Sana UP421 (hypoimmune primary donor islets)

Overview

UP421 is an investigational, genetically engineered primary human deceased-donor islet therapy developed by Sana Biotechnology and evaluated in an investigator-sponsored first-in-human clinical trial at Uppsala University Hospital led by Professor Per-Ola Carlsson (NCT06239636).

Unlike Sana's preclinical commercial candidate SC451 (which starts from induced pluripotent stem cells, covered separately in sana-sc451-hypoimmune), UP421 starts with mature pancreatic islets isolated from a deceased organ donor. The donor islets are dissociated into single cells, engineered ex vivo with Sana's three-modification Hypoimmune (HIP) gene-editing platform, and re-aggregated into pseudo-islets:

1. B2M knockout (CRISPR-Cas12b): Ablates beta-2 microglobulin, eliminating cell-surface HLA class I expression so host CD8+ cytotoxic T cells (both alloreactive and T1D autoreactive) cannot recognize the graft.
2. CIITA knockout (CRISPR-Cas12b): Ablates the class II MHC transactivator, eliminating HLA class II expression so host CD4+ helper T cells cannot trigger alloimmune or autoimmune rejection.
3. CD47 overexpression (lentiviral transduction): Expresses high surface levels of CD47, delivering an inhibitory "don't eat me" signal through SIRPα on host natural killer (NK) cells and macrophages, which would otherwise destroy HLA-null ("missing-self") cells.

Key Clinical Evidence

1. First-in-Human 12-Week Readout (New England Journal of Medicine, August/September 2025, PMID: 40757665)

In NCT06239636, a 42-year-old man with long-standing Type 1 Diabetes, undetectable baseline stimulated C-peptide, and baseline HbA1c of 10.9% (96 mmol/mol) received 79.6 million engineered UP421 islet cells (~7% of a standard full replacement islet dose, selected as a conservative first-in-human safety dose) via 17 intramuscular injections into the left brachioradialis (forearm) muscle under general anesthesia, with zero systemic or local immunosuppression (no steroids, no calcineurin inhibitors, no anti-inflammatory induction):

• Graft Function & Imaging: Circulating fasting and meal-stimulated C-peptide became detectable by Week 4 and remained stable through Week 12 during mixed-meal tolerance tests (MMTT). Forearm MRI and 68Ga-exendin-4 PET-MRI (which binds GLP-1 receptors on living beta cells) confirmed viable, vascularized endocrine graft tissue at the intramuscular injection tracks at 12 weeks.
• Built-In Human Immune Control Proof: Because ex vivo editing of primary islets is incomplete, the infused cell batch contained three distinct sub-populations that acted as an internal control inside the patient:
  1. Unedited wild-type donor cells (HLA-I+ HLA-II+): Rapidly destroyed by a robust host T-cell and donor-specific antibody response.
  2. Partially edited double-knockout cells (B2M-/- CIITA-/- without high CD47): Eliminated by host innate immune cells (NK cells and macrophages).
  3. Fully HIP-edited cells (B2M-/- CIITA-/- CD47+): Completely evaded both adaptive (CD8+/CD4+ T cells and antibodies) and innate (NK/macrophage) killing, proving in a human with autoimmune T1D that all three genetic edits are required and sufficient for immune cloaking.
• Safety: Through 12 weeks, there were 4 mild-to-moderate adverse events (including superficial IV-catheter thrombophlebitis and transient forearm paresthesia related to the intramuscular injection procedure), 0 serious adverse events (0 SAEs), and 0 adverse events attributed to the UP421 cells.

2. Fourteen-Month Follow-Up (New England Journal of Medicine, July/August 2026, PMID: 42430558)

In July/August 2026, Carlsson, Hu, Scholz, and colleagues published a 14-month (60-week) follow-up letter in the New England Journal of Medicine (PMID: 42430558):

• 52-Week PET-MRI: Repeat 68Ga-exendin-4 PET-MRI at 1 year confirmed persistent physical survival of the GLP-1R-positive beta-cell graft in the forearm muscle without immunosuppressive drugs.
• Reversible Glucotoxic Fatigue vs Immune Rejection: At intermediate visits at Months 9 and 12, the patient's fasting and MMTT-stimulated C-peptide declined during a period of looser exogenous insulin dosing and elevated ambient blood glucose (well above the 70–180 mg/dL [3.9–10.0 mmol/L] target range). Rather than representing late immune rejection, immune assays showed zero T-cell, antibody, or NK reactivity against the HIP cells, and once exogenous insulin therapy was re-titrated to reduce ambient hyperglycemia, both fasting and MMTT-stimulated C-peptide rebounded at Month 14 (Week 60) to levels comparable to the first 6 months.
• Because the safety dose represented only ~7% of a full replacement beta-cell mass, the patient remained on exogenous insulin throughout the 14-month follow-up.

Relationship to SC451 & Key Limitations

1. Sub-Therapeutic Safety Dose (n = 1): UP421 proved human immune evasion and beta-cell survival without immunosuppression, but did not test a curative replacement dose (~500M–1B cells) capable of delivering insulin independence.
2. Bridge to SC451: Primary deceased-donor islets cannot be clonally selected for 100% editing purity or scaled to treat millions of people with T1D. Sana designed UP421 as an academic human proof-of-concept to de-risk the identical B2M-/- CIITA-/- CD47+ genetic edits in SC451 (sana-sc451-hypoimmune), its clonally engineered iPSC-derived islet candidate currently in preclinical IND-enabling development.

Summary of Strengths & Limitations

Strengths

• First peer-reviewed demonstration in human medicine (Carlsson et al., NEJM Aug 2025 & Aug 2026) that genetically engineered allogeneic beta cells can survive and function for over a year in a person with Type 1 Diabetes with zero systemic or local immunosuppression
• {'Internal human control proof': "the patient's immune system destroyed residual unedited wild-type cells (via T cells and antibodies) and double-knockout B2M-/- CIITA-/- cells lacking high CD47 (via NK cells and macrophages), while sparing the fully edited B2M-/- CIITA-/- CD47+ beta cells"}
• Fourteen-month NEJM follow-up (PMID 42430558) and 52-week 68Ga-exendin-4 PET-MRI confirmed persistent graft survival in the forearm brachioradialis muscle, with C-peptide rebounding after tighter exogenous insulin control resolved transient glucotoxic beta-cell fatigue

Limitations

• Published human clinical evidence is from a single recipient (n = 1; target enrollment n = 2 in NCT06239636) treated at a single academic center
• Administered at a sub-therapeutic safety dose (79.6 million islet cells, ~7% of a full replacement dose) into the forearm muscle; the patient remained dependent on exogenous insulin throughout follow-up
• UP421 itself relies on scarce deceased-donor human pancreata (further reduced by ex vivo dissociation, CRISPR/lentiviral editing, and re-aggregation losses) and serves primarily as a clinical proof-of-concept bridge for Sana's preclinical iPSC-derived candidate SC451