Victoria Johnson

This article was orginally published in GeneTherapyLive.

Among the myriad of conditions benefitting from blood donation is sickle cell disease (SCD), in which cell and gene therapies are currently being evaluated as possible avenues of treatment. Research into cell and gene therapies for SCD is especially important right now, with blood supply shortages prompting the Red Cross to declare its first ever blood crisis this January.1 Since January is National Blood Donor Month, we’ve compiled the latest updates on cell and gene therapies in development for SCD.

Aruvant Sciences is currently evaluating 

, a modified γ-globin lentiviral gene-edited cell therapy in the phase 1/2 Momentum study (NCT02186418). Data presented at the 63rd Annual American Society of Hematology (ASH) Meeting, December 11-14, 2021, by Punam Malik, MD, director, Cincinnati Comprehensive Sickle Cell Center; program leader, Hematology and Gene Therapy Program; and Marjory J. Johnson Chair, Gene and Cell Therapy, Cincinnati Children’s Medical Hospital, demonstrated the therapy’s promising safety and efficacy in SCD.2

The trial has treated 4 patients as of July 28, 2021, all of which have experienced 

 and improved SCD manifestation and greatly decreased instances of vaso-occlusion events from baseline. Patients have experienced adverse events (AEs) such as transient neutropenia and thrombocytopenia. ARU-1801 has received rare pediatric disease and orphan drug designations from the FDA.

, a zinc finger nuclease gene-edited cell therapy candidate. The candidate was previously being developed in collaboration with Sanofi, who announced the collaboration’s termination in January 2022 to take effect in June 2022.3 The phase 1/2 PRECIZN-1 study (NCT03653247) will be completed as planned and Sangamo is currently seeking another collaborative partner to develop the cell therapy.

Sangamo previously reported positive tolerability and durability data on SAR445136 from the PRECIZN-1 study at the 

.4 All 4 treated patients no longer required blood transfusions after infusion with SAR445136 and total hemoglobin stabilized in these patients by week 26. In all 4 patients, the cell therapy had on-target BCL11A gene modification, and fetal hemoglobin and percent F cells were significantly increased at up to 91 weeks from screening levels.

The turbulent development oflovotibeglogeneautotemcel(bb1111; lovo-cel; LentiGlobin) by bluebird bio has hit another bump in the road, with the FDA placing the program on 

 in December 2021 following a report of persistent anemia in an adolescent patient.5 It is the second clinical hold for the program, the first of which was lifted in June 2021 after the company demonstrated that their lentiviral vector was not associated with patients developing acute myeloid leukemia and myelodysplastic syndrome. 

Lovotibeglogene autotemcel is currently being evaluated in the phase 3 HGB-210 study (NCT04293185) and previous positive efficacy data has been presented from the phase 1/2 HGB-206 study (NCT02140554).6 The gene therapy has been granted orphan drug, fast track, regenerative medicine, and rare pediatric disease designations by the FDA.

 is being developed by Vertex Pharmaceuticals and CRISPR Therapeutics, with Vertex 

 in developing and commercializing the CRISPR/Cas9-based gene editing candidate for the potential treatment of both SCD and β-thalassemia.7 It is currently being evaluated for efficacy and safety in SCD in the phase 1/2/3 CLIMB SCD-121 study (NCT03745287).

Results from the phase 1/2 study were presented at the 

European Hematology Association Annual Meeting, June 9-17, 2021.

 Seven patients with severe SCD were free of vaso-occlusion events after treatment for at least 3 months to up to a year of follow-up. Patients had clinically meaningful improvements in total hemoglobin and fetal hemoglobin levels, and no treatment-related AEs were reported.8 The gene therapy has been granted regenerative medicine, fast track, and orphan drug designations by the FDA.

 is being evaluated in the phase 1/2 CEDAR trial (NCT04819841). Details on the trial were presented at ASH 2021.9 The first patient in the study has been enrolled and preliminary data will be presented at the end of 2022. The trial is primarily assessing safety and secondary outcomes include pharmacodynamics and efficacy measures such as levels of adult hemoglobin (HbA), sickle hemoglobin (HbS), total hemoglobin and VOEs, and acute chest syndrome.

The autologous CD34+ hematopoietic stem cell therapy was developed using Graphite’s next-generation, targeted, Cas9 gene integration platform. GPH101 previously demonstrated a reduction in HbS production and restored HbA expression in preclinical studies. The candidate has been granted orphan drug designation by the FDA.

The FDA recently cleared Beam Therapeutics’ 

, a CRIPSR, ex vivo base editing autologous cell therapy product for the potential treatment of both SCD and β-thalassemia.13 The therapy will be evaluated in the phase 1/2 BEACON-101 trial.

Beam is also developing another base editing candidate for SCD called BEAM-102, which they have initiated IND-enabling studies for. BEAM-101 makes single base changes without double strand DNA breakage to mimic single nucleotide polymorphisms seen in SCD and β-thalassemia while BEAM-102 directly corrects the SCD causative mutation by recreating HbG Makassar.

The Assistance Publique - Hôpitaux de Paris isconducting the phase 1/2 

 trial (NCT03964792) of the titular cell therapy, which consists of autologous CD34+ cells transduced ex vivo with the GLOBE1 lentiviral vector expressing the βAS3 globin gene.

Results from the Drepaglobe trial were presented at ASH 2021 by Elisa Magrin, PharmD, Assistance Publique-Hôpitaux de Paris.10 Three treated patients with follow-up of at least 6 months showed no serious treatment-related AEs. Investigators found that 2 patients clinically benefitted from treatment, but the third did not due to engraftment issues. The observed variable efficacy of the treatment puts its future into question and further research and analysis to define critical parameters for success is needed.

βAS3-FB Vector Transduced Peripheral Blood CD34+ Cells

The UCLA Broad Stem Cell Research Center, in collaboration with the California Institute for Regenerative Medicine, is conducting a phase 1/2 clinical trial (NCT02247843) of a cell therapy candidate consisting of 

autologous, βAS3-FB vector-transduced peripheral blood CD34+ cells

.11 The trial is currently recruiting up to 6 participants with SCD.

The study’s primary objectivesare to assess safety and feasibility, and its secondary objectives are to assess efficacy by measuring engraftment, βAS3-globin gene expression, red blood cell function, and clinical hematologic and disease parameters. Participants will be followed up every 3 months for 2 years and then as part of a long-term follow-up study for 15 years.

CD34+ BCH-BB694 Lentiviral Vector Cells with BCL11A-Targeted shRNA in MicroRNA

Boston Children’s Hospital is conducting a phase 1 study (NCT03282656) of a cell therapy consisting of 

autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector

, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA. The study is currently recruiting up to 15 participants with SCD.

Results were published in January 2021 that demonstrated positive engraftment results and a tolerable safety profile.12 All evaluable patients had robust and stable HbF induction and reduced clinical manifestations of SCD.

1. Red Cross declares first-ever blood crisis amid Omicron surge. News release. American Red Cross. January 11, 2022. 

https://www.redcross.org/about-us/news-and-events/press-release/2022/blood-donors-needed-now-as-omicron-intensifies.html


2. Grimley M, Asnani M, Shrestha A, et al. Safety and efficacy of Aru-1801 in patients with sickle cell disease: Early results from the phase 1/2 Momentum study of a modified gamma globin gene therapy and reduced intensity conditioning. Presented at: 63rd Annual ASH Meeting; December 11-14, 2021, Atlanta, GA. Abstract 3970.
3. Sangamo announces transition of SAR445136 sickle cell disease program from Sanofi to Sangamo. News release. Sangamo Therapeutics. January 6, 2022. 

https://investor.sangamo.com/news-releases/news-release-details/sangamo-announces-transition-sar445136-sickle-cell-disease


4. Sangamo Therapeutics announces updated preliminary SAR445136 phase 1/2 proof-of-concept data showing tolerability and sustained effects in sickle cell disease. News release. Sangamo Therapeutics. December 12, 2021. 

https://investor.sangamo.com/news-releases/news-release-details/sangamo-therapeutics-announces-updated-preliminary-sar445136


5. bluebird bio Announces Partial Clinical Hold for Patients Under 18 in Sickle Cell Gene Therapy Clinical Program. News release. bluebird bio. December 20, 2021. 

https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-partial-clinical-hold-patients-under-18


6. Walters MC, Thompson AA, Kwiatkowski JL, et al. Resolution of Serious Vaso-Occlusive Pain Crises: Results from the ongoing phase 1/2 HGB-206 group C study of lentiglobin for sickle cell disease (SCD; bb1111) gene therapy. Presented at: 2021 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, February 8-12, 2021. Abstract 13.
7. Vertex Pharmaceuticals and CRISPR Therapeutics amend collaboration for development, manufacturing and commercialization of CTX001™ in sickle cell disease and beta thalassemia. News release. Vertex Pharmaceuticals. April 20, 2021. 

https://investors.vrtx.com/news-releases/news-release-details/vertex-pharmaceuticals-and-crispr-therapeutics-amend


8. Vertex and CRISPR Therapeutics present new data in 22 patients with greater than 3 months follow-up post-treatment with investigational CRISPR/Cas9 gene-editing therapy, CTX001™ at European Hematology Association Annual Meeting. News release. Vertex Pharmaceuticals. June 11, 2021. 

https://www.businesswire.com/news/home/20210611005069/en/


9. Graphite Bio presents overview of phase 1/2 CEDAR trial evaluating investigational gene editing therapy GPH101 in sickle cell disease at 63rd ASH Annual Meeting and Exposition. News release. Graphite Bio. December 11, 2021. 

https://www.businesswire.com/news/home/20211211005014/en/Graphite-Bio-Presents-Overview-of-Phase-12-CEDAR-Trial-Evaluating-Investigational-Gene-Editing-Therapy-GPH101-in-Sickle-Cell-Disease-at-63rd-ASH-Annual-Meeting-and-Exposition


10. Magrin E, Magnani A, Semeraro M, et al. Clinical results of the Drepaglobe trial for sickle cell disease patients. Presented at 63rd Annual ASH Meeting; December 11-14, 2021, Atlanta, GA. Abstract 1854.
11. Stem cell gene therapy for sickle cell disease. NIHUS National Library of Medicine. August 31, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02247843


12. EsrickEB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med 2021; 384:205-215. doi: 10.1056/NEJMoa2029392
13. Beam Therapeutics provides business and pipeline updates and reports third quarter 2021 financial results. News release. November 8, 2021. https://investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-provides-business-and-pipeline-updates-and-0

Articles

Exciting new therapies for sickle cell disease are on the horizon. We explored some of the most promising investigational therapies in recognition of National Blood Donor Month.

The State of Gene and Cell Therapy for Sickle Cell Disease

This article was originally published in NeurologyLive.

New data shows patients with neurodegenerative diseases (NDD) treated with pimavanserin (Nuplazid) did not experience negative 

 with up to 9 months of treatment compared to placebo.

2021 American Academy of Neurology (AAN) Annual Meeting

, April 17-22, by Clive Ballard, MD, professor, age-related diseases, and pro-vice-chancellor and executive dean, University of Exeter Medical School. Ballard and colleagues sought to evaluate pimavanserin’s impact on cognition in patients with neuropsychiatric manifestations of NDD across multiple studies.

“Neuropsychiatric symptoms, including psychosis, are common among patients with dementia and are associated with poorer clinical outcomes. No therapies are approved in the United States for treating dementia-related psychosis (DRP). Off-label antipsychotic use is associated with significant adverse outcomes, including accelerated cognitive decline,” Ballard and colleagues wrote in the abstract.

The researchers analyzed cognitive function via the Mini-Mental State Examination (MMSE) that was an outcome in 3 parallel-arm, double-blind studies (019, 032, 046) that compared 34 mg of pimavanserin with placebo as well as the phase 3 randomized withdrawal HARMONY study. This study consisted of a 12-week open label phase followed by a randomized, double-blind period. There were 697 patients receiving pimavanserin across all studies, and 622 had DRP. Cognition related treatment-emergent adverse events (TEAEs) were also analyzed.

Ballard and colleagues found that the MMSE score least squares mean (LSMO change from baseline to week 12 was –0.25 (standard error [SE], 0.42) in study 019 and 0.0 (SE, 0.57) in study 032, and similar to placebo in both. LSM change from baseline to week 8 was 1.2 (SE, 0.21; n = 132) for pimavanserin and 0.5 (SE, 0.21; n = 128) for placebo in the interim analysis of study 046.

In the HARMONY study, the mean change from baseline to week 12 was 1.0 (SE, 0.22; n = 145). During the double-blind period, mean MMSE score with pimavanserin treatment did not decline and was similar to placebo. Patients treated with pimavanserin for the whole 9 months of the study (n = 46) had a mean change from baseline of 1.2 (SE, 0.51).

The researchers also found that confusion and memory impairment were the only cognition-related TEAEs reported. These TEAEs were infrequent and occurred at rates similar to placebo.

“Across studies, mean MMSE score changes in pimavanserin-treated patients with NDD were small and were similar to placebo. Cognition-related TEAEs were reported infrequently. Overall, pimavanserin did not have a negative impact on cognitive function with up to 9 months of treatment,” Ballard and colleagues concluded.

Pimavanserin, a selective serotonin inverse agonist and antagonist preferentially targeting 5HT2A receptors, was previously approved for the treatment of hallucinations and delusions associated with Parkinson disease psychosis in April 2016.

 to Acadia Pharmaceuticals due to deficiencies in their supplemental new drug application (sNDA) filing for pimavanserin for the treatment of DRP.

The FDA stated that the treatment cannot be accepted with the sNDA in its current form, citing a lack of statistical significance in some of the subgroups of dementia, and insufficient numbers of patients with certain less common dementia subtypes as lack of substantial evidence of effectiveness to support approval.

The study presented at the 2021 AAN Meeting follows the complete response letter issued by the FDA to Acadia Pharmaceuticals due to deficiencies in their sNDA.

Pimavanserin Doesn’t Cause Negative Cognition Treating Dementia-Related Psychosis

In a recent study, a research team evaluated several Alzheimer disease (AD) biomarkers, including cerebrospinal (CSF) neurofilament light (NfL), neurogranin (Ng), and total-tau (t-tau) to clarify how these markers are differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH).

The research group found that higher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t-tau was associated with decreasing temporal lobe and AD meta region of interest (ROI) cortical thickness.

“It is important to understand what information different neurodegenerative biomarkers provide to aid in both diagnosis and prognosis, especially because each marker is likely to be reflective of a different composite of pathological processes,” wrote first author Michelle M. Mielke, PhD, professor of epidemiology and neurology, and researcher, Mayo Clinic, and colleagues.

Mielke and colleagues analyzed data from 536 participants without dementia from the Mayo Clinic Study of Aging. CSF NfL, Ng, t-tau, amyloid beta (Aβ) 42 and longitudinal MRI scans were performed. They used linear mixed models to assess longitudinal associations between CSF markers and MRI changes.

Participants’ mean age was 74.9 years (standard deviation [SD], 7.3) and 304 (57%) were men. Out of all participants, 154 (29%) had an apolipoprotein E (APOE) ɛ4 allele and 70 (13%) had a clinical diagnosis of mild cognitive impairment (MCI). The participants had an average follow-up of 2.4 years (SD, 1.8) with 2.2 (SD, 1.0) visits.

Mielke and colleagues found that CSF Ng was strongly associated with t-tau (Spearman’s rho = 0.831; 

 <.0001) and t-tau (Spearman’s rho = 0.477; 

 <.0001). CSF NfL was moderately associated with Ng (Spearman’s rho = 0.321; 

Multivariable analyses revealed that that higher CSF NfL levels were cross-sectionally associated with lower AD meta- region of interest (ROI) cortical thickness (b, –0.149 [standard error (SE), 0.044]; 

 <.001) and with lower cortical thickness in the frontal (b, –0.224 [SE, 0.046]; 

 <.001), parietal (b, –0.163 [SE, 0.043]; 

 <.001), and temporal (b, –0.134 [SE, 0.042]; 

There were few cross-sectional associations between either CSF t-tau or Ng with most neuroimaging measures, with the exception that higher levels of t-tau (b, 0.209 [SE, 0.076]; 

 <.002) were associated with higher corpus callosum FA. Higher CSF t-tau levels were also associated with lower temporal lobe thickness in amyloid positive participants compared to amyloid negative in multivariable analyses (b, –0.215 [SE, 0.081]; 

Associations between CSF t-tau or Ng and neuroimaging markers did not differ in those with or without MCI after adjusting for age, sex, and CSF Aβ42. However, higher levels of CSF NfL were associated with reduced cortical thickness in participants with MCI in the frontal (b, –0.524 [SE, 0.131]; 

 <.001), parietal (b, –0.437 [SE, 0.125]; 

 <.001), and temporal lobes (b, -0.482 [SE, 0.121]; 

 <.001) and in an AD meta-ROI (b, –0.653 [SE, 0.125]; 

Higher CSF t-tau was longitudinally associated with declines in temporal lobe cortical thickness (b, –0.189 [SE, 0.068]; 

 = .006) and the AD signature region (b, –0.281 [SE, 0.073]; 

 <.001). Higher CSF NfL was associated with declines in the corpus callosum (b, – 0.283 [SE, 0.096]; 

 = .003) and cingulum (b, –0.308 [SE, 0.096]; 

 = .006) FA and WMH (b, 0.149 [SE, 0.055]; 

 = .007). No associations were seen between CSF Ng and longitudinal neuroimaging measures. Restricted analyses only including 268 participants with all neuroimaging modalities confirmed associations in all above analyses.

Mielke and colleagues found that associations between CSF t-tau or NfL and longitudinal neuroimaging markers did not differ by CSF Aβ42 status after adjusting for age and sex. Higher CSF Ng was associated with greater declines in temporal lobe thickness (b, –0.464 [SE, 0.140]; 

 <.001), AD meta-ROI thickness (b, –0.471 [SE, 0.151]; 

 = .002), and cingulum FA (b, –0.662 [SE, 0.240]; 

 = .006) in amyloid-positive individuals compared to amyloid-negative individuals. Restricting the analyses to participants with all neuroimaging modalities yielded similar results, with the exception that the interaction between CSF Ng and CSF Aβ42 for cingulum FA was no longer significant (

Lastly, increasing levels of CSF t-tau (b, –0.579 [SE, 0.218]; 

 = .008) and Ng (b, –0.664 [SE, 0.231]; 

 = .007) were associated with greater reduction in AD meta-ROI cortical thickness longitudinally in participants with MCI compared to those without. No differences were seen between CSF NfL and all neuroimaging outcomes between participants with or without diagnosed MCI.

“The present study contributes further insight regarding information each of these three candidate CSF markers may provide and how they can best be used for clinical and research purposes. Of the three, CSF Ng appears to be the best marker of AD-related pathological neurodegeneration (NfL, Ng, and t-tau) and will be most helpful for AD diagnosis and AD-related prognosis,” Mielke and colleagues wrote.

“Although CSF t-tau provides some indication of AD pathology, it appears to be less specific than Ng. Last, CSF NfL is non-specific to AD pathology. The measurement of CSF NfL has the added benefit of providing information regarding non-AD related pathologies, potentially due to vascular and other causes, and will add information about overall prognosis,” they concluded.

Researchers examine how biomarkers are differentially mapped to MRI measures of cortical thickness. 

Researchers Clarify Alzheimer Disease Biomarkers and MRI Measures

Visceral adiposity (VA) is strongly associated with obstructive sleep apnea (OSA) in elderly patients, while general adiposity is strongly associated with OSA in non-elderly patients, according to new research.

 resulted in an area under the curve (AUC) of 0.580 with a sensitivity of 0.382 and specificity of 0.790 in predicting moderate-to-severe-OSA in elderly patients. In non-elderly patients, body mass index (BMI) over 24.7 kg/m2 resulted in an AUC of 0.550 with a sensitivity of 0.883 and specificity of 0.484 in predictive power.

"Although some subjects may have never been clinically categorized as overweight or obese, if they have increased VA, they may be at increased risk of OSA and its adverse health outcomes. However, this hypothesis needs yet to be tested in the elderly,” wrote senior author Xinmin Liu, MD, president and respiratory specialist, Peking University First Hospital, and colleagues.

Liu and colleagues analyzed data from 169 patients aged at least 65 years (elderly) and 142 patients aged less than 65 years (non-elderly) referred for overnight polysomnography (PSG). More than 80% of participants were men (82.3% in elderly and 84.5% in non-elderly). Mild or no OSA was present in 69 participants (41% of total; 38 in elderly and 31 in non-elderly), moderate OSA was present in 104 (62% of total; 47 in elderly and 57 in non-elderly) and severe OSA was present in 138 (82% of total; 84 in elderly and 534 in non-elderly).

Patients reported smoking (25.1%) and drinking (23.2%), as well as comorbidities such as dyslipidemia (n = 263), hypertension (n = 229), thyroid diseases (n = 171), fatty liver (n =139), coronary heart disease (n = 122), diabetes (n = 105), gastroesophageal reflux disease (n = 69), hyperuricemia (n = 78), stroke (n = 66), chronic obstructive pulmonary disease (n = 25), cancer (n = 24), and chronic kidney disease (n = 20).

Increasing OSA severity was associated with increasing markers of obesity such as BMI, waist circumference (WC), hip circumference (HC), WC/HC ratio, NC/height (H) ratio, WC/H ratio, conicity index, SA, and VA (all P <.02) but was not associated with neck circumference (NC) and VA/subcutaneous adiposity (SA) ratio.

The researchers found a significant interaction between OSA severity and age only for VA/SA (

 <.005), which increased with OSA severity in the non-elderly and decreased in the elderly, although both VA and SA increased with OSA severity. Compared with the non-elderly, the elderly showed higher conicity index. VA/SA, lower BMI, NC, WC, HC and SA. WC/HC, NC/H, WC/H and VA increased with OSA severity across both groups (all 

Univariate analyses showed that BMI, WC, HC, WC/HC, WC/H, conicity index, VA and SA were significantly associated with apnea-hypopnea index (AHI) in the elderly, while BMI, NC, WC, HC, WC/HC, NC/H, WC/H, VA, SA and VA/SA were significantly associated with AHI in the non-elderly.

The strongest correlations were WC/H with AHI in the elderly (β = 0.296; 

 <.01) in the non-elderly. After adjusting for age, sex, cigarette smoking, alcohol drinking and main comorbidities, BMI, VA and VA/SA, explained 25.9% of AHI variability in the non-elderly and 17.2% variability in the elderly.

All told, Liu and colleagues found that VA over 128 cm

 resulted in an AUC of 0.580 with a sensitivity of 0.382 and specificity of 0.790 in predicting moderate-to-severe-OSA in elderly patients. In non-elderly patients, BMI over 24.7 kg/m2 resulted in an AUC of 0.550 with a sensitivity of 0.883 and specificity of 0.484 in predictive power.

VA/SA ratio less than 0.41 resulted in an AUC of 0.553 with a sensitivity of 0.176 and specificity of 0.947 in predictive power in elderly patients. In non-elderly patients, WA/SA predicted moderate-to-severe OSA with an AUC of 0.667, sensitivity of 0.550, and specificity of 0.710.

The differences in OSA associations “may suggest the need for age-specific screening and therapeutic strategies. However, our results should be considered preliminary and point to the need for future prospective longitudinal studies in a large cohort to elucidate this issue and to explore possible etiological differences between the elderly and the non-elderly,” Liu and colleagues concluded.

Increasing OSA severity was associated with increasing markers of obesity.