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Robert Califf, MD, MACC, a cardiologist and former FDA commissioner, discussed the necessity of policy and funding efforts for neuromuscular disorders, the stress on the clinical care system, and the need to acknowledge healthcare inequities.

Urgency of Funding and Equity in Neuromuscular Research and Care

The former FDA commissioner discussed the necessity of policy and funding efforts for neuromuscular disorders, the stress on the clinical care system, and the need to acknowledge healthcare inequities.

Robert M Califf, MD, MACC, on Urgency of Funding and Equity in Neuromuscular Research and Care

The commissioner of food and drugs at the FDA discussed the year's approvals and what may be coming on the horizon in the realm of advanced therapeutics.

Robert M Califf, MD, MACC, on 2023’s Landmark FDA Approvals of Cell and Gene Therapies

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 

This video originally appeared on our sister site, 

The professor of neurology at the University of Texas Health Science Center San Antonio discussed the genetic basis of oculopharyngeal muscular dystrophy, as well as the primary challenges in diagnosing and treating the condition.

Matthew Wicklund, MD, on OPMD and Advancements in Genetic Research

"While we don’t have definitive treatments yet for OPMD, the hope lies in emerging preclinical research and gene therapies that could one day transform how we manage this disease."

Oculopharyngeal muscular dystrophy (OPMD) constitutes a rare, autosomal dominant disorder. Its symptoms include progressive weakness in muscles controlling eye movement, swallowing, and limb strength. Trinucleotide repeat expansion in the 

 gene are the root cause of the disorder, which typically presents with ptosis, dysphagia, and proximal limb weakness when patients are aged in their 40s or 50s. OPMD remains underdiagnosed despite its recognition, and management of the disease is primarily focused on addressing symptoms instead of the underlying genetic cause.

Matthew Wicklund, MD, a professor of neurology at the University of Texas Health Science Center San Antonio, recently chaired a session on clinical and preclinical advances in OPMD as part of the “Lab to Life Track” at 

the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference

, held March 16-19, in Dallas, Texas.  Guy Rouleau, PhD; Bernard Brais, MDCM, PhD; Jerel Banks, PhD; and Claudia Cote, PhD, were among the other prominent clinicians featured in the session.

, Wicklund highlighted promising preclinical research exploring genetic-based therapies, including CRISPR gene editing and RNA silencing techniques. These approaches aim to either repair the mutated gene or prevent the production of the abnormal protein responsible for OPMD. Although these therapies are still in the early stages, they offer hope for more effective treatments in the future. In addition, Wicklund discussed the challenges clinicians face in diagnosing OPMD, noting that because of its late onset and symptom overlap with other neuromuscular disorders, OPMD can often be mistaken for other conditions. As research continues, he stressed the need for targeted, personalized treatment strategies to address the unique needs of each patient.

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The chair of the department of medicine at Roswell Park Comprehensive Cancer Center discussed the innovations necessary to make CAR-T therapy effective in solid tumor indications.

Renier Brentjens, MD, PhD, on Using Armored CAR T-Cells to Tackle Solid Tumors

“I think over the brief 20 year span that I've been doing this work, I think we philosophically kind of changed how we look at [CAR T-cells as cytotoxic agents], and we realized that that the CAR T-cell may be more of a spark rather than the actual explosion. It's the spark that sets off a downstream effect where an immune system that is actually quite reasonably sophisticated in recognizing cancer cells can overcome the defenses that cancer cells create around themselves to stop cell therapies from working.”

Over the past 5 to 10 years, chimeric antigen receptor T-cell (CAR-T) therapy has established itself as an effective treatment modality for blood cancers, with several products having been approved by the FDA for such indications. Although, attempts to apply the same approach to solid tumor indications have proven difficult because of key differences in solid tumor biology. As such, it has become clear that a modified approach to CAR-T therapy will be necessary to make the modality able to provide clinically meaningful benefit for solid tumors. One such approach is the concept of “armored CAR T-cells", CAR-T products that have additional genetic modifications intended to combat cancer cells beyond the use of the CAR itself.

 recently spoke with Renier Brentjens, MD, PhD, the chair of the department of medicine and the deputy director at Roswell Park Comprehensive Cancer Center, about how armored CAR T-cells can help bridge the gap necessary to make CAR-T effective in solid tumors. Brentjens pointed out that unlike blood cancers, solid tumors are more complex, often surrounded by nontumor cells that block immune responses. Armored CAR T-cells can reshape this environment and trigger the body’s natural immune system to help attack the cancer. Furthermore, he emphasized that in solid tumors armored CAR T-cells may help address antigen escape, which is typically an even greater challenge for solid tumors than it is in blood cancers.

An FDA Cellular, Tissue, and Gene Therapies Advisory Committee (AdComm) has voted against BrainStorm Cell Therapeutics’ debamestrocel (NurOwn), an investigational autologous mesenchymal stem cell (MSC) neurotrophic factor–secreting cell therapy product intended to treat amyotrophic lateral sclerosis (ALS), ahead of its Prescription Drug User Fee Act action date, which is slated for December 8, 2023.

 Notably, in the days leading up to the AdComm meeting, BrainStorm requested to change the indication targeted with NurOwn from “ALS” to “mild to moderate ALS”.

The committee overwhelmingly voted negatively, with 17 members voting no and 1 member voting yes to the question: “Do the data presented demonstrate substantial evidence of effectiveness for treatment of mild to moderate ALS?” One member abstained. In the public hearing portion of the AdComm, a number of patients, caregivers, and family members spoke in favor of approval based on their personal experiences with NurOwn.

“It's possible that this therapy has some benefit for some patients,” Lynn A. Raymond, MD, PhD, the director of the Djavad Mowafaghian Centre for Brain Health, said after voting no.

 “But we look at the total when we have to decide whether this goes forward to public market and there wasn't evidence for the whole group that this was effective and there was evidence to potentially suggest it was actually deleterious at least for those who are maybe more advanced with ALS, causing more deaths and causing more bulbar dysfunction. So for that reason, I vote no...”

BrainStorm’s argument in favor of approval of 

 largely focused on the potential impact of the floor effect on the results of the pivotal phase 3 clinical trial (NCT03280056) that evaluated the treatment against a placebo in patients with ALS, which did not meet any of its primary or key secondary end points. Regarding the floor effect, Brainstorm noted that in a prespecified subgroup of patients with less advanced disease, who had a score of at least 35 on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), a statistically significant difference in the change from baseline in ALSFRS-R was observed favoring the group of patients who received NurOwn compared with the group of patients who received a placebo.

 A posthoc sensitivity analysis of patients who had an ALSFFRS-R score of 26 or higher also found that participants treated with NurOwn progressed 2 points less on the ALSFRS-R scale on average compared with patients who received the placebo.

BrainStorm also included data from the phase 3 study 

 including neurofilament light (NfL) in its argument. After accounting for baseline disease covariates, treated participants had reduced NfL values from baseline to week 20 compared to placebo (

The FDA’s response focused mainly on the fact that the prespecified primary and key secondary end points were not met and that posthoc analyses, such as the analyses related to the floor effect that BrainStorm presented, are not sufficient to support approval on their own. The FDA emphasized that prespecification is the cornerstone of reliable evidence in clinical trials and that the results seen in the posthoc analysis are not reliable. An additional concern brought up was that more deaths occurred in the group of patients treated with NurOwn in the trial than in the placebo group. With regard to the NfL and other biomarker data from the trial, the FDA stated that the analysis did not support efficacy, as a greater NfL reduction was associated with worse outcomes in the modified intention to treat population and there was no clear association between changes in the levels of other biomarkers, including galectin-1, LAP (TGFβ-1), MCP-1, and VEGF, and measurements of clinical benefit. Further concerns noted by the FDA were the absent or incomplete critical manufacturing controls and lack of established product quality.

Overall, the FDA concluded that the available data do not support approval of NurOwn for either ALS or mild to moderate ALS indications. The agency suggested that the exploratory data regarding the floor effect may inform the basis of a new clinical trial aimed at demonstrating efficacy, if BrainStorm chooses to continue to pursue the product’s approval.

“I think it is very clear that I include data that no one else considers as real data...” Kathleen O’Sullivan-Fortin, Esq., the founder of ALD Connect, Inc., said while making the sole ‘yes’ vote.

 “I think there's no bigger risk than imminent certain deaths from ALS and these are unique and desperate circumstances that would require us to exercise flexibility. With everyone else here, I wish that the sponsor’s data was definitive and broad and fixed and helped and saved everyone, and it wasn't going to be that, but I still think there was a value.”

The meeting concluded with a discussion of potential design decisions for future clinical trials evaluating the therapy that could more effectively demonstrate efficacy. Some suggestions included accounting for the floor effect in prespecified analyses, using a different measure of efficacy than the ALSFRS-R in order to avoid the floor effect altogether, and developing an allogeneic version of the therapy in order to ensure more standardization of the product ultimately administered to patients.

“My suggestion to the sponsor would be to add a key secondary end point or quality of life measure that would capture the anecdotal improvements in daily activities and capture the testimonials of benefit [mentioned during the public hearing],” Wendy B. London, PhD, an associate professor of pediatrics at Boston Children’s Hospital/Dana-Farber Cancer Institute, who voted no, added during this portion.

1. 74th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. September 27, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-september-27-2023-meeting-announcement
2. Brainstorm Cell Therapeutics announces FDA advisory committee meeting to review NurOwn® biologics license application scheduled for September 27, 2023. News release. BrainStorm Cell Therapeutics Inc. June 6, 2023. Accessed September27, 2023. https://ir.brainstorm-cell.com/2023-06-06-BrainStorm-Cell-Therapeutics-Announces-FDA-Advisory-Committee-Meeting-to-Review-NurOwn-R-Biologics-License-Application-Scheduled-for-September-27,-2023
3. BrainStorm Cell Therapeutics data show treatment with NurOwn significantly reduces NfL, a key biomarker of neurodegeneration. News release. BrainStorm Cell Therapeutics. July 7, 2023. Accessed September 27, 2023. https://prnmedia.prnewswire.com/news-releases/brainstorm-cell-therapeutics-data-show-treatment-with-nurown-significantly-reduces-nfl-a-key-biomarker-of-neurodegeneration-301871918.html

Committee members were overwhelmingly against the available data supporting NurOwn as an effective treatment for mild to moderate ALS, with 17 no votes, 1 yes vote, and 1 abstention. 

FDA AdComm Votes Down BrainStorm Cell Therapeutics’ ALS Cell Therapy NurOwn 

This article originally appeared on our sister site,

On the last day of February each year, Rare Disease Day is held. An international awareness campaign, Rare Disease Day is intended to to shine light on the challenges faced by people living with rare diseases and to facilitate advocacy for equitable access to diagnosis, research, and treatment. Originally launched in 2008 by the European Organization for Rare Diseases (EURORDIS), Rare Disease Day has garnered global participation in the years since. It involves patient advocacy groups, healthcare professionals, those involved in scientific research, policymakers, and the general public.

Rare diseases are defined as those affecting fewer than 1 in 2000 people. More than 7000 rare diseases have been identified to date, and together these disease affect more than 300 million people across the globe.

One such rare disease is SLC6A1-related neurodevelopmental disorder, also known as SLC6A1 Deficiency Disorder, a rare genetic condition characterized by mild-to-moderate developmental delay and/or intellectual disability, hypotonia, epilepsy, movement disorders, and neurobehavioral and/or psychiatric manifestations. Fewer than 500 people in the world have reported cases of SLC6A1 as of 2020, indicating an estimated incidence of 2.65 in 100,000 births for the disease.

In 2018, Amber Freed founded SLC6A1 Connect, an advocacy organization dedicated to raising awareness, advancing research, and supporting families affected by SLC6A1-related disorders. Freed, whose son was diagnosed with the condition, sat down with

®, to shed light on the daily struggles faced by families, from disrupted routines to the challenges of caregiving and finding informed clinicians. Highlighting the importance of Rare Disease Day, she emphasized the urgent need for funding and awareness to advance gene therapy research, particularly her collaboration with the Steve Gray Lab to develop a potential cure. Overall, she advocates for precision medicine as the future of treatment for rare diseases and called for greater activism within the community to accelerate progress.

 What are some of the lesser-known aspects of SLC6A1 disease?

 I founded SLC6A1 Connect when my son Maxwell was diagnosed with the genetic variant SLC6A1. It’s a rare genetic epilepsy, and along with seizures come a lot of behavioral deficits, a movement disorder, speech apraxia, and intellectual disability. He just struggles. I think one thing people don’t really understand about the disorder is that there’s so much more than just epilepsy. It’s everyday tasks. It’s trying to teach someone whose brain is “on fire” and having an incredibly hard time trying to learn.

 is a gene that codes for GAT1, which controls the body’s most important neuroinhibitory transmitter. If your brain is not inhibited, that’s bad—you can just imagine trying to get through your day like that. Rare Disease Day helps bring awareness to just how important these conditions are and what the daily struggles look like. Our community has a huge unmet need. The term autism is very broadly used, but when you narrow it down to the symptoms, it highlights what a typical day is like. Our poor kids have a really hard time sleeping—they don’t understand the difference between day and night. It’s really hard for them to be awake during the day, and meal times are all messed up. That’s not going to change because of this genetic abnormality. As you can imagine, that leads to a very tough family life. Siblings want to have sports and school activities, but it’s hard when it typically takes the full-time attention of two parents to care for just one child.

Are there any SLC6A1-related research or initiatives that need greater attention or focus?

When Maxwell was diagnosed, we figured out he’s missing half of a pretty important gene. The most eloquent solution is to just replace what’s missing, and the technology exists today to do that. The only thing holding us back is money. Since his diagnosis in 2018, we’ve had a laser focus on achieving that. We’re working with the Steve Gray lab at UT Southwestern, and we’ve raised $6 million philanthropically to get to that goal. Now, this Rare Disease Day, we’re announcing the next step: toxicology. Our next fundraising goal is $750,000 to get through the final toxicology studies and then actually start treating humans. That will be the closest thing to a cure our kids will see in our lifetime.

It’s super expensive for us, but like with any technology, it starts big and costly, like old cell phones, and eventually becomes smaller, more accessible, and affordable. The work we’re doing today is going to help so many people in the future.

Are there ways we can help patients with their intellectual disabilities?

Intellectual disability and behavior are really tough. For kids with rare genetic epilepsies, it’s hard to know what their intellect truly is because they’re trapped in their bodies. We all know there’s so much more going on inside than what we see on the outside. But a lot of times, they’re nonverbal or can’t express themselves. I believe the future for epilepsy and rare diseases lies in personalized, precision medicine, just like how cancer treatment has evolved.

You’re no longer diagnosed with just “breast cancer.” It’s a specific variant, and your doctor designs a treatment just for you. There’s no reason we can’t do the same for epilepsy and neurological conditions. The earlier we treat people with a precision approach, the better. It keeps them from carrying these challenges into adulthood. Parents live with this dark fear—what happens to my child when I die? Who will take care of them? There’s no place for them in society, and they need full-time caretakers. That’s such a sad life for them. Let’s fix it from the beginning. Let’s replace what’s missing so they can go on to be the best versions of themselves.

How difficult is it to find a clinician who’s versed in SLC6A1 disease?

It’s very difficult to find a doctor who fully understands SLC6A1. It’s taken a lot of, for lack of a better term, “dating” to find doctors who are passionate about research, inspired by the rare disease community, and who truly understand the unmet need. I coach patients to feel empowered to educate their doctors about the disease. Take in a one-pager that explains what it’s like. Don’t hold back. Don’t sugarcoat things—you’ve got 15 to 30 minutes of their time, so make it count.

This Rare Disease Day, I want to encourage patients, doctors, and scientists to be activists. Think about where we were in the ‘80s and ‘90s with HIV/AIDS or with cancers in the early 2000s—that’s where we are with rare diseases now. For the first time, we’re able to identify not just a gene diagnosis but a potential cure. It’s going to take more awareness, more action, more walks, and more outreach to our senators and congresspeople. We need to educate them on why this matters. We have a chance to change the future of medicine today, so let’s take it. We’re never going to solve complex diseases like Alzheimer disease if we can’t knock out these simpler diseases first.

This transcript has been edited for clarity.

In honor of Rare Disease Day, observed this year on February 28, Amber Freed, the founder of SLC6A1 Connect, shared thoughts on advocacy and efforts to raise awareness for rare genetic disease SLC6A1.

Robert M Califf, MD, MACC

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