experienced treatment-failure with allogeneic transplant in the form of autologous reconstitution was administered thrombopoietin receptor agonist therapy for 5 months. No multilineage engraftment of transduced cells or malignancy occurred and there was no indication of clonal expansion or replication competent lentivirus.

1. 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
2. Orchard Therapeutics announces acceptance of biologics license application for OTL-200 in MLD and receives priority review. News release. Orchard Therapeutics. September 18, 2023. Accessed September 18, 2023. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-acceptance-biologics-license
3. Fumagalli F, Calbi V, De Mattia F, et al. Long-term clinical outcomes of atidarsageneautotemcel (autologous hematopoietic stem cell gene therapy) preserves cognitive and motor development in early-onset metachromatic leukodystrophy with up to 12 years follow-up. Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #92
4. Gallo V, Calbi V, De Mattia F, et al. Lentiviral hematopoietic stem cell gene therapy (atidarsageneautotemcel) for late juvenile metachromatic leukodystrophy (MLD). Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #96

The gene-edited cell therapy has been approved as Lenmeldy by the FDA. 

Phase 3 Trial Seeks to Continue Supporting Arsa-Cel Gene Therapy for MLD 

Great Ormond Street Hospital for Children National Health Service Foundation Trust is currently evaluating pCHIM-p47, a lentiviral vector-based gene therapy product, for the treatment of a form of chronic granulomatous disease (CGD) referred to as p47 AR-CGD in a phase 1/2 clinical trial (NCT05207657).

® has decided to take a closer look at this active study.

pCHIM-p47 is intended to provide a functional copy of 

, mutations in which are the cause of p47 AR-CGD. The treatment involves collection of patients’ CD34-positive blood-forming stem cells from the bone marrow, transduction of these cells with a lentiviral vector carrying 

, and subsequent reinfusion of the cells into the patient. pCHIM-p47 is intended to provide an alternative treatment option for p47 AR-CGD to matched sibling donor bone marrow transplant, which is the current standard of care. Although a matched sibling donor bone marrow transplant can be curative for CGD, such a donor is not always available and transplantations from unmatched donors have substantially worse outcomes for patients with CGD.

The nonrandomized, open-label clinical trial for pCHIM-p47, which launched on March 20, 2023, is expected to enroll approximately 5 patients in total and is taking place at Great Ormond Street Hospital in London, United Kingdom. According to the clinicaltrials.gov page for the study, which was most recently updated on May 16, 2025, the study is currently recruiting patients. The estimated completion date for the trial is April 1, 2029. Claire Booth, MBBS, PhD, a consultant pediatric immunologist at Great Ormond Street Hospital, is serving as the principal investigator for the study.

The trial’s primary end points will assess safety and efficacy. Observation of adverse events after treatment will form the basis of the safety assessment along with lentivirus integration site analysis in different cell subpopulations, with the intent of evaluating specific clonal expansions. Furthermore, droplet digital polymerase chain reaction methodology will be used to quantify transgene copy numbers on sorted cell populations. The time frame for safety analysis is 6 months to 1 year post treatment. Efficacy of the gene therapy treatment will be assessed with regard to treatment failure, which is defined by the nonpresence of 

 functioning granulocytes or as less than 5% of expressing cells 12 months after the treatment. A dihydrorhodamine test will be used to assess the efficacy end point.

The trial is open to patients 23 months or older who have p47 AR-CGD as confirmed by DNA sequencing and nonpresence or reduction by more than 95%of hydrogenated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase biochemical activity. Eligible patients must have experienced at least 1 prior, ongoing, or refractory severe infection or inflammatory complication necessitating hospitalization despite conventional therapy. In addition, patients must not have any fully matched 10/10 human leukocyte antigen donor available following an initial search of the National Marrow Donor Program registries within the past year, unless there is an unacceptable risk associated with an allogeneic procedure. Patients must also be free of coinfection with HIV, hepatitis B or C virus, cytomegalovirus (CMV), adenovirus, parvovirus B19, or toxoplasmosis within 8 weeks prior to mobilization, apheresis, or bone marrow harvest. Patients with CMV may be eligible if the infection is controlled.

Patients will be excluded if they have a weight of more than 35 kg. Contraindications for leukapheresis, including hemoglobin levels below 8 g/dL, cardiovascular instability, or severe coagulopathy, will also preclude participation. Additional exclusion criteria cover a broad range of organ system dysfunctions.

Hematologic exclusions include anemia with hemoglobin less than 8 g/dL, neutropenia with absolute granulocyte counts below 1,000/mm

, thrombocytopenia with platelet counts below 150,000/mm

, or prothrombin time or partial thromboplastin time more than twice the upper limit of normal. It is noted that patients with a correctable deficiency controlled by medication may be able to participate.

Patients with cytogenetic abnormalities associated with hematopoietic defects will also be excluded. Pulmonary exclusion criteria include resting oxygen saturation below 90% on room air. Cardiac exclusions include abnormal electrocardiogram results indicating pathology, uncorrected congenital heart malformations with symptoms, active cardiac disease such as congestive heart failure or cyanosis, hypotension, and a left ventricular ejection fraction below 40% on echocardiogram. Neurologic exclusions cover significant abnormalities on examination and uncontrolled seizure disorders. Renal exclusions include serum creatinine levels of 1.5 mg/dL or more, proteinuria of 3+ or greater, or severe serum abnormalities in sodium, potassium, calcium, and magnesium at grade 3 or 4 according to the Common Terminology Criteria for Adverse Events version 4.0. Hepatic exclusions include serum transaminase levels more than 5 times the upper limit of normal, serum bilirubin levels more than twice the upper limit of normal, or serum glucose levels more than 1.5 times the upper limit of normal. Patients who show evidence of active malignant disease will also be excluded.

Additional exclusions apply to patients with an expected survival of less than 6 months, major congenital anomalies, or ineligibility for autologous hematopoietic stem cell (HSC) transplant by trial site criteria. Contraindications to conditioning medications, known sensitivity to busulfan, or administration of interferon gamma within 30 days of infusion of the study therapy will also preclude participation. Patients will also not be eligible if they have taken part in another experimental therapeutic protocol within 6 months. Patients may also be excluded if, in the judgment of the investigator, there are any additional conditions that would compromise safety, adherence, or successful completion of the trial, or if the patient or their parent or guardian is unable or unwilling to comply with protocol requirements.

Notably, Booth previously worked on a preclinical study evaluating the use of lentiviral gene therapy to treat phosphorylated protein p47 (p47

) CGD in human cells, murine cells, and mice.

 in 2020 and demonstrated the ability of the gene therapy to restore expression of p47

 and biochemical NADPH oxidase function in human and murine cells that were deficient in p47

. In addition, the gene therapy was able to reduce bacterial load in p47

 serovar Typhimurium compared with mice that were not treated with the gene therapy.

“Taken together, the results presented here show that our lentiviral gene therapy protocol by the use of the pCCLCHIMp47

 expression and NADPH oxidase function in relevant cells and ameliorate infections,” Booth and colleagues wrote in the paper’s discussion section.

 “Targeted insertion of the therapeutic 

 safe harbour locus or targeted correction of the GT base pair deletion at the start of 

 exon 2 have recently been proposed as alternatives to a gene addition protocol. However, despite rapid advances in the gene editing field for monogenic blood disorders, protocols that contemplate the need for cell proliferation/activation in order to promote homology-directed repair could prove unsuited for HSC that [is] already compromised by chronic inflammation and may show an accelerated loss of stem cell phenotype upon culture. We believe that a lentiviral transduction protocol that entails short-term ex vivo cell culture will offer a rationale treatment option for p47

REFERENCES
1. Lentiviral gene therapy for p47 AR-CGD. ClinicalTrials.gov. Accessed August 18, 2025. https://clinicaltrials.gov/study/NCT05207657
2. Schejtman A, Aragão-Filho WC, Clare S, et al. Lentiviral gene therapy rescues p47phox chronic granulomatous disease and the ability to fight Salmonella infection in mice. 

The nonrandomized, open-label clinical trial for pCHIM-p47, which launched on March 20, 2023, is taking place at Great Ormond Street Hospital in London.

Great Ormond Street Hospital Tackling Chronic Granulomatous Disease With Gene Therapy in Phase 1/2 Trial

One of the challenges of treating neurodegenerative diseases with adeno-associated virus (AAV) vector-based gene therapy is crossing the blood-brain barrier. Among the ways of potentially addressing this challenge currently under research is the use of focused ultrasound.

the American Society of Gene & Cell Therapy (ASGCT) 28th Annual Meeting

, held May 13 to 17, 2025, in New Orleans, Louisiana, Bernie Owusu-Yaw, PhD, a postdoctoral research fellow at Brigham and Women's Hospital, presented her research on this topic, and 

® sat down with Owusu-Yaw on the conference floor to learn more. She went over the key results she presented, their implications, and next steps for the research.

: Can you give some background context about your presentation at ASGCT this year?

 I work on focused ultrasound, which is a noninvasive way of disrupting the blood-brain barrier to enable the delivery of different therapeutics. I work with AAV, so my presentation was about working on optimizing the parameters for focused ultrasound to improve the delivery of AAVs for the treatment of neurodegenerative diseases.

Can you give an overview of the key results?

The efficacy of focused ultrasound-mediated delivery depends on different factors: the AAV serotype, the promoter, the dose, the region that you're targeting, and the ultrasound parameters. We decided to modify the ultrasound parameters to see if we could improve AAV9 transduction but also find the best set of parameters where we get high transduction efficiency within our targeted read in the striatum and also minimize tissue damage. That was the goal of this project. 

We looked at different pressures. We tested 3 different pressures, and we tested 3 different microbubble doses to see if we could improve transduction efficiency any further. What we were able to see is that we were able to achieve successful blood-brain barrier opening for all the pressures and microbubble doses that we tested. We saw a significant increase in blood-brain barrier permeability in the high-pressure group compared with the medium-pressure group and in the high-pressure group compared with the low-pressure group. We were happy with that. 

Then we went on to assess tissue damage, and we actually did not see any signs of tissue damage across any of the pressure doses. We had a high-, medium-, and a low-pressure group, and we tested 3 microbubble doses: 20, 40, and 80 μL/kg. There were no signs of tissue damage. 

Then we went on to assess neuronal transduction efficiency. We treated the right striatum for delivery, and we used the left side as a control, and we saw a significant increase in neuronal transduction in the right-treated striatum compared with the untreated side. This was true across the 3 pressures and the 3 microbubble doses we tested. However, we did not observe any significant differences between the pressure doses or the microbubble doses. With this, we were able to see that although we are significantly increasing transduction efficiency on the treated side compared with the untreated side, within changing the pressure and changing the dose, we're not really maximizing efficiency any further. We saw a range of 2% to 10% of neurons being transduced. So we then decided to change the AAV serotype in collaboration with Fengfeng Bei, PhD, using novel capsids—AAV cell-penetrating peptide (CPP) capsids that were generated by incorporating CPPs into the receptor-binding region of AAV9. We tested the delivery of 2 novel capsids, AAV.CPP.16 and AAV.CPP.21, and we compared it with AAV9 and AAV-PHP.B in BALB/c mice, and with the novel capsids, using focused ultrasound-mediated delivery, we saw a significant increase in neuronal transduction efficiency in the treated cortex—over 60% transduction in the cortex with the 2 novel capsids and over 40% neuronal transduction in the treated striatum. We're really happy with these results moving forward. 

Moving forward, using these optimized parameters and these novel AAV CPP capsids, our research program is really interested in Huntington disease, so we're going to use these capsids to deliver therapeutic agents targeting MSH3 to see if knocking down the MSH3 can reduce the CAG repeat expansion using this method. Those are our steps moving forward.

How would you summarize the big picture implications that you would want physicians and the broader health care community to take away from this?

Focused ultrasound is a rapidly emerging technology, and so far, we've had safe and repeatable blood-brain barrier opening demonstrated in patients with Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and glioblastoma tumors. For our next steps, we're really looking forward to having clinical trials where we open the blood-brain barrier and we deliver AAV. That would be the next leap to get AAVs in patients using focused ultrasound.

Are there any areas of interest that have been identified for further research?

I think even though we increased different parameters and we weren't seeing substantial increases, I think it just shows that the delivery following focused ultrasound, using AAVs, is dependent on many different factors. I think more research needs to be done to tease out the different factors and see how much they contribute so we know how to modify the different factors to get the best outcome while minimizing damage in patients, which I think is an important step as we think about transitioning to the clinic.

This transcript has been edited for clarity.

Click here to view more coverage of the 2025 ASGCT Annual Meeting.

REFERENCE
Owusu-Yaw B. Optimizing focused ultrasound parameters for enhanced AAV delivery across the blood-brain barrier for the treatment of neurodegenerative diseases. Abstract presented at: American Society of Gene & Cell Therapy 28th Annual Meeting; May 13-17, 2025; New Orleans, LA. Abstract 48.

The postdoctoral research fellow at Brigham and Women's Hospital discussed research on focused ultrasound aimed at enhancing AAV delivery across the blood-brain barrier.

Bernie Owusu-Yaw, PhD, on Focused Ultrasound-Mediated Delivery for AAV Gene Therapy

The senior scientist at Voyager Therapeutics discussed the company’s work on developing AAV capsids capable of overcoming patients’ preexisting immunity.

Damien Maura, PhD, on AAV Capsids That Evade Neutralizing Antibodies

“In the field of AAV gene therapy, there is between 30% and 65% of patients who cannot receive an AAV gene therapy treatment due to the presence of neutralizing antibodies. The goal of our work was to try and find a solution for that problem.”

Over the past few years, adeno-associated virus (AAV) vector-based gene therapy has gained a foothold as a key gene therapy modality, and it is currently represented by several FDA-approved products and numerous investigational therapeutic candidates. Although AAV vector-based gene therapies have transformative potential for some indications, a substantial number of patients may be unable to receive these products because they have preexisting immunity to the AAV capsid in use by a particular therapy.

Voyager Therapeutics is currently seeking to overcome this challenge through the development of novel AAV capsids that target the central nervous system and are able to evade the body’s immune response. Notably, Damien Maura, PhD, a senior scientist at Voyager, presented preclinical research on this topic at 

, held May 13 to 17, 2025, in New Orleans, Louisiana.

® sat down with Maura to learn more. Maura explained that using the company's proprietary Tropism Redirection of AAV by Cell-type-specific Expression of RNA (TRACER) technology, Voyager redesigned capsid surfaces to remove antibody epitopes in order to improve immune evasion.

Maura highlighted the discovery of a third-generation TRACER capsid that preserves the brain transduction efficiency and cellular tropism of its parent capsid while adding mutations for antibody resistance. He also pointed out that machine learning models further identified additional mutations that could enhance both brain transduction and immune evasion.

Maura emphasized that although these findings are promising, translation to humans remains the biggest unknown until clinical trials begin. He also touched on Voyager’s future plans for the technology, which will focus on further expanding patient eligibility by incorporating additional mutations to capsid epitopes.

Videos

Iovance Biotherapeutics’ lifileucel (Amtagvi), a tumor-derived autologous tumor-infiltrating lymphocyte therapy (TIL), has received a Notice of Compliance with conditions (NOC/c) from Health Canada for advanced melanoma.

Specifically, the market authorization applies to adults with unresectable or metastatic melanoma who have no satisfactory alternative treatment options and whose disease has progressed after or during treatment with at least 1 previous line of systemic therapy that included a PD-1–blocking antibody. Furthermore, if the patient’s disease is positive for a 

 V600 mutation, they must also have received a BRAF inhibitor.

The NOC/c was issued based on results of the completed phase 2 C-144-01 clinical trial (NCT02360579). Notably, lifileucel’s market authorization in Canada is conditional and depends upon future trial data confirming clinical benefit of the therapy. An ongoing phase 3 clinical trial referred to as TILVANCE-301 (NCT05727904), which was initiated on March 30, 2023, is evaluating lifileucel in frontline advanced melanoma and some other solid tumor indications.

“This approval in Canada is our first marketing authorization outside the US and marks a significant step forward for Iovance as we prepare to introduce Amtagvi in countries with a high prevalence of advanced melanoma and address substantial unmet needs in solid tumor cancers,” Frederick Vogt, PhD, JD, the interim CEO and president of Iovance, said in a statement.

 “We expect to authorize our first Canadian treatment center within the next few months, and we continue to advance our ex-US strategy for Amtagvi in additional markets.”

 since February 2024 and is indicated by the FDA for adults with unresectable or metastatic melanoma previously treated with a PD-1–blocking antibody or treated with a BRAF inhibitor in the instance that the patient has 

 It was the first cellular therapy to have received the aforementioned indication. Notably, the therapy was granted accelerated approval by the FDA. Iovance Biotherapeutics had previously noted that if lifileucel received accelerated approval in the US, TILVANCE-301 may transition into a confirmatory trial to support the therapy’s full approval.

 The FDA’s announcement of the approval decision reiterated that data from TILVANCE-301 would be utilized as such.

 from patients with advanced melanoma treated in C-144-01 showing that lifileucel had produced durable responses was presented at 

the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting

, held May 30 to June 3, in Chicago, Illinois, and was simultaneously published in the

 The analysis included 153 patients with a median follow-up of 57.8 months who had completed or discontinued participation in C-144-01, of whom 28 (18.3%) had completed the 5-year study follow-up. The objective response rate was 31.4%, with a partial response rate of 25.5% and a complete response rate of 5.9%, and the patients achieved a median duration of response of 36.5 months (95% CI, 8.3-not reached).

“This 5-year analysis of the C-144-01 trial is the longest follow-up of the largest group of patients with melanoma treated with TILs in a single study,” first author Theresa Medina, MD, a medical oncologist at the University of Colorado Cancer Center on the Anschutz Medical Campus, and colleagues wrote in the ASCO abstract.

 “This study illustrates lifileucel’s continued durability of response and survival benefit up to 5 years after a single administration without any long-term safety concerns.”

REFERENCES
1. Iovance’s Amtagvi (lifileucel) receives Health Canada approval for advanced melanoma. News release. Iovance Biotherapeutics Inc. August 18, 2025. Accessed August 19, 2025. https://ir.iovance.com/news-releases/news-release-details/iovances-amtagvir-lifileucel-receives-health-canada-approval
2. FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. FDA. February 16, 2024. Accessed August 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma
3. FDA approves first cellular therapy to treat patients with unresectable or metastatic melanoma. News release. FDA. February 16, 2024. Accessed August 19, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma
4. Iovance’s AMTAGVI (lifileucel) receives U.S. FDA accelerated approval for advanced melanoma. News release. Iovance Biotherapeutics Inc. February 16, 2024. Accessed August 19, 2025. https://ir.iovance.com/news-releases/news-release-details/iovances-amtagvitm-lifileucel-receives-us-fda-accelerated
5. Medina T. Lifileucel in patients with advanced melanoma: five-year outcomes of the C-144-01 study. Abstract presented at: 2025 American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2025; Chicago, IL. Abstract 9515.
6. The Journal of Clinical Oncology publishes five-year analysis of Amtagvi (lifileucel) in patients with advanced melanoma. News release. Iovance Biotherapeutics Inc. June 2, 2025. Accessed August 19, 2025. https://ir.iovance.com/news-releases/news-release-details/journal-clinical-oncology-publishes-five-year-analysis-amtagvir

Lifileucel has been approved in the US since February 2024.

Annaiz Grimm, BS

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