Yang Liu

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HSC · Healing Source Code

赶在髓鞘塌掉之前——脑白质营养不良的 HSC 基因治疗,与治疗窗口 Before the Myelin Gives Way: HSC Gene Therapy for Leukodystrophy, and the Treatment Window

2026-10-09 · MLD, CALD, lentiviral, ex vivo, atidarsagene autotemcel, microglia

在米兰那项 MLD 基因治疗研究里,所有 late-infantile 患儿和其中四名 early-juvenile 患儿,都是因为家里有一位年长的患病同胞(older affected sibling),才在症状出现之前被确诊、被送进试验。论文作者在讨论部分补了一句:这位同胞在多数情况下已经病重到没有机会接受治疗。这几乎把整个故事压缩在了里面:基因治疗能让缺失的酶活性在体内重新建立起来,但这需要时间,而这种病往往不给时间。

一种拆掉髓鞘的病

metachromatic leukodystrophy(MLD)由 ARSA 基因突变引起,患者缺乏 arylsulfatase A,sulfatides 在神经系统里堆积,带来进行性的 dysmyelination 和神经退行。按首次出现症状的年龄分为 late-infantile(30 个月及以内)、juvenile(early juvenile 为 30 个月至 6 岁)等型。Fumagalli 等人 2022 年在 Lancet 上写道,late-infantile 患儿的快速进展几乎紧接着症状出现而来,early-juvenile 则起初进展较慢。

基因治疗之前,手里的牌是异基因移植。Boucher 等人 2015 年报告的 40 名患者里,21 人(53%)在移植后中位 12 年仍然存活,作者认为较晚发病的表型可能最受益于症状前移植。Groeschel 等人 2016 年在 JAMA Neurol 上比较了 24 名移植的与 41 名未移植的 juvenile MLD 患者:移植时运动功能尚好(GMFC-MLD 0 或 1 级)、IQ 至少 85 者,病程更可能稳定。

进脑的是什么

HSC 基因治疗让造血干细胞的后代携带过表达的 ARSA,再由这些细胞把酶分发出去(酶工厂的逻辑见前文)。难点在”进脑”这一步。2010 年,Ginhoux 等人在 Science 上用谱系追踪证明,成年小鼠的 microglia 来自胚胎第 8 天之前出现的原始髓系前体,出生后的造血祖细胞在稳态下对成年 microglia 并无显著贡献。2012 年,Capotondo 等人在 PNAS 上于小鼠里看到,只有 conditioning 足以清除脑内原有髓系前体时,供者细胞才真正更替 microglia;2017 年又在 Sci Adv 上报告,把造血干祖细胞直接注入小鼠侧脑室,能很快得到 microglia-like cells,并增加了 MLD 小鼠模型脑内的治疗性蛋白递送;论文在引言里承认,这些细胞是否称得上 bona fide microglia 仍有待证明。

人体里的细胞证据来自异基因移植。1993 年,Unger 等人用 Y 染色体原位杂交检查五名女性受者的延髓切片,发现供者来源的单个核细胞进入了看上去正常的脑,并可转变为血管周围细胞,是否变成分支状 microglia 作者说仍待证实。2023 年,Loeb 等人在 Blood Adv 上用免疫组化加 XY FISH 检查 19 名接受异基因移植的女性受者的大脑皮层:男性供者细胞占全部细胞的 0.14% 至 3.0%、占 microglia 的 1.2% 至 25%,至少 80% 的供者细胞表达 Iba-1,作者称其与 bone marrow-derived macrophages 相符。这些受者不是 MLD 或 CALD 的基因治疗患者。就后者而言,在笔者检索到的文献里(Europe PMC / PubMed,截至 2026 年 10 月),没有脑组织层面检出供者细胞的报道。Fumagalli 2022 的依据是治疗后脑脊液里的 ARSA 活性恢复到正常水平,作者称之为”间接证据”,提示一部分被基因修饰的细胞或其后代穿过了血脑屏障。

走到症状之前

人体数据的主线是同一个中心、同一个载体、一步步扩大的三篇文章。2013 年,Biffi 等人在 Science 上报告了三名症状前的 late-infantile 患儿:ARSA 在各造血谱系和脑脊液里达到高水平,疾病在超过预测发病年龄 7 至 21 个月时没有出现也没有进展。2016 年,Sessa 等人在 Lancet 上给出九名早发型患儿的 ad-hoc 分析(NCT01560182):八名阻止了发病或停住了进展,其中七名是症状前治疗,获益程度似乎与治疗距预期发病时间的间隔有关。

2022 年,Fumagalli 等人把它放大到 29 名患儿,并与 31 名按年龄和亚型匹配的自然史对照比较。治疗后 2 年,PBMC 里的 ARSA 活性平均升高,late-infantile 为 18.7 倍,early-juvenile 为 5.7 倍;粗大运动功能总分与对照的平均差异,在 late-infantile 为 66%,early-juvenile 为 42%。论文要点写明,获益见于症状前的 late-infantile、症状前和早期症状的 early-juvenile 患儿,这些患者是在进入快速进展期之前接受治疗的。对早期症状的 early-juvenile 患者,作者的回顾性分析提示应进一步限定为没有认知下降(IQ ≥85)、尚未丧失独立行走(GMFC-MLD 1 级或以下)、筛选到输注期间没有明显恶化者。

论文把两个时间放在一起讨论:ARSA 活性在 PBMC 和脑脊液里重建需要 3 至 12 个月,而 late-infantile 患儿一旦发病,快速进展几乎立刻开始,所以患者必须被迅速诊断和治疗。监管适应证与这一思路一致。欧盟的 Libmeldy 在 2020 年 12 月 17 日获批,对象包括无临床表现的 late-infantile 与 early-juvenile 患儿,以及仍能独立行走、尚无认知衰退的早期症状 early-juvenile 患儿。美国的 Lenmeldy(atidarsagene autotemcel)在 2024 年 3 月 18 日获批,FDA 当天的说明把适应证写成症状前的 late-infantile、症状前的 early-juvenile 和早期症状的 early-juvenile 三种。FDA 评估依据 37 名患儿的数据,症状前 late-infantile 患儿治疗后 6 岁时均存活,自然史组为 58%。

这样的窗口很难靠”等孩子出现症状再诊断”碰上。Fumagalli 等人写道,多数已有症状的患者因进展太快而不符合治疗条件,并呼吁新生儿筛查。2021 年,Hong 等人在 Genet Med 上用两级干血斑方案筛查了 27,335 名新生儿,发现两个高风险个体,ARSA 测序确认一个是 MLD 患者,另一个是杂合子;这是研究性筛查,不是已建立的公共卫生项目。

另一种脑白质病

X-linked adrenoleukodystrophy(ALD)的 cerebral 形式(CALD)同样以脱髓鞘和神经退行为特征,Eichler 等人 2017 年写道,已知能让进展停下来的办法只有异基因造血干细胞移植。ALD 蛋白由 ABCD1 编码,是一种 ATP-binding cassette transporter。

2009 年,Cartier 等人在 Science 上治疗了两名没有匹配供者的 ALD 男孩:自体 CD34+ 细胞经慢病毒 ABCD1 载体校正,清髓之后回输。随访 24 至 30 个月,各类白细胞中有 9% 至 14% 表达 ALD 蛋白;进行性的脑脱髓鞘从输注后 14 至 16 个月开始停止,结果与异基因移植相当。这 14 至 16 个月衡量的是脑脱髓鞘何时停止,Fumagalli 的 3 至 12 个月衡量的是 engraftment 与 ARSA 活性重建,指标不同,不能相加或互换;二者只共同说明,从回输到起效之间存在延迟。

2017 年,Eichler 等人在 N Engl J Med 上发表了 phase 2-3 的 STARBEAM 研究(NCT01896102)的中期分析:入组的是早期脑病变、MRI 钆增强阳性的男孩,17 人接受 Lenti-D 治疗,中位随访 29.4 个月,15 人(88%)存活且没有重大功能障碍。此后的长期随访带来了新问题:2024 年,Duncan 等人在 N Engl J Med 上报告,截至 2024 年 4 月 25 日,接受 elivaldogene autotemcel 的 67 名患者中有 7 人发生血液系统肿瘤(MDS 或 AML);在有数据的 6 人中,占优势的克隆含多个位点的载体插入,包括 MECOM-EVI1(5 人)或 PRDM16(1 人)。FDA 随后更新的数字是:截至 2025 年 7 月,67 名临床试验参与者中有 10 人(15%)确诊血液肿瘤。两个数字的分母相同,截点不同;细节留到 Skysona 那篇。

还没解决的部分

最直接的缺口是窗口之外的孩子。Fumagalli 等人提出,新生儿筛查普及之前可以探索把基因修饰的祖细胞、慢病毒或 AAV 直接注入中枢神经系统,以更快供应 ARSA;这不是已有的疗法。第二个缺口在”进脑”本身:MLD 基因治疗患者自己的脑内供者细胞,检索到的文献里尚无直接报道;microglia-like 与 bona fide microglia 之间的距离,领域自己也没有宣布缩短。第三个缺口是 conditioning 的代价:Fumagalli 那组所有患者都至少出现过一次 3 级及以上不良事件,多数与 conditioning 或基础疾病有关。

回到开头那位年长的患病同胞。他们错过的不是答案,而是时间:今天已获批的 HSC 基因治疗,能做的是在髓鞘塌下来之前,把一个会制造酶的新系统装进孩子的骨髓;能不能赶在那之前被发现,在 Fumagalli 等人看来,要靠新生儿筛查。

参考文献

  1. Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158. DOI
  2. Sessa M, Lorioli L, Fumagalli F, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. 2016;388(10043):476-87. DOI (NCT01560182)
  3. Fumagalli F, Calbi V, Natali Sora MG, et al. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access. Lancet. 2022;399(10322):372-83. DOI
  4. Boucher AA, Miller W, Shanley R, et al. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. Orphanet J Rare Dis. 2015;10:94. DOI
  5. Groeschel S, Kühl JS, Bley AE, et al. Long-term outcome of allogeneic hematopoietic stem cell transplantation in patients with juvenile metachromatic leukodystrophy compared with nontransplanted control patients. JAMA Neurol. 2016;73(9):1133-40. DOI
  6. Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841-5. DOI
  7. Capotondo A, Milazzo R, Politi LS, et al. Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation. Proc Natl Acad Sci U S A. 2012;109(37):15018-23. DOI
  8. Capotondo A, Milazzo R, Garcia-Manteiga JM, et al. Intracerebroventricular delivery of hematopoietic progenitors results in rapid and robust engraftment of microglia-like cells. Sci Adv. 2017;3(12):e1701211. DOI
  9. Unger ER, Sung JH, Manivel JC, et al. Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant recipients: a Y-chromosome specific in situ hybridization study. J Neuropathol Exp Neurol. 1993;52(5):460-70. DOI
  10. Hong X, Daiker J, Sadilek M, et al. Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots. Genet Med. 2021;23(3):555-61. DOI
  11. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326(5954):818-23. DOI
  12. Eichler F, Duncan C, Musolino PL, et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med. 2017;377(17):1630-8. DOI (NCT01896102)
  13. Duncan CN, Bledsoe JR, Grzywacz B, et al. Hematologic cancer after gene therapy for cerebral adrenoleukodystrophy. N Engl J Med. 2024;391(14):1287-1301. DOI (NCT01896102, NCT03852498, NCT02698579)
  14. U.S. Food and Drug Administration. FDA approves first gene therapy for children with metachromatic leukodystrophy (Lenmeldy; news release, content current as of March 18, 2024). https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystrophy
  15. European Medicines Agency. Libmeldy (atidarsagene autotemcel) — EPAR; marketing authorisation 17 December 2020. https://www.ema.europa.eu/en/medicines/human/EPAR/libmeldy
  16. Loeb AM, Pattwell SS, Meshinchi S, Bedalov A, Loeb KR. Donor bone marrow-derived macrophage engraftment into the central nervous system of patients following allogeneic transplantation. Blood Adv. 2023;7(19):5851-5859. DOI
  17. U.S. Food and Drug Administration. FDA approves required labeling changes for increased risk of hematologic malignancy following treatment with Skysona (elivaldogene autotemcel). 2025-08-07. https://www.fda.gov/vaccines-blood-biologics/fda-approves-required-labeling-changes-increased-risk-hematologic-malignancy-following-treatment

In the Milan MLD gene therapy study, every late-infantile child and four of the early-juvenile children were diagnosed before symptoms appeared, and enrolled in the trial, because the family had an older affected sibling. The authors add in the discussion that, in most cases, that sibling was already too ill to have any chance of treatment. This nearly compresses the whole story: gene therapy can re-establish the missing enzyme activity in the body, but that takes time, and this disease often does not allow time.

A disease that strips the myelin

Metachromatic leukodystrophy (MLD) is caused by mutations in the ARSA gene. Patients lack arylsulfatase A, sulfatides accumulate in the nervous system, and progressive dysmyelination and neurodegeneration follow. By age at first symptoms the disease is divided into late-infantile (up to 30 months), juvenile (early juvenile being 30 months to 6 years), and other forms. Fumagalli and colleagues wrote in the 2022 Lancet paper that rapid progression in late-infantile children follows almost immediately after symptom onset, whereas early-juvenile disease initially progresses more slowly.

Before gene therapy, the card in hand was allogeneic transplantation. In the 40 patients reported by Boucher and colleagues in 2015, 21 (53%) were alive at a median of 12 years after transplant, and the authors suggested that later-onset phenotypes may benefit most from presymptomatic transplantation. In 2016 in JAMA Neurol, Groeschel and colleagues compared 24 transplanted and 41 non-transplanted patients with juvenile MLD: those with good motor function at transplant (GMFC-MLD level 0 or 1) and an IQ of at least 85 were more likely to have a stable course.

What reaches the brain

HSC gene therapy has the progeny of hematopoietic stem cells carry an overexpressed ARSA, and those cells then distribute the enzyme (the logic being that the cells act as an enzyme factory). The hard part is reaching the brain. In 2010 in Science, Ginhoux and colleagues used lineage tracing to show that adult mouse microglia derive from primitive myeloid precursors that appear before embryonic day 8, and that postnatal hematopoietic progenitors make no significant contribution to adult microglia at steady state. In 2012 in PNAS, Capotondo and colleagues saw in mice that donor cells replace microglia only when conditioning is sufficient to clear the resident myeloid precursors in the brain; in 2017 in Sci Adv they reported that injecting hematopoietic stem and progenitor cells directly into the lateral ventricles of mice rapidly yielded microglia-like cells and increased delivery of a therapeutic protein into the brain of an MLD mouse model. In the introduction, that paper acknowledges that whether these cells are bona fide microglia remains to be demonstrated.

Cellular evidence in humans comes from allogeneic transplantation. In 1993, Unger and colleagues used Y-chromosome in situ hybridization on medulla sections from five female recipients and found that donor-derived mononuclear cells had entered the brain, which looked normal, and could transform into perivascular cells; whether they became ramified microglia, the authors said, remained to be confirmed. In 2023 in Blood Adv, Loeb and colleagues used immunohistochemistry plus XY FISH on the cerebral cortex of 19 female recipients of allogeneic transplants: male donor cells made up 0.14% to 3.0% of all cells and 1.2% to 25% of microglia, and at least 80% of the donor cells expressed Iba-1, which the authors described as consistent with bone marrow-derived macrophages. These recipients were not MLD or CALD gene therapy patients. For the latter, in the literature the author searched (Europe PMC / PubMed, up to October 2026), no report detects donor cells at the level of brain tissue. The basis in Fumagalli 2022 is that ARSA activity in cerebrospinal fluid recovered to normal levels after treatment, which the authors described as indirect evidence suggesting that some gene-modified cells or their progeny crossed the blood-brain barrier.

Reaching the child before symptoms

The main line of human data is three papers from the same center and the same vector, each larger than the last. In 2013 in Science, Biffi and colleagues reported three presymptomatic late-infantile children: ARSA reached high levels in the hematopoietic lineages and in cerebrospinal fluid, and the disease had neither appeared nor progressed 7 to 21 months beyond the predicted age of onset. In 2016 in Lancet, Sessa and colleagues gave an ad-hoc analysis of nine early-onset children (NCT01560182): eight had onset prevented or progression halted, seven of them treated presymptomatically, and the degree of benefit appeared to be related to the interval between treatment and expected time of onset.

In 2022, Fumagalli and colleagues scaled this up to 29 children, compared with 31 natural-history controls matched for age and subtype. Two years after treatment, ARSA activity in PBMCs had risen on average 18.7-fold in late-infantile and 5.7-fold in early-juvenile children; the mean difference in total gross motor function score from controls was 66% in late-infantile and 42% in early-juvenile. The key points of the paper state that benefit was seen in presymptomatic late-infantile children and in presymptomatic and early-symptomatic early-juvenile children, who were treated before entering the rapid phase of disease progression. For early-symptomatic early-juvenile patients, the authors’ retrospective analysis suggested a further restriction: no cognitive decline (IQ at least 85), independent walking not yet lost (GMFC-MLD level 1 or below), and no marked deterioration between screening and infusion.

The paper discusses two timescales side by side: re-establishing ARSA activity in PBMCs and cerebrospinal fluid takes 3 to 12 months, whereas in late-infantile children rapid progression begins almost immediately once symptoms appear, so patients must be diagnosed and treated quickly. The regulatory indications are consistent with this line of thought. In the EU, Libmeldy was approved on 17 December 2020, for children with late-infantile and early-juvenile disease without clinical manifestations, and for early-symptomatic early-juvenile children who can still walk independently and have no cognitive decline. In the US, Lenmeldy (atidarsagene autotemcel) was approved on 18 March 2024, and the FDA’s statement that day gave the indications as presymptomatic late-infantile, presymptomatic early-juvenile, and early-symptomatic early-juvenile. The FDA evaluation drew on data from 37 children; presymptomatic late-infantile children were all alive at age 6 after treatment, against 58% in the natural-history group.

A window like this is hard to hit by waiting for a child to show symptoms and then diagnosing. Fumagalli and colleagues wrote that most patients who already have symptoms do not qualify for treatment because progression is too fast, and they called for newborn screening. In 2021 in Genet Med, Hong and colleagues screened 27,335 newborns with a two-tier dried blood spot protocol and found two high-risk individuals; ARSA sequencing confirmed one as an MLD patient and the other as a carrier. This was investigational screening, not an established public health program.

A different white matter disease

The cerebral form of X-linked adrenoleukodystrophy (ALD), CALD, likewise features demyelination and neurodegeneration, and Eichler and colleagues wrote in 2017 that the only known way to halt its progression is allogeneic hematopoietic stem cell transplantation. The ALD protein is encoded by ABCD1 and is an ATP-binding cassette transporter.

In 2009 in Science, Cartier and colleagues treated two boys with ALD who had no matched donor: autologous CD34+ cells were corrected with a lentiviral ABCD1 vector and reinfused after myeloablation. Over 24 to 30 months of follow-up, 9% to 14% of white blood cells of various types expressed ALD protein; progressive cerebral demyelination stopped starting 14 to 16 months after infusion, with results comparable to allogeneic transplantation. The 14 to 16 months measure when brain demyelination stopped, whereas Fumagalli’s 3 to 12 months measures engraftment and the re-establishment of ARSA activity; the endpoints differ and cannot be added or interchanged. All they share is that a delay exists between reinfusion and effect.

In 2017 in N Engl J Med, Eichler and colleagues published the interim analysis of the phase 2-3 STARBEAM study (NCT01896102), which enrolled boys with early cerebral lesions and gadolinium-enhancing MRI: 17 received Lenti-D, and at a median follow-up of 29.4 months, 15 (88%) were alive without major functional disability. Longer follow-up has since raised a new problem: in 2024 in N Engl J Med, Duncan and colleagues reported that, as of 25 April 2024, 7 of 67 patients who received elivaldogene autotemcel developed a hematologic malignancy (MDS or AML); in the 6 with data, the predominant clones contained vector insertions at multiple loci, including MECOM-EVI1 (5 patients) or PRDM16 (1 patient). The FDA’s later updated figure is that, as of July 2025, 10 of 67 clinical trial participants (15%) had a confirmed hematologic malignancy. The denominators of the two figures are the same; the cutoff dates differ. The details are left to the Skysona piece.

What remains unresolved

The most direct gap is the children outside the window. Fumagalli and colleagues proposed that, until newborn screening is widespread, one could explore injecting gene-modified progenitors, or lentiviral or AAV vectors, directly into the central nervous system to supply ARSA faster; this is not an existing therapy. The second gap is in reaching the brain itself: for the brains of MLD gene therapy patients, the author found no direct report of donor cells in the searched literature, and the field itself has not declared the distance between microglia-like cells and bona fide microglia to have closed. The third gap is the cost of conditioning: every patient in the Fumagalli cohort had at least one grade 3 or higher adverse event, most related to conditioning or the underlying disease.

Back to that older affected sibling. What they missed was not an answer but time: what an approved HSC gene therapy can do today is install, in a child’s bone marrow, a new system that makes the enzyme, before the myelin comes down; whether the child can be found in time before that point depends, in Fumagalli and colleagues’ view, on newborn screening.

References

  1. Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158. DOI
  2. Sessa M, Lorioli L, Fumagalli F, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. 2016;388(10043):476-87. DOI (NCT01560182)
  3. Fumagalli F, Calbi V, Natali Sora MG, et al. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access. Lancet. 2022;399(10322):372-83. DOI
  4. Boucher AA, Miller W, Shanley R, et al. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. Orphanet J Rare Dis. 2015;10:94. DOI
  5. Groeschel S, Kühl JS, Bley AE, et al. Long-term outcome of allogeneic hematopoietic stem cell transplantation in patients with juvenile metachromatic leukodystrophy compared with nontransplanted control patients. JAMA Neurol. 2016;73(9):1133-40. DOI
  6. Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841-5. DOI
  7. Capotondo A, Milazzo R, Politi LS, et al. Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation. Proc Natl Acad Sci U S A. 2012;109(37):15018-23. DOI
  8. Capotondo A, Milazzo R, Garcia-Manteiga JM, et al. Intracerebroventricular delivery of hematopoietic progenitors results in rapid and robust engraftment of microglia-like cells. Sci Adv. 2017;3(12):e1701211. DOI
  9. Unger ER, Sung JH, Manivel JC, et al. Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant recipients: a Y-chromosome specific in situ hybridization study. J Neuropathol Exp Neurol. 1993;52(5):460-70. DOI
  10. Hong X, Daiker J, Sadilek M, et al. Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots. Genet Med. 2021;23(3):555-61. DOI
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