Collaborative science to advance gene therapies in resource-limited parts of the world
Authors: Joseph M. McCune, Susan C. Stevenson, Brian P. Doehle, Cameron C. Trenor, Emily H. Turner, Jonathan M. Spector
Journal: Molecular Therapy (2021)

Main textIn the context of dramatic advances in the field of cell and gene therapies that have recently led to the approval of curative interventions for a number of diseases,1Dunbar C.E. High K.A. Joung J.K. Kohn D.B. Ozawa K. Sadelain M. Gene therapy comes of age.Science. 2018; 359: eaan4672Crossref PubMed Scopus (622) Google Scholar it is important that these gains be extended for the benefit of patients everywhere.[2]Makani J. et al.GBD 2019 Diseases and Injuries CollaboratorsFinding a cure for sickle cell disease..Nature Medicine. 2019; 25: 1811Crossref PubMed Scopus (2) Google Scholar The first wave of technologies have, by nature, been associated with highly complex medical interventions that limit access and widespread use in resource-limited settings. Now, by updating an assessment of emerging platforms and technologies, and by incorporating the firsthand perspectives of stakeholders from all parts of the world, the opportunity exists to organize from the outset around safe and effective delivery of gene therapies in global settings.To ensure that gene therapies become available to all, it will be crucial to plan ahead. Specific needs in resource-limited parts of the world include: (1) emphasizing, whenever possible, single administration "shot in the arm" interventions that target and edit long-lived cells, e.g., hematopoietic stem cells (HSCs), in vivo in contrast to ex vivo approaches that require complex laboratory-based cellular modification;3Peluso M.J. Deeks S.G. McCune J.M. HIV "cure": a shot in the arm?.EBioMedicine. 2019; 42: 3-5Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar (2) ensuring that local health systems are equipped to promptly diagnose patients who will benefit and to support their well being until therapy can be administered; and (3) devising financial and delivery models that make gene therapies accessible to all.4Dybul M. Attoye T. Baptiste S. Cherutich P. Dabis F. Deeks S.G. Dieffenbach C. Doehle B. Goodenow M.M. Jiang A. et al.Sunnylands 2019 Working GroupThe case for an HIV cure and how to get there.Lancet HIV. 2021; 8: e51-e58Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar These requirements present formidable scientific, clinical, economic, and social hurdles that will only be cleared with a level of patience, persistence, and partnership not normally achievable by global health stakeholders acting alone.Given the philanthropic mission of the Bill & Melinda Gates Foundation to "help all people lead healthy and productive lives," the Gates Foundation's HIV Frontiers Program was initiated in early 2019 to bring disparate and necessary strengths to the fore, encouraging the sharing of expertise and resources required to tackle the otherwise risky, aspirational, and long-term goal of discovering gene therapies accessible to all.5McCune J.M. Turner E.H. Jiang A. Doehle B.P. Bringing gene therapies for HIV disease to resource-limited parts of the world.Hum. Gene Ther. 2021; 32: 21-30Crossref PubMed Scopus (2) Google Scholar Conspicuous disease areas for initial focus include HIV and sickle cell disease (SCD), life-threatening disorders afflicting millions in sub-Saharan Africa and other regions, for which standard-of-care therapy is inadequate and genetic cures are now in sight.6Ndung'u T. McCune J.M. Deeks S.G. Why and where an HIV cure is needed and how it might be achieved.Nature. 2019; 576: 397-405Crossref PubMed Scopus (54) Google Scholar,7Tisdale J.F. Thein S.L. Eaton W.A. Treating sickle cell anemia.Science. 2020; 367: 1198-1199Crossref PubMed Scopus (179) Google Scholar Particularly in the case of SCD, it is increasingly evident that ex vivo manipulation of HSCs is likely to provide clinical benefits that, for cost and complexity reasons alone, will be challenging to distribute at scale to most of those in need.7Tisdale J.F. Thein S.L. Eaton W.A. Treating sickle cell anemia.Science. 2020; 367: 1198-1199Crossref PubMed Scopus (179) Google ScholarThus, in the fall of 2019, the Gates Foundation and the National Institutes of Health (NIH) entered a memorandum of understanding to help expand the reach of in vivo gene therapies for HIV and SCD to resource-limited parts of the world (https://www.nih.gov/news-events/news-releases/nih-launches-new-collaboration-develop-gene-based-cures-sickle-cell-disease-hiv-global-scale).8Cohen J. Kaiser J. Gates and NIH join forces on HIV and sickle cell diseases.Science. 2019; 366: 558-559Crossref PubMed Scopus (5) Google Scholar This collaboration has enabled each party to align goals and to transparently share information relevant to in vivo targeting and editing, thereby highlighting areas in need of more attention as well as overlapping work that might be better coordinated for synergies. It is anticipated that such proactive coordination will facilitate a strategic and unified approach to moving candidate therapies into the clinic. Notably, this endeavor is dedicated to bringing the best of innovative in vivo approaches to the most in need, first those with SCD and then—learning from that example—those with HIV disease who cannot, for whatever reason, access and/or remain on lifelong treatment with antiretroviral therapy.To further accelerate this effort, the Gates Foundation recently initiated a collaborative effort focused on SCD with Novartis (https://www.gatesfoundation.org/ideas/articles/gene-therapy-mike-mccune; https://www.novartis.com/news/media-releases/novartis-and-bill-melinda-gates-foundation-collaborate-discover-and-develop-accessible-vivo-gene-therapy-sickle-cell-disease), a global medicines company with a proven track record of progressing advanced therapeutic innovations, including cell and gene therapies, from the lab bench to patients. The aspiration of this effort is to discover a therapeutic candidate that will target long-term repopulating HSCs for durable effect, deliver editing machinery to these cells without toxicity or immune disturbances, and accomplish sufficient in situ genome editing efficiency to achieve lasting clinical benefit. With funding from the Gates Foundation, Novartis will conduct drug discovery research at its laboratories and explore work with other academic and biotechnology groups in this endeavor. A guiding principle is that the best candidate for full development will progress.The selection criteria for such "best candidates" for the durable in vivo "cure" of SCD and HIV disease can be envisioned within a matrix of metrics describing both biologic activity and developability, all of which present formidable challenges that have yet to be met.9Lewin S.R. Attoye T. Bansbach C. Doehle B. Dubé K. Dybul M. SenGupta D. Jiang A. Johnston R. Lamplough R. et al.Sunnylands 2019 Working GroupMulti-stakeholder consensus on a target product profile for an HIV cure.Lancet HIV. 2021; 8: e42-e50Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,10Kohn D.B. Gene therapy for blood diseases.Curr. Opin. Biotechnol. 2019; 60: 39-45Crossref PubMed Scopus (20) Google Scholar Which viral or non-viral vector, for instance, is most likely to selectively target its payload to the desired cell types in vivo (e.g., HSCs in the setting of HIV and SCD and T stem cell memory cells and B cells in the setting of HIV), without off-target effects and with minimal immunogenicity? Which genetic modifying machinery (e.g., CRISPR-Cas, base editors, prime editors, etc.) will be best suited to specifically generate desired changes within these targeted cells, be it correction of sickle hemoglobin (HbS), upregulation of fetal hemoglobin (HbF), or the introduction of a variety of modifications designed to keep the rebound competent reservoir of HIV at bay? Of those vectors and cargos that are biologically active, which is most likely to safely generate a durable therapeutic effect with the least amount of complexity (e.g., without the need for immunosuppression, repeated dosing, or intensive post-procedural monitoring)? Of those meeting such biologic criteria, which in vivo approach is most likely to be developable and made accessible to the largest number of individuals in a cost-effective manner? Once distributed, which companion diagnostics should be developed and made available to identify patients and to assess the efficacy and durability of the interventions? And, not least, what economic model will enable the equitable and global distribution of such interventions?It is the explicit intent of these collaborations to address such challenges head on so that effective therapies can be brought to patients in limited-resource settings. Access planning will begin at the outset of research and development to help pave the way for successful distribution of potential breakthrough treatments as quickly as possible after they are proven safe and effective. Two main considerations relating to access include the target product profile (TPP) of gene therapy candidates as well as partnerships with stakeholders that live and work in geographies where new gene therapies are expected to be used. Fundamental to the TPP will be a formulation and workflow process consistent with pragmatic use in health systems in developing countries, and therefore, it will be developed through close consultation with collaborative networks (e.g., academic and government organizations, patient advocate groups, health workers, implementing agencies including non-governmental organizations, and others) in regions where HIV and SCD are prevalent. Involvement of local partners will be equally critical to identify prospective clinical trial sites, to help address capability gaps for trial conduct, and to plan for post-trial access to therapy, including technical as well as cultural aspects of gene therapy adoption.To our knowledge, the concerted efforts of the Gates Foundation, NIH, Novartis, and other laboratories and partners constitute the first deliberate attempt to discover gene therapies that are fully accessible to populations in both low- and high-resource settings. A functional "cure" of SCD by in vivo gene therapy would historically transform the clinical management of the disease while also potentially generating technology platforms that could be applicable to in vivo gene therapies for other diseases, including HIV. Given the importance and unmet global needs in patients with SCD and HIV, the implications of this work extend well beyond two disease areas. Especially in this day and age when healthcare inequities are so glaringly obvious, the need for such partnerships has never been more urgent. Acknowledging upfront that it will take years to level the playing field, now is the time to plan for that future. As importantly, we hope that these collaborative efforts will inform other programs similarly focused on expanding the reach of state-of-the-art medicines to all of those in need, wherever they may live. Main textIn the context of dramatic advances in the field of cell and gene therapies that have recently led to the approval of curative interventions for a number of diseases,1Dunbar C.E. High K.A. Joung J.K. Kohn D.B. Ozawa K. Sadelain M. Gene therapy comes of age.Science. 2018; 359: eaan4672Crossref PubMed Scopus (622) Google Scholar it is important that these gains be extended for the benefit of patients everywhere.[2]Makani J. et al.GBD 2019 Diseases and Injuries CollaboratorsFinding a cure for sickle cell disease..Nature Medicine. 2019; 25: 1811Crossref PubMed Scopus (2) Google Scholar The first wave of technologies have, by nature, been associated with highly complex medical interventions that limit access and widespread use in resource-limited settings. Now, by updating an assessment of emerging platforms and technologies, and by incorporating the firsthand perspectives of stakeholders from all parts of the world, the opportunity exists to organize from the outset around safe and effective delivery of gene therapies in global settings.To ensure that gene therapies become available to all, it will be crucial to plan ahead. Specific needs in resource-limited parts of the world include: (1) emphasizing, whenever possible, single administration "shot in the arm" interventions that target and edit long-lived cells, e.g., hematopoietic stem cells (HSCs), in vivo in contrast to ex vivo approaches that require complex laboratory-based cellular modification;3Peluso M.J. Deeks S.G. McCune J.M. HIV "cure": a shot in the arm?.EBioMedicine. 2019; 42: 3-5Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar (2) ensuring that local health systems are equipped to promptly diagnose patients who will benefit and to support their well being until therapy can be administered; and (3) devising financial and delivery models that make gene therapies accessible to all.4Dybul M. Attoye T. Baptiste S. Cherutich P. Dabis F. Deeks S.G. Dieffenbach C. Doehle B. Goodenow M.M. Jiang A. et al.Sunnylands 2019 Working GroupThe case for an HIV cure and how to get there.Lancet HIV. 2021; 8: e51-e58Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar These requirements present formidable scientific, clinical, economic, and social hurdles that will only be cleared with a level of patience, persistence, and partnership not normally achievable by global health stakeholders acting alone.Given the philanthropic mission of the Bill & Melinda Gates Foundation to "help all people lead healthy and productive lives," the Gates Foundation's HIV Frontiers Program was initiated in early 2019 to bring disparate and necessary strengths to the fore, encouraging the sharing of expertise and resources required to tackle the otherwise risky, aspirational, and long-term goal of discovering gene therapies accessible to all.5McCune J.M. Turner E.H. Jiang A. Doehle B.P. Bringing gene therapies for HIV disease to resource-limited parts of the world.Hum. Gene Ther. 2021; 32: 21-30Crossref PubMed Scopus (2) Google Scholar Conspicuous disease areas for initial focus include HIV and sickle cell disease (SCD), life-threatening disorders afflicting millions in sub-Saharan Africa and other regions, for which standard-of-care therapy is inadequate and genetic cures are now in sight.6Ndung'u T. McCune J.M. Deeks S.G. Why and where an HIV cure is needed and how it might be achieved.Nature. 2019; 576: 397-405Crossref PubMed Scopus (54) Google Scholar,7Tisdale J.F. Thein S.L. Eaton W.A. Treating sickle cell anemia.Science. 2020; 367: 1198-1199Crossref PubMed Scopus (179) Google Scholar Particularly in the case of SCD, it is increasingly evident that ex vivo manipulation of HSCs is likely to provide clinical benefits that, for cost and complexity reasons alone, will be challenging to distribute at scale to most of those in need.7Tisdale J.F. Thein S.L. Eaton W.A. Treating sickle cell anemia.Science. 2020; 367: 1198-1199Crossref PubMed Scopus (179) Google ScholarThus, in the fall of 2019, the Gates Foundation and the National Institutes of Health (NIH) entered a memorandum of understanding to help expand the reach of in vivo gene therapies for HIV and SCD to resource-limited parts of the world (https://www.nih.gov/news-events/news-releases/nih-launches-new-collaboration-develop-gene-based-cures-sickle-cell-disease-hiv-global-scale).8Cohen J. Kaiser J. Gates and NIH join forces on HIV and sickle cell diseases.Science. 2019; 366: 558-559Crossref PubMed Scopus (5) Google Scholar This collaboration has enabled each party to align goals and to transparently share information relevant to in vivo targeting and editing, thereby highlighting areas in need of more attention as well as overlapping work that might be better coordinated for synergies. It is anticipated that such proactive coordination will facilitate a strategic and unified approach to moving candidate therapies into the clinic. Notably, this endeavor is dedicated to bringing the best of innovative in vivo approaches to the most in need, first those with SCD and then—learning from that example—those with HIV disease who cannot, for whatever reason, access and/or remain on lifelong treatment with antiretroviral therapy.To further accelerate this effort, the Gates Foundation recently initiated a collaborative effort focused on SCD with Novartis (https://www.gatesfoundation.org/ideas/articles/gene-therapy-mike-mccune; https://www.novartis.com/news/media-releases/novartis-and-bill-melinda-gates-foundation-collaborate-discover-and-develop-accessible-vivo-gene-therapy-sickle-cell-disease), a global medicines company with a proven track record of progressing advanced therapeutic innovations, including cell and gene therapies, from the lab bench to patients. The aspiration of this effort is to discover a therapeutic candidate that will target long-term repopulating HSCs for durable effect, deliver editing machinery to these cells without toxicity or immune disturbances, and accomplish sufficient in situ genome editing efficiency to achieve lasting clinical benefit. With funding from the Gates Foundation, Novartis will conduct drug discovery research at its laboratories and explore work with other academic and biotechnology groups in this endeavor. A guiding principle is that the best candidate for full development will progress.The selection criteria for such "best candidates" for the durable in vivo "cure" of SCD and HIV disease can be envisioned within a matrix of metrics describing both biologic activity and developability, all of which present formidable challenges that have yet to be met.9Lewin S.R. Attoye T. Bansbach C. Doehle B. Dubé K. Dybul M. SenGupta D. Jiang A. Johnston R. Lamplough R. et al.Sunnylands 2019 Working GroupMulti-stakeholder consensus on a target product profile for an HIV cure.Lancet HIV. 2021; 8: e42-e50Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,10Kohn D.B. Gene therapy for blood diseases.Curr. Opin. Biotechnol. 2019; 60: 39-45Crossref PubMed Scopus (20) Google Scholar Which viral or non-viral vector, for instance, is most likely to selectively target its payload to the desired cell types in vivo (e.g., HSCs in the setting of HIV and SCD and T stem cell memory cells and B cells in the setting of HIV), without off-target effects and with minimal immunogenicity? Which genetic modifying machinery (e.g., CRISPR-Cas, base editors, prime editors, etc.) will be best suited to specifically generate desired changes within these targeted cells, be it correction of sickle hemoglobin (HbS), upregulation of fetal hemoglobin (HbF), or the introduction of a variety of modifications designed to keep the rebound competent reservoir of HIV at bay? Of those vectors and cargos that are biologically active, which is most likely to safely generate a durable therapeutic effect with the least amount of complexity (e.g., without the need for immunosuppression, repeated dosing, or intensive post-procedural monitoring)? Of those meeting such biologic criteria, which in vivo approach is most likely to be developable and made accessible to the largest number of individuals in a cost-effective manner? Once distributed, which companion diagnostics should be developed and made available to identify patients and to assess the efficacy and durability of the interventions? And, not least, what economic model will enable the equitable and global distribution of such interventions?It is the explicit intent of these collaborations to address such challenges head on so that effective therapies can be brought to patients in limited-resource settings. Access planning will begin at the outset of research and development to help pave the way for successful distribution of potential breakthrough treatments as quickly as possible after they are proven safe and effective. Two main considerations relating to access include the target product profile (TPP) of gene therapy candidates as well as partnerships with stakeholders that live and work in geographies where new gene therapies are expected to be used. Fundamental to the TPP will be a formulation and workflow process consistent with pragmatic use in health systems in developing countries, and therefore, it will be developed through close consultation with collaborative networks (e.g., academic and government organizations, patient advocate groups, health workers, implementing agencies including non-governmental organizations, and others) in regions where HIV and SCD are prevalent. Involvement of local partners will be equally critical to identify prospective clinical trial sites, to help address capability gaps for trial conduct, and to plan for post-trial access to therapy, including technical as well as cultural aspects of gene therapy adoption.To our knowledge, the concerted efforts of the Gates Foundation, NIH, Novartis, and other laboratories and partners constitute the first deliberate attempt to discover gene therapies that are fully accessible to populations in both low- and high-resource settings. A functional "cure" of SCD by in vivo gene therapy would historically transform the clinical management of the disease while also potentially generating technology platforms that could be applicable to in vivo gene therapies for other diseases, including HIV. Given the importance and unmet global needs in patients with SCD and HIV, the implications of this work extend well beyond two disease areas. Especially in this day and age when healthcare inequities are so glaringly obvious, the need for such partnerships has never been more urgent. Acknowledging upfront that it will take years to level the playing field, now is the time to plan for that future. As importantly, we hope that these collaborative efforts will inform other programs similarly focused on expanding the reach of state-of-the-art medicines to all of those in need, wherever they may live. In the context of dramatic advances in the field of cell and gene therapies that have recently led to the approval of curative interventions for a number of diseases,1Dunbar C.E. High K.A. Joung J.K. Kohn D.B. Ozawa K. Sadelain M. Gene therapy comes of age.Science. 2018; 359: eaan4672Crossref PubMed Scopus (622) Google Scholar it is important that these gains be extended for the benefit of patients everywhere.[2]Makani J. et al.GBD 2019 Diseases and Injuries CollaboratorsFinding a cure for sickle cell disease..Nature Medicine. 2019; 25: 1811Crossref PubMed Scopus (2) Google Scholar The first wave of technologies have, by nature, been associated with highly complex medical interventions that limit access and widespread use in resource-limited settings. Now, by updating an assessment of emerging platforms and technologies, and by incorporating the firsthand perspectives of stakeholders from all parts of the world, the opportunity exists to organize from the outset around safe and effective delivery of gene therapies in global settings. To ensure that gene therapies become available to all, it will be crucial to plan ahead. Specific needs in resource-limited parts of the world include: (1) emphasizing, whenever possible, single administration "shot in the arm" interventions that target and edit long-lived cells, e.g., hematopoietic stem cells (HSCs), in vivo in contrast to ex vivo approaches that require complex laboratory-based cellular modification;3Peluso M.J. Deeks S.G. McCune J.M. HIV "cure": a shot in the arm?.EBioMedicine. 2019; 42: 3-5Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar (2) ensuring that local health systems are equipped to promptly diagnose patients who will benefit and to support their well being until therapy can be administered; and (3) devising financial and delivery models that make gene therapies accessible to all.4Dybul M. Attoye T. Baptiste S. Cherutich P. Dabis F. Deeks S.G. Dieffenbach C. Doehle B. Goodenow M.M. Jiang A. et al.Sunnylands 2019 Working GroupThe case for an HIV cure and how to get there.Lancet HIV. 2021; 8: e51-e58Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar These requirements present formidable scientific, clinical, economic, and social hurdles that will only be cleared with a level of patience, persistence, and partnership not normally achievable by global health stakeholders acting alone. Given the philanthropic mission of the Bill & Melinda Gates Foundation to "help all people lead healthy and productive lives," the Gates Foundation's HIV Frontiers Program was initiated in early 2019 to bring disparate and necessary strengths to the fore, encouraging the sharing of expertise and resources required to tackle the otherwise risky, aspirational, and long-term goal of discovering gene therapies accessible to all.5McCune J.M. Turner E.H. Jiang A. Doehle B.P. Bringing gene therapies for HIV disease to resource-limited parts of the world.Hum. Gene Ther. 2021; 32: 21-30Crossref PubMed Scopus (2) Google Scholar Conspicuous disease areas for initial focus include HIV and sickle cell disease (SCD), life-threatening disorders afflicting millions in sub-Saharan Africa and other regions, for which standard-of-care therapy is inadequate and genetic cures are now in sight.6Ndung'u T. McCune J.M. Deeks S.G. Why and where an HIV cure is needed and how it might be achieved.Nature. 2019; 576: 397-405Crossref PubMed Scopus (54) Google Scholar,7Tisdale J.F. Thein S.L. Eaton W.A. Treating sickle cell anemia.Science. 2020; 367: 1198-1199Crossref PubMed Scopus (179) Google Scholar Particularly in the case of SCD, it is increasingly evident that ex vivo manipulation of HSCs is likely to provide clinical benefits that, for cost and complexity reasons alone, will be challenging to distribute at scale to most of those in need.7Tisdale J.F. Thein S.L. Eaton W.A. Treating sickle cell anemia.Science. 2020; 367: 1198-1199Crossref PubMed Scopus (179) Google Scholar Thus, in the fall of 2019, the Gates Foundation and the National Institutes of Health (NIH) entered a memorandum of understanding to help expand the reach of in vivo gene therapies for HIV and SCD to resource-limited parts of the world (https://www.nih.gov/news-events/news-releases/nih-launches-new-collaboration-develop-gene-based-cures-sickle-cell-disease-hiv-global-scale).8Cohen J. Kaiser J. Gates and NIH join forces on HIV and sickle cell diseases.Science. 2019; 366: 558-559Crossref PubMed Scopus (5) Google Scholar This collaboration has enabled each party to align goals and to transparently share information relevant to in vivo targeting and editing, thereby highlighting areas in need of more attention as well as overlapping work that might be better coordinated for synergies. It is anticipated that such proactive coordination will facilitate a strategic and unified approach to moving candidate therapies into the clinic. Notably, this endeavor is dedicated to bringing the best of innovative in vivo approaches to the most in need, first those with SCD and then—learning from that example—those with HIV disease who cannot, for whatever reason, access and/or remain on lifelong treatment with antiretroviral therapy. To further accelerate this effort, the Gates Foundation recently initiated a collaborative effort focused on SCD with Novartis (https://www.gatesfoundation.org/ideas/articles/gene-therapy-mike-mccune; https://www.novartis.com/news/media-releases/novartis-and-bill-melinda-gates-foundation-collaborate-discover-and-develop-accessible-vivo-gene-therapy-sickle-cell-disease), a global medicines company with a proven track record of progressing advanced therapeutic innovations, including cell and gene therapies, from the lab bench to patients. The aspiration of this effort is to discover a therapeutic candidate that will target long-term repopulating HSCs for durable effect, deliver editing machinery to these cells without toxicity or immune disturbances, and accomplish sufficient in situ genome editing efficiency to achieve lasting clinical benefit. With funding from the Gates Foundation, Novartis will conduct drug discovery research at its laboratories and explore work with other academic and biotechnology groups in this endeavor. A guiding principle is that the best candidate for full development will progress. The selection criteria for such "best candidates" for the durable in vivo "cure" of SCD and HIV disease can be envisioned within a matrix of metrics describing both biologic activity and developability, all of which present formidable challenges that have yet to be met.9Lewin S.R. Attoye T. Bansbach C. Doehle B. Dubé K. Dybul M. SenGupta D. Jiang A. Johnston R. Lamplough R. et al.Sunnylands 2019 Working GroupMulti-stakeholder consensus on a target product profile for an HIV cure.Lancet HIV. 2021; 8: e42-e50Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,10Kohn D.B. Gene therapy for blood diseases.Curr. Opin. Biotechnol. 2019; 60: 39-45Crossref PubMed Scopus (20) Google Scholar Which viral or non-viral vector, for instance, is most likely to selectively target its payload to the desired cell types in vivo (e.g., HSCs in the setting of HIV and SCD and T stem cell memory cells and B cells in the setting of HIV), without off-target effects and with minimal immunogenicity? Which genetic modifying machinery (e.g., CRISPR-Cas, base editors, prime editors, etc.) will be best suited to specifically generate desired changes within these targeted cells, be it correction of sickle hemoglobin (HbS), upregulation of fetal hemoglobin (HbF), or the introduction of a variety of modifications designed to keep the rebound competent reservoir of HIV at bay? Of those vectors and cargos that are biologically active, which is most likely to safely generate a durable therapeutic effect with the least amount of complexity (e.g., without the need for immunosuppression, repeated dosing, or intensive post-procedural monitoring)? Of those meeting such biologic criteria, which in vivo approach is most likely to be developable and made accessible to the largest number of individuals in a cost-effective manner? Once distributed, which companion diagnostics should be developed and made available to identify patients and to assess the efficacy and durability of the interventions? And, not least, what economic model will enable the equitable and global distribution of such interventions? It is the explicit intent of these collaborations to address such challenges head on so that effective therapies can be brought to patients in limited-resource settings. Access planning will begin at the outset of research and development to help pave the way for successful distribution of potential breakthrough treatments as quickly as possible after they are proven safe and effective. Two main considerations relating to access include the target product profile (TPP) of gene therapy candidates as well as partnerships with stakeholders that live and work in geographies where new gene therapies are expected to be used. Fundamental to the TPP will be a formulation and workflow process consistent with pragmatic use in health systems in developing countries, and therefore, it will be developed through close consultation with collaborative networks (e.g., academic and government organizations, patient advocate groups, health workers, implementing agencies including non-governmental organizations, and others) in regions where HIV and SCD are prevalent. Involvement of local partners will be equally critical to identify prospective clinical trial sites, to help address capability gaps for trial conduct, and to plan for post-trial access to therapy, including technical as well as cultural aspects of gene therapy adoption. To our knowledge, the concerted efforts of the Gates Foundation, NIH, Novartis, and other laboratories and partners constitute the first deliberate attempt to discover gene therapies that are fully accessible to populations in both low- and high-resource settings. A functional "cure" of SCD by in vivo gene therapy would historically transform the clinical management of the disease while also potentially generating technology platforms that could be applicable to in vivo gene therapies for other diseases, including HIV. Given the importance and unmet global needs in patients with SCD and HIV, the implications of this work extend well beyond two disease areas. Especially in this day and age when healthcare inequities are so glaringly obvious, the need for such partnerships has never been more urgent. Acknowledging upfront that it will take years to level the playing field, now is the time to plan for that future. As importantly, we hope that these collaborative efforts will inform other programs similarly focused on expanding the reach of state-of-the-art medicines to all of those in need, wherever they may live. The authors would like to acknowledge Dr. Kwaku Ohene-Frempong (Sickle Cell Foundation of Ghana), Dr. Julie Makani (Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania), and Dr. Amy Patterson and Mr. Allan Shipp (NHLBI, NIH) for their review and input. This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation . Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. S.C.S., J.M.S., and C.C.T. are employees at Novartis Institutes for BioMedical Research.