Sickle Cell Disease: From Ancient Origins to Modern Breakthroughs in Gene Therapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In the manuscript  “Sickle Cell Disease: From Ancient Origins to Modern Break-2 throughs in Gene Therapy” by Drs. Bawo Ikolo et al, the authors  examine various aspects of sickle cell anemia (SCA), ranging from the disease's historical origins to its molecular characteristics and clinical manifestations. They also review inheritance patterns, screening strategies, and the spectrum of current and emerging treatment modalities.

The manuscript provides comprehensive information, and the data are presented clearly. I have no substantive objections; I would merely like to clarify a few details.

- Patients with sickle cell anemia (SCA) exhibit a disproportionately high rate of comorbid psychiatric disorders compared to healthy individuals. However, the causal relationship between SCA and mental health conditions is complex and not yet fully understood; a complex bidirectional association is believed to exist. There are existing publications on this topic, and I believe it would be appropriate to give them due attention.

- Research indicates a link between chronic inflammation and schizophrenia. In particular, many individuals with schizophrenia exhibit elevated levels of inflammatory markers (cytokines, C-reactive protein (CRP)).

- As the authors rightly note, sickle-shaped erythrocytes underlie a number of biological processes that contribute to chronic inflammation. Research indicates a link between chronic inflammation and schizophrenia. In particular, elevated levels of peripheral inflammation markers - such as cytokines (e.g., IL-6) and C-reactive protein (CRP)) - are observed in many individuals with schizophrenia. Microglia and platelets play a significant role in this process; interestingly, there is additional evidence linking inflammation and mental disorders not only to pathological conditions but also to phenomena involving transplantation (doi: 10.1134/s1990519x25600346). It would be great to know the authors' opinion on this matter.

- Is preimplantation genetic diagnosis (PGD) combined with in vitro fertilization, as discussed by the authors - legalized without restrictions? What are the legal aspects of its use in the countries where this technology is employed?

The manuscript is written clearly and logically, and I would be pleased to recommend it for publication following the minor revisions outlined above.

Author Response

Response to Reviewer 1

Manuscript ID: biomedicines-4403250  |  Journal: Biomedicines (MDPI)

Title: Sickle Cell Disease: From Ancient Origins to Modern Breakthroughs in Gene Therapy

Special Issue: Advances in Rare and Complex Multisystem Disorders: From Molecular Mechanisms to Clinical Practice

 

We thank Reviewer 1 for a careful and constructive reading of our manuscript, and for the recommendation to publish following minor revision. The reviewer’s comments prompted us to broaden the clinical scope of the review to encompass the psychological and psychiatric dimensions of SCD, which we agree were underrepresented in the original submission. Our point-by-point responses follow; all corresponding changes are marked in the tracked-changes manuscript.

Comment 1. Patients with SCA exhibit a disproportionately high rate of comorbid psychiatric disorders, and a complex, bidirectional association is believed to exist; the existing literature on this topic deserves due attention.

Response. We agree, and we have added a new subsection, Section 4.5 (“Psychological, Psychosocial, and Quality-of-Life Dimensions”), that gives this area explicit attention. It documents the elevated burden of depression and anxiety relative to the general population, the role of health-related stigma, and the resulting impact on quality of life, and it acknowledges that the relationship between SCD and mental-health conditions is complex and, in part, bidirectional. The subsection draws on a systematic review of depression in adults with SCD [44], on the documented burden of stigma [15], on the psychosocial literature [75], and on the 2026 consensus report of the National Academies of Sciences, Engineering, and Medicine [45].

Comment 2. Research indicates a link between chronic inflammation and schizophrenia, with elevated inflammatory markers (cytokines, C-reactive protein) observed in many affected individuals.

Response. This is now addressed in the second paragraph of Section 4.5. We note that SCD is characterized by a chronic inflammatory state with sustained elevation of circulating cytokines such as IL-6 and of C-reactive protein, and that chronic peripheral inflammation of this kind has been implicated in the pathophysiology of several major psychiatric disorders. We present this as a biologically coherent rationale linking the two, while being careful not to overstate the strength of the evidence.

Comment 3. Because sickled erythrocytes contribute to chronic inflammation, and given the role of microglia and platelets and the emerging evidence connecting inflammation and mental disorders to transplantation (doi: 10.1134/s1990519x25600346), the authors’ opinion on this matter would be valuable.

Response. We have incorporated the reviewer’s suggested reference [46] and offered our opinion explicitly in Section 4.5. Our considered view is a deliberately cautious one: the inflammatory biology of SCD provides a plausible mechanistic rationale for heightened neuropsychiatric vulnerability, and the intersection of haematopoietic and cellular processes, including those relevant to transplantation, with mental-health phenotypes is a legitimate and intriguing question. However, a direct causal link between SCD and specific disorders such as schizophrenia remains unestablished in the current literature, and the well-documented excess of depression and anxiety in this population is more parsimoniously explained by the combined effects of chronic pain, disability, and sustained psychosocial stress. We therefore frame the inflammation–neuropsychiatric interface as a promising direction for future mechanistic research rather than a settled feature of the disease. We believe this measured framing both honours the reviewer’s point and preserves the scientific rigour expected of a review of this kind.

Comment 4. Is preimplantation genetic diagnosis (PGD) combined with IVF legalized without restrictions? What are the legal aspects of its use across the countries where the technology is employed?

Response. We have expanded Section 5 to address this directly. The revised text explains that the legal status of preimplantation genetic testing is far from uniform: it is tightly regulated in much of Europe, where dedicated statutory authorities restrict the conditions under which it may be used; it is essentially unregulated at the federal level in the United States; and it remains restricted, prohibited, or simply unavailable in many other jurisdictions. We note that this regulatory patchwork shapes access to embryo selection for SCD, drives cross-border “reproductive tourism,” and raises distinct ethical and equity concerns. Two comparative policy analyses are now cited in support [51,52].

Summary of revisions in response to Reviewer 1

Reviewer 1 comment	Author response and action taken	Location
1. Psychiatric comorbidity in SCD deserves due attention (bidirectional association).	New Section 4.5 added on depression, anxiety, stigma, and quality of life; bidirectional complexity acknowledged. Refs [44], [15], [45], [75].	Section 4.5
2. Chronic inflammation–schizophrenia link (IL-6, CRP).	Section 4.5 now discusses the chronic inflammatory state of SCD (IL-6, CRP) and its implication in psychiatric pathophysiology.	Section 4.5 (para 2)
3. Inflammation, microglia/platelets, and transplantation link; authors’ opinion requested (doi:10.1134/s1990519x25600346).	Suggested reference cited [46]; authors’ measured opinion provided—mechanistically plausible, but SCD–schizophrenia causation unestablished; flagged as a future research priority.	Section 4.5 (para 2)
4. Legal status of PGD/IVF across countries.	Section 5 expanded: Europe regulated, U.S. federally unregulated, restricted/unavailable elsewhere; reproductive tourism and equity noted. Refs [51,52].	Section 5

 

On behalf of all authors,

Dr. Felicia Ikolo

Department of Biochemistry, School of Medicine, St. George’s University (SGU), Grenada

Sickle Cell Association of Grenada (SCAG)

Email: fikolo@sgu.edu  ·  ORCiD: 0000-0002-7711-903X

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for submitting this important work. Please consider the following suggestions to strengthen the manuscript:

Line 52: With human migration now spanning every continent, what was once geographically concentrated is now a diagnosis encountered in hematology clinics from London to Los Angeles. Consider using the term "worldwide" instead of two city points, and perhaps remove hematology, as many individuals with SCD do not have access to hematology clinics.

 Line 71: The sentence about hydroxyurea and other treatments would benefit from more current references. 

Line 81: It seems that the SCD community prefers the words transformative therapy to cure. 

The section about Noel Clement would be stronger with citations from Todd Savitt, such as: Savitt, T.L., & Goldberg, M.F. (1989). Herrick's 1910 Case Report of Sickle Cell Anemia: The Rest of the Story. I encourage you to explore other papers by Dr. Savitt in this area. His work is among the most authoritative historical sources and needs to be included. 

Beginning at line 204, clinical manifestations do not include a whole-person approach. There is nothing about the significant psychological impact of SCD, including factors such as health-related stigma and depression. Moreover, the word quality of life is only mentioned once in the manuscript (line 257). This might be a helpful resource: National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Care Services; Committee on Sickle Cell Disease in Social Security Disability Evaluations, Consensus Study Report, Spicer, C. M., Koop, J. I., & Volberding, P. A. (Eds.). (2026). National Academies Press (US). https://doi.org/10.17226/29319 

Line 430: The list prices of Casgevy and Lyfgenia in the United States are $2.2 million and $3.1 million per patient, respectively. References?

This paper has the potential to make important contributions to the SCD landscape. There are a few areas for improvement, the most important being updating and the inclusion of key references. The writing style is appreciated, considering the complexity of SCD.

 

Author Response

Response to Reviewer 2

Manuscript ID: biomedicines-4403250  |  Journal: Biomedicines (MDPI)

Title: Sickle Cell Disease: From Ancient Origins to Modern Breakthroughs in Gene Therapy

Special Issue: Advances in Rare and Complex Multisystem Disorders: From Molecular Mechanisms to Clinical Practice

 

We are grateful to Reviewer 2 for a generous and detailed reading, and for the encouraging assessment of the manuscript’s writing and potential contribution. The reviewer’s central recommendation, to update and strengthen key references and to broaden the clinical perspective, has improved the paper. Our point-by-point responses follow; all corresponding changes are marked in the tracked-changes manuscript.

Comment 1. Line 52: “…encountered in hematology clinics from London to Los Angeles.” Consider “worldwide” instead of two city points, and consider removing “hematology clinics,” as many individuals with SCD do not have access to them.

Response. Revised as suggested. The sentence now reads “…is now a diagnosis encountered worldwide,” and the reference to hematology clinics has been removed. We appreciate the reviewer’s point that framing access around specialist clinics understates the reality for many patients.

Comment 2. Line 71: The sentence on hydroxyurea and other treatments would benefit from more current references.

Response. We have strengthened this passage with the landmark REACH trial (Tshilolo et al., New England Journal of Medicine, 2019) [54], and added a clause noting that hydroxyurea has since been shown to be feasible, safe, and effective for children in sub-Saharan Africa—the setting of greatest disease burden—thereby providing a strong, current evidence base for expanding access.

Comment 3. Line 81: The SCD community appears to prefer the term “transformative therapy” to “cure.”

Response. We have revised the flagged sentence to read “A transformative therapy, it might now be said, is finally in sight.” We have adopted “transformative” in the manuscript’s framing language in deference to the community’s preference. We have, however, retained “cure” and “curative” in the specific scientific contexts where they are technically accurate—namely, allogeneic haematopoietic stem-cell transplantation and gene therapy, which are potentially curative in the strict sense—so that clinical precision is preserved. We hope this balance addresses the reviewer’s concern while remaining scientifically exact.

Comment 4. The section on Walter Clement Noel would be stronger with citations from Todd Savitt, in particular Savitt & Goldberg (1989), “Herrick’s 1910 Case Report of Sickle Cell Anemia: The Rest of the Story.”

Response. We agree and have added this authoritative source [18]. Drawing on Savitt and Goldberg’s reconstruction of the case, we now note that it was Herrick’s intern, Ernest E. Irons, who first performed the blood work and observed the sickled cells before bringing them to Herrick’s attention—a detail that enriches the historical account and appropriately distributes credit for the discovery.

Comment 5. From line 204, the clinical manifestations lack a whole-person approach: there is nothing on the psychological impact of SCD, including health-related stigma and depression, and “quality of life” appears only once (line 257). The 2026 National Academies consensus report (doi: 10.17226/29319) may be a helpful resource.

Response. We have addressed this substantively by adding Section 4.5 (“Psychological, Psychosocial, and Quality-of-Life Dimensions”). The new subsection integrates the psychological burden of the disease - depression and anxiety, health-related stigma, and diminished quality of life - alongside the organ-system manifestations, and explicitly adopts a whole-person framing. We are grateful for the suggested resource, which we now cite [45], together with a systematic review of depression in SCD [44], the stigma literature [15], and the broader psychosocial literature [75].

Comment 6. Line 430: The list prices of Casgevy and Lyfgenia in the United States ($2.2 million and $3.1 million per patient, respectively) require references.

Response. A supporting reference has been added: the Congressional Budget Office’s 2024 analysis of the budgetary impact of gene therapy for SCD, which documents these list prices and the associated access implications [71].

Summary of revisions in response to Reviewer 2

Reviewer 2 comment	Author response and action taken	Location
1. “London to Los Angeles” → “worldwide”; remove “hematology clinics.”	Revised to “encountered worldwide”; “hematology clinics” removed.	Section 1 (line ~52)
2. Hydroxyurea sentence needs more current references.	Added the REACH trial (Tshilolo et al., NEJM 2019) [54] with a clause on feasibility/safety/efficacy in sub-Saharan Africa.	Section 6.1 (line ~71)
3. Community prefers “transformative therapy” to “cure.”	Flagged sentence changed to “a transformative therapy”; “cure/curative” retained only where scientifically precise (HSCT, gene therapy).	Section 1 (line ~81)
4. Add Todd Savitt citations to the Noel section.	Savitt & Goldberg (1989) added [18]; Ernest E. Irons’ role in the original blood work now noted.	Section 2
5. Clinical manifestations lack a whole-person approach (stigma, depression, QoL).	New Section 4.5 added on psychological/psychosocial burden and quality of life. Refs [45], [44], [15], [75].	Section 4.5
6. References for Casgevy/Lyfgenia list prices.	Congressional Budget Office (2024) added [71] to support the $2.2M / $3.1M figures.	Section 7 (line ~430)

 

On behalf of all authors,

Dr. Felicia Ikolo

Department of Biochemistry, School of Medicine, St. George’s University (SGU), Grenada

Sickle Cell Association of Grenada (SCAG)

Email: fikolo@sgu.edu  ·  ORCiD: 0000-0002-7711-903X

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for being responsive to my suggestions to strengthen the manuscript.